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Sample records for hypomaturation amelogenesis imperfecta

  1. Enamel ultrastructure in pigmented hypomaturation amelogenesis imperfecta.

    PubMed

    Wright, J T; Lord, V; Robinson, C; Shore, R

    1992-10-01

    Hypomaturation amelogenesis imperfecta (AI) is a hereditary condition of enamel that is presumed to result from defects during the maturation stage of enamel development. This study characterized the enamel ultrastructure and enamel crystallite morphology, as well as the distribution of organic material in enamel affected with pigmented hypomaturation AI. Enamel exhibiting autosomal recessive pigmented hypomaturation AI was sectioned or fractured and examined using light microscopy, scanning electron microscopy and transmission electron microscopy. Enamel samples were treated with 30% NaOCl or 8 M urea to remove organic components and determine the effect of deproteinization on crystallite morphology. These were compared with untreated normal enamel samples. The enamel crystallites in hypomaturation AI exhibited considerable variability in size and morphology. Examination of deproteinized tissue indicated that the AI crystallites had a thick coating, presumably of organic or partially mineralized material, which was not visible in normal enamel. The results of this investigation provide further evidence that hypomaturation AI is associated with the retention of organic material that is most probably enamel protein. Enamel protein retention is likely to be involved in the inhibition of normal crystallite growth resulting in the morphological crystallite abnormalities associated with this disorder.

  2. Exonal deletion of SLC24A4 causes hypomaturation amelogenesis imperfecta.

    PubMed

    Seymen, F; Lee, K-E; Tran Le, C G; Yildirim, M; Gencay, K; Lee, Z H; Kim, J-W

    2014-04-01

    Amelogenesis imperfecta is a heterogeneous group of genetic conditions affecting enamel formation. Recently, mutations in solute carrier family 24 member 4 (SLC24A4) have been identified to cause autosomal recessive hypomaturation amelogenesis imperfecta. We recruited a consanguineous family with hypomaturation amelogenesis imperfecta with generalized brown discoloration. Sequencing of the candidate genes identified a 10-kb deletion, including exons 15, 16, and most of the last exon of the SLC24A4 gene. Interestingly, this deletion was caused by homologous recombination between two 354-bp-long homologous sequences located in intron 14 and the 3' UTR. This is the first report of exonal deletion in SLC24A4 providing confirmatory evidence that the function of SLC24A4 in calcium transport has a crucial role in the maturation stage of amelogenesis.

  3. Hypomaturation Amelogenesis Imperfecta Caused By A Novel SLC24A4 Mutation

    PubMed Central

    Herzog, Curtis R.; Reid, Bryan M.; Seymen, Figen; Koruyucu, Mine; Tuna, Elif Bahar; Simmer, James P.; Hu, Jan C-C.

    2014-01-01

    In this case report of autosomal recessive pigmented hypomaturation amelogenesis imperfecta (AI), we identify a novel homozygous missense mutation (g.165151T>G; c.1317T>G; p.Leu436Arg) in SLC24A4, a gene encoding a potassium-dependent sodium-calcium exchanger that is critical for hardening dental enamel during tooth development. PMID:25442250

  4. Hypomaturation amelogenesis imperfecta caused by a novel SLC24A4 mutation.

    PubMed

    Herzog, Curtis R; Reid, Bryan M; Seymen, Figen; Koruyucu, Mine; Tuna, Elif Bahar; Simmer, James P; Hu, Jan C-C

    2015-02-01

    In this case report of autosomal recessive pigmented hypomaturation amelogenesis imperfecta (AI), we identify a novel homozygous missense mutation (g.165151 T>G; c.1317 T>G; p.Leu436 Arg) in SLC24A4, a gene encoding a potassium-dependent sodium-calcium exchanger that is critical for hardening dental enamel during tooth development.

  5. Noninvasive esthetic treatment for hypomaturation amelogenesis imperfecta: a case report.

    PubMed

    Nahsan, Flávia Pardo Salata; Silva, Luciana Mendonça da; Lima, Thiago Mendes de; Bertocco, Verônica Pereira de Lima; Chui, Fabíola Mendonça da Silva; Martins, Leandro de Moura

    2016-01-01

    Enamel alterations, such as amelogenesis imperfecta, can compromise the harmony of the smile and the patient's self-esteem and may cause tooth sensitivity. A simple and effective treatment approach uses the natural stratification of composite resins to mask deficient enamel formation and mimic the natural appearance of the substrate. The operative steps and principles for restorative success are described in this case report with 36-month follow-up.

  6. Mutations in the beta propeller WDR72 cause autosomal-recessive hypomaturation amelogenesis imperfecta.

    PubMed

    El-Sayed, Walid; Parry, David A; Shore, Roger C; Ahmed, Mushtaq; Jafri, Hussain; Rashid, Yasmin; Al-Bahlani, Suhaila; Al Harasi, Sharifa; Kirkham, Jennifer; Inglehearn, Chris F; Mighell, Alan J

    2009-11-01

    Healthy dental enamel is the hardest and most highly mineralized human tissue. Though acellular, nonvital, and without capacity for turnover or repair, it can nevertheless last a lifetime. Amelogenesis imperfecta (AI) is a collective term for failure of normal enamel development, covering diverse clinical phenotypes that typically show Mendelian inheritance patterns. One subset, known as hypomaturation AI, is characterised by near-normal volumes of organic enamel matrix but with weak, creamy-brown opaque enamel that fails prematurely after tooth eruption. Mutations in genes critical to enamel matrix formation have been documented, but current understanding of other key events in enamel biomineralization is limited. We investigated autosomal-recessive hypomaturation AI in a consanguineous Pakistani family. A whole-genome SNP autozygosity screen identified a locus on chromosome 15q21.3. Sequencing candidate genes revealed a point mutation in the poorly characterized WDR72 gene. Screening of WDR72 in a panel of nine additional hypomaturation AI families revealed the same mutation in a second, apparently unrelated, Pakistani family and two further nonsense mutations in Omani families. Immunohistochemistry confirmed intracellular localization in maturation-stage ameloblasts. WDR72 function is unknown, but as a putative beta propeller is expected to be a scaffold for protein-protein interactions. The nearest homolog, WDR7, is involved in vesicle mobilization and Ca2+-dependent exocytosis at synapses. Vesicle trafficking is important in maturation-stage ameloblasts with respect to secretion into immature enamel and removal of cleaved enamel matrix proteins via endocytosis. This raises the intriguing possibility that WDR72 is critical to ameloblast vesicle turnover during enamel maturation.

  7. Amelogenesis imperfecta

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001578.htm Amelogenesis imperfecta To use the sharing features on this page, please enable JavaScript. Amelogenesis imperfecta is a tooth development disorder. It causes the ...

  8. Amelogenesis imperfecta: a clinician's challenge.

    PubMed

    Chamarthi, V; Varma, B R; Jayanthi, M

    2012-01-01

    Defective enamel formation can be explained as defects occurring at the stages of enamel formation. Quantitative defects in matrix formation leads to hypoplastic form of amelogenesis imperfecta. Inadequate mineralization of matrix leads to hypocalcification and hypomaturation variants. The demarcation of matrix formation and mineralization is not so distinct. This paper describes a case of a 7-year-old boy with amelogenesis imperfecta - Type IA i.e., hypoplastic pitted autosomal dominant.

  9. Interradicular dentin dysplasia associated with amelogenesis imperfecta with taurodontism or trichodentoosseous syndrome: a diagnostic dilemma.

    PubMed

    Hegde, Veda; Srikanth, K

    2014-01-01

    Amelogenesis imperfecta is a hereditary disorder with diverse clinical presentation, where enamel is the tissue that is primarily affected either quantitatively or qualitatively. Hypomaturation/hypoplastic amelogenesis imperfecta with taurodontism is a rare variant of amelogenesis imperfecta which is often confused with trichodentoosseous syndrome. We report a rare case of hereditary enamel defect with taurodontism associated with interradicular dentin dysplasia.

  10. Genetics Home Reference: amelogenesis imperfecta

    MedlinePlus

    ... Me Understand Genetics Home Health Conditions amelogenesis imperfecta amelogenesis imperfecta Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Amelogenesis imperfecta is a disorder of tooth development. This condition ...

  11. Amelogenesis imperfecta

    PubMed Central

    Crawford, Peter JM; Aldred, Michael; Bloch-Zupan, Agnes

    2007-01-01

    Amelogenesis imperfecta (AI) represents a group of developmental conditions, genomic in origin, which affect the structure and clinical appearance of enamel of all or nearly all the teeth in a more or less equal manner, and which may be associated with morphologic or biochemical changes elsewhere in the body. The prevalence varies from 1:700 to 1:14,000, according to the populations studied. The enamel may be hypoplastic, hypomineralised or both and teeth affected may be discoloured, sensitive or prone to disintegration. AI exists in isolation or associated with other abnormalities in syndromes. It may show autosomal dominant, autosomal recessive, sex-linked and sporadic inheritance patterns. In families with an X-linked form it has been shown that the disorder may result from mutations in the amelogenin gene, AMELX. The enamelin gene, ENAM, is implicated in the pathogenesis of the dominant forms of AI. Autosomal recessive AI has been reported in families with known consanguinity. Diagnosis is based on the family history, pedigree plotting and meticulous clinical observation. Genetic diagnosis is presently only a research tool. The condition presents problems of socialisation, function and discomfort but may be managed by early vigorous intervention, both preventively and restoratively, with treatment continued throughout childhood and into adult life. In infancy, the primary dentition may be protected by the use of preformed metal crowns on posterior teeth. The longer-term care involves either crowns or, more frequently these days, adhesive, plastic restorations. PMID:17408482

  12. Homozygous and compound heterozygous MMP20 mutations in amelogenesis imperfecta.

    PubMed

    Gasse, B; Karayigit, E; Mathieu, E; Jung, S; Garret, A; Huckert, M; Morkmued, S; Schneider, C; Vidal, L; Hemmerlé, J; Sire, J-Y; Bloch-Zupan, A

    2013-07-01

    In this article, we focus on hypomaturation autosomal-recessive-type amelogenesis imperfecta (type IIA2) and describe 2 new causal Matrix metalloproteinase 20 (MMP20) mutations validated in two unrelated families: a missense mutation p.T130I at the expected homozygous state, and a compound heterozygous mutation having the same mutation combined with a nucleotide deletion, leading to a premature stop codon (p.N120fz*2). We characterized the enamel structure of the latter case using scanning electron microscopy analysis and microanalysis (Energy-dispersive X-ray Spectroscopy, EDX) and confirmed the hypomaturation-type amelogenesis imperfecta as identified in the clinical diagnosis. The mineralized content was slightly decreased, with magnesium substituting for calcium in the crystal structure. The anomalies affected enamel with minimal inter-rod enamel present and apatite crystals perpendicular to the enamel prisms, suggesting a possible new role for MMP20 in enamel formation.

  13. Amelogenesis imperfecta: an introduction.

    PubMed

    Gadhia, K; McDonald, S; Arkutu, N; Malik, K

    2012-04-27

    Amelogenesis imperfecta (AI) is an inherited disorder that is associated with mutations in five genes (AMEL; ENAM; MMP20; KLK4 and FAM83H) with a wide range of clinical presentations (phenotypes). It affects the structure and appearance of enamel of all teeth, both in the primary and secondary dentition. In this review paper, we look at the epidemiology, classification, aetiology, clinical description and diagnosis of AI. In the following three papers of this series, we aim to describe the role of paediatric dentists, orthodontists and restorative dentists in the clinical management of patients with AI.

  14. Amelogenesis imperfecta: the orthodontic perspective.

    PubMed

    Arkutu, N; Gadhia, K; McDonald, S; Malik, K; Currie, L

    2012-05-25

    Orthodontics in patients with amelogenesis imperfecta can be complicated by commonly occurring dental features in this group as well as patient factors. In this article we examine ways to avoid the common pitfalls of orthodontic management and the importance of adequate and timely liaison between the general dental practitioner and the multidisciplinary team.

  15. Enamel formation and amelogenesis imperfecta.

    PubMed

    Hu, Jan C-C; Chun, Yong-Hee P; Al Hazzazzi, Turki; Simmer, James P

    2007-01-01

    Dental enamel is the epithelial-derived hard tissue covering the crowns of teeth. It is the most highly mineralized and hardest tissue in the body. Dental enamel is acellular and has no physiological means of repair outside of the protective and remineralization potential provided by saliva. Enamel is comprised of highly organized hydroxyapatite crystals that form in a defined extracellular space, the contents of which are supplied and regulated by ameloblasts. The entire process is under genetic instruction. The genetic control of amelogenesis is poorly understood, but requires the activities of multiple components that are uniquely important for dental enamel formation. Amelogenesis imperfecta (AI) is a collective designation for the variety of inherited conditions displaying isolated enamel malformations, but the designation is also used to indicate the presence of an enamel phenotype in syndromes. Recently, genetic studies have demonstrated the importance of genes encoding enamel matrix proteins in the etiology of isolated AI. Here we review the essential elements of dental enamel formation and the results of genetic analyses that have identified disease-causing mutations in genes encoding enamel matrix proteins. In addition, we provide a fresh perspective on the roles matrix proteins play in catalyzing the biomineralization of dental enamel.

  16. Defining a new candidate gene for amelogenesis imperfecta: from molecular genetics to biochemistry.

    PubMed

    Urzúa, Blanca; Ortega-Pinto, Ana; Morales-Bozo, Irene; Rojas-Alcayaga, Gonzalo; Cifuentes, Víctor

    2011-02-01

    Amelogenesis imperfecta is a group of genetic conditions that affect the structure and clinical appearance of tooth enamel. The types (hypoplastic, hypocalcified, and hypomature) are correlated with defects in different stages of the process of enamel synthesis. Autosomal dominant, recessive, and X-linked types have been previously described. These disorders are considered clinically and genetically heterogeneous in etiology, involving a variety of genes, such as AMELX, ENAM, DLX3, FAM83H, MMP-20, KLK4, and WDR72. The mutations identified within these causal genes explain less than half of all cases of amelogenesis imperfecta. Most of the candidate and causal genes currently identified encode proteins involved in enamel synthesis. We think it is necessary to refocus the search for candidate genes using biochemical processes. This review provides theoretical evidence that the human SLC4A4 gene (sodium bicarbonate cotransporter) may be a new candidate gene.

  17. Multiple unerupted teeth with amelogenesis imperfecta in siblings.

    PubMed

    Hegde, Shruthi

    2012-05-01

    Amelogenesis imperfecta encompasses a group of inherited abnormalities that are generally considered to primarily affect the formation and/or calcification of enamel. This case report describes the unusual presentation of amelogenesis imperfecta in siblings as multiple unerupted teeth, multiple pulpal calcifications, and multiple dilacerations of roots along with the defect in the enamel. The intent of our report is to highlight a rare co-occurrence of amelogenesis imperfecta with multiple morphologic alterations in siblings.

  18. Periodontal management and restoration of an amelogenesis imperfecta patient: a case report.

    PubMed

    Horowitz, Robert A; Gautam, D K; Karol, Suneet; Kumari, Bindiya

    2014-02-01

    This report describes the treatment of a young male patient diagnosed with amelogenesis imperfecta (AI), a hereditary disorder that affects the enamel of both primary and permanent dentition. For management and rehabilitation, it is crucial to determine the type of AI-hypoplastic, hypomaturation, or hypocalcified. As with this patient, who presented with tricho-dento osseous syndrome, patients may present with associated expression of a syndrome (partial or full) and secondary changes in the periodontium. AI is a serious problem; therefore extensive treatment using a multidisciplinary approach must be instituted, especially if the patient is syndrome-associated.

  19. Amelogenesis imperfecta and localised aggressive periodontitis: A rare clinical entity.

    PubMed

    Gundannavar, Gayatri; Rosh, Radhika M; Chandrasekaran, Shoba; Hussain, Ahad M

    2013-01-01

    This case report presents two female patients whose chief complaint was discoloration of teeth. On careful clinical examination it was found that the patients had features of amelogenesis imperfecta and localised aggressive periodontitis. This article will give an insight of clinical and radiographic features of amelogenesis imperfecta with localised aggressive periodontitis, which is a rare clinical entity.

  20. Amelogenesis imperfecta: review of diagnostic findings and treatment concepts.

    PubMed

    Sabandal, Martin M I; Schäfer, Edgar

    2016-09-01

    Mineralization defects like amelogenesis imperfecta are often of hereditary origin. This article reviews the diagnostic findings and summarizes the suggested treatment approaches. Currently, there are no defined therapy recommendations available for patients suffering from amelogenesis imperfecta. The mentioned therapies are more or less equal but no comprehensive therapy recommendation is evident. When treating patients suffering from amelogenesis imperfecta, a comprehensive therapy of almost every dental discipline has to be considered. The earlier the diagnosis of amelogenesis imperfecta is confirmed, the better the outcome is. Optimal treatment approaches consist of early diagnosis and treatment approach and frequent dental recall appointments to prevent progressive occlusal wear or early destruction by caries. Full-mouth prosthetic treatment seems to be the best treatment option.

  1. Amelogenesis Imperfecta with Coronal Resorption: Report of Three Cases.

    PubMed

    Bhatia, Shannu K; Hunter, M Lindsay; Ashley, Paul F

    2015-12-01

    Intracoronal resorption of the permanent dentition in cases of amelogenesis imperfecta (AI) is a rare finding which poses an added complication to the already complex management of this condition. This paper presents three cases of AI associated with delayed eruption of permanent teeth in which asymptomatic intracoronal resorption occurred. CPD/Clinical Relevance: This paper highlights the fact that teeth affected with amelogenesis imperfecta may undergo asymptomatic intracoronal resorption which is only identifiable radiographically.

  2. Amelogenesis imperfecta and the treatment plan - interdisciplinary team approach.

    PubMed

    Suchancova, B; Holly, D; Janska, M; Stebel, J; Lysy, J; Thurzo, A; Sasinek, S

    2014-01-01

    Amelogenesis imperfecta is a set of hereditary defects representing mainly the development defects of enamel without the presence of whole-body symptoms. Developmental disorders can manifest a complete absence of enamel, which is caused by improper differentiation of ameloblasts. This article describes the diagnosis and treatment of a patient with amelogenesis imperfecta, as well as the need for interdisciplinary cooperation to achieve the best possible morphological, skeletal, functional and aesthetic rehabilitation of the patients with this diagnosis. Furthermore, the article reviews literature dealing with other anomalies occurring in association with amelogenesis imperfect (Fig. 12, Ref. 20).

  3. Amelogenesis Imperfecta: Genotype-Phenotype Studies in 71 Families

    PubMed Central

    Wright, J. Timothy; Torain, Melody; Long, Kimberly; Seow, Kim; Crawford, Peter; Aldred, Michael J.; Hart, P. Suzanne; Hart, Tom C.

    2011-01-01

    Amelogenesis imperfecta (AI) represents hereditary conditions affecting the quality and quantity of enamel. Six genes are known to cause AI (AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72). Our aim was to determine the distribution of different gene mutations in a large AI population and evaluate phenotype-genotype relationships. Affected and unaffected family members were evaluated clinically and radiographically by one examiner. Genotyping was completed using genomic DNA obtained from blood or saliva. A total of 494 individuals were enrolled, with 430 (224 affected, 202 unaffected, and 4 not definitive) belonging to 71 families with conditions consistent with the diagnosis of AI. Diverse clinical phenotypes were observed (i.e. hypoplastic, hypocalcified, and hypomaturation). Genotyping revealed mutations in all 6 candidate genes. A molecular diagnosis was made in 132 affected individuals (59%) and in 26 of the families (37%). Mutations involved 12 families with FAM83H (46%), 6 families with AMELX (23%), 3 families with ENAM (11%), 2 families with KLK4 and MMP20 (8% for each gene), and 1 family with a WDR72 mutation (4%). Phenotypic variants were associated with allelic FAM83H and AMELX mutations. Two seemingly unrelated families had the same KLK4 mutation. Families affected with AI where candidate gene mutations were not identified could have mutations not identifiable by traditional gene sequencing (e.g. exon deletion) or they could have promoter sequence mutations not evaluated in this study. However, the results suggest that there remain new AI causative genes to be identified. PMID:21597265

  4. Interdisciplinary approach to oral rehabilitation of patient with amelogenesis imperfecta.

    PubMed

    Yilmaz, Burak; Oz, Ulas; Yilmaz, Hasan Guney

    2014-03-01

    Amelogenesis imperfecta is a hereditary condition that affects the development of enamel, causing quantity, structural and compositional anomalies that involve all dentitions. Consequently, the effects can extend to both the primary and secondary dentitions. Patients with amelogenesis imperfecta may present with clinical difficulties, such as insufficient crown length, tooth sensitivity and orthodontic discrepancies, all of which can be resolved successfully with an interdisciplinary approach. This case report describes the interdisciplinary approach to the treatment of a 22-year-old patient with amelogenesis imperfecta. The proper alignment of anterior teeth and gingivo-cervical line was provided with orthodontic and periodontal treatments. All-ceramic crowns were placed on anterior, and metal-ceramic restorations were placed on posterior teeth to reduce sensitivity and improve esthetics with function. Improved esthetic appearance, reduced tooth sensitivity and the resolution of a potentially harmful psychosocial condition were achieved. Patient remained satisfied in the 12-month follow-up examination.

  5. Treatment considerations for patient with Amelogenesis Imperfecta: a review.

    PubMed

    Chen, Chiung-Fen; Hu, Jan Cc; Bresciani, Eduardo; Peters, Mathilde C; Estrella, Maria Regina

    Amelogenesis imperfecta (AI) is a group of inherited disorders primary affecting the structural of enamel. Patients with AI experience poor esthetic, excessive tooth sensitivity and compromised chewing function that dental treatments are frequently required at early age. This review describes the non-enamel implications, stage-specific management strategies and outcomes of selected restorative materials based on literature evidence.

  6. Rehabilitation of amelogenesis imperfecta using a reorganized approach: a case report.

    PubMed

    Chan, Kingsley H C; Ho, Edward H T; Botelho, Michael G; Pow, Edmond H N

    2011-05-01

    Amelogenesis imperfecta is a genetic disorder that causes defective enamel development in both the primary and permanent dentitions. Significant tooth structure damage often results in various pulpal symptoms, occlusal disharmony, impaired function, and esthetic disfigurement. These problems pose great challenges to the clinician when rehabilitating patients with amelogenesis imperfecta. This case report describes an uncomplicated and logical way to reorganize, temporize, and completely restore an extensively damaged dentition caused by amelogenesis imperfecta.

  7. Amelogenesis imperfecta and anterior open bite: Etiological, classification, clinical and management interrelationships.

    PubMed

    Alachioti, Xanthippi Sofia; Dimopoulou, Eleni; Vlasakidou, Anatoli; Athanasiou, Athanasios E

    2014-01-01

    Although amelogenesis imperfecta is not a common dental pathological condition, its etiological, classification, clinical and management aspects have been addressed extensively in the scientific literature. Of special clinical consideration is the frequent co-existence of amelogenesis imperfecta with the anterior open bite. This paper provides an updated review on amelogenesis imperfecta as well as anterior open bite, in general, and documents the association of these two separate entities, in particular. Diagnosis and treatment of amelogenesis imperfecta patients presenting also with anterior open bite require a lengthy, comprehensive and multidisciplinary approach, which should aim to successfully address all dental, occlusal, developmental, skeletal and soft tissue problems associated with these two serious clinical conditions.

  8. Restoring Function and Aesthetics in a Class II Division 1 Patient with Amelogenesis Imperfecta: A Clinical Report

    PubMed Central

    Doruk, Cenk; Ozturk, Firat; Sari, Fatih; Turgut, Mehmet

    2011-01-01

    Amelogenesis imperfecta (AI) encompasses a complicated group of hereditary conditions that cause developmental alterations in the structure of the enamel in the absence of a systemic disorder. AI primarily affects the quality and/or quantity of dental enamel, and it may affect all or only some of the teeth in the primary and/or permanent dentition. This clinical report describes the oral rehabilitation of a 21-year-old man diagnosed with hypomaturation-type AI. He presented with discolored and mutilated teeth. Cephalometrically, the patient has skeletal class II malocclusion due to mandibular deficiency considered as a result of maxillary constriction. The interdisciplinary approach was followed because of the complex needs of the patient. The aim of treatment was to restore aesthetics, improve malocclusion and masticatory function. Aesthetic and functional expectations were met with metal ceramic restorations. In this report, the interdisciplinary approach for a patient with AI and a malocclusion is described. PMID:21494393

  9. Amelogenesis Imperfecta Due to a Mutation of the Enamelin Gene: Clinical Case With Genotype-phenotype Correlations

    PubMed Central

    Lindemeyer, Rochelle G.; Gibson, Carolyn W.; Wright, Timothy J.

    2010-01-01

    The major protein components of the enamel matrix include the most abundant amelogenin proteins as well as less plentiful proteins such as enamelin and ameloblastin. The enamel defect in amelogenesis imperfecta (AI) generally results in enamel that is too thin (hypoplastic) or too soft (hypocalcification or hypomaturation). Previous reports indicate that mutations in the human enamelin gene (ENAM) cause hypoplastic AI through autosomaldominant inheritance patterns and patients may also exhibit an anterior open bite. Although crown resorption of unerupted teeth occurs more frequently in AI patients, this finding has not been previously associated with known ENAM mutations. The purpose of this article was to report the genotype-phenotype correlations for a 9-year, 11-month-old boy with a homozygous ENAM mutation (c.1258_1259insAG). PMID:20298654

  10. Clinical and molecular analysis of the enamelin gene ENAM in Colombian families with autosomal dominant amelogenesis imperfecta

    PubMed Central

    Gutiérrez, Sandra; Torres, Diana; Briceño, Ignacio; Gómez, Ana Maria; Baquero, Eliana

    2012-01-01

    In this study, we analyzed the phenotype, clinical characteristics and presence of mutations in the enamelin gene ENAM in five Colombian families with autosomal dominant amelogenesis imperfecta (ADAI). 22 individuals (15 affected and seven unaffected) belonging to five Colombian families with ADAI and eight individuals (three affected and five unaffected) belonging to three Colombian families with autosomal recessive amelogenesis imperfecta (ARAI) that served as controls for molecular alterations and inheritance patterns were studied. Clinical, radiographic and genetic evaluations were done in all individuals. Eight exons and three intron-exon boundaries were sequenced for mutation analysis. Two of the five families with ADAI had the hypoplasic phenotype, two had the hypocalcified phenotype and one had the hypomaturative phenotype. Anterior open bite and mandibular retrognathism were the most frequent skeletal abnormalities in the families with ADAI. No mutations were found. These findings suggest that ADAI in these Colombian families was unrelated to previously described mutations in the ENAM gene. These results also indicate that other regions not included in this investigation, such as the promoter region, introns and other genes should be considered as potential ADAI candidates. PMID:23055792

  11. Clinical and molecular analysis of the enamelin gene ENAM in Colombian families with autosomal dominant amelogenesis imperfecta.

    PubMed

    Gutiérrez, Sandra; Torres, Diana; Briceño, Ignacio; Gómez, Ana Maria; Baquero, Eliana

    2012-07-01

    In this study, we analyzed the phenotype, clinical characteristics and presence of mutations in the enamelin gene ENAM in five Colombian families with autosomal dominant amelogenesis imperfecta (ADAI). 22 individuals (15 affected and seven unaffected) belonging to five Colombian families with ADAI and eight individuals (three affected and five unaffected) belonging to three Colombian families with autosomal recessive amelogenesis imperfecta (ARAI) that served as controls for molecular alterations and inheritance patterns were studied. Clinical, radiographic and genetic evaluations were done in all individuals. Eight exons and three intron-exon boundaries were sequenced for mutation analysis. Two of the five families with ADAI had the hypoplasic phenotype, two had the hypocalcified phenotype and one had the hypomaturative phenotype. Anterior open bite and mandibular retrognathism were the most frequent skeletal abnormalities in the families with ADAI. No mutations were found. These findings suggest that ADAI in these Colombian families was unrelated to previously described mutations in the ENAM gene. These results also indicate that other regions not included in this investigation, such as the promoter region, introns and other genes should be considered as potential ADAI candidates.

  12. A missense mutation in ITGB6 causes pitted hypomineralized amelogenesis imperfecta

    PubMed Central

    Poulter, James A.; Brookes, Steven J.; Shore, Roger C.; Smith, Claire E. L.; Abi Farraj, Layal; Kirkham, Jennifer; Inglehearn, Chris F.; Mighell, Alan J.

    2014-01-01

    We identified a family in which pitted hypomineralized amelogenesis imperfecta (AI) with premature enamel failure segregated in an autosomal recessive fashion. Whole-exome sequencing revealed a missense mutation (c.586C>A, p.P196T) in the I-domain of integrin-β6 (ITGB6), which is consistently predicted to be pathogenic by all available programmes and is the only variant that segregates with the disease phenotype. Furthermore, a recent study revealed that mice lacking a functional allele of Itgb6 display a hypomaturation AI phenotype. Phenotypic characterization of affected human teeth in this study showed areas of abnormal prismatic organization, areas of low mineral density and severe abnormal surface pitting in the tooth's coronal portion. We suggest that the pathogenesis of this form of AI may be due to ineffective ligand binding of ITGB6 resulting in either compromised cell–matrix interaction or compromised ITGB6 activation of transforming growth factor-β (TGF-β) impacting indirectly on ameloblast–ameloblast interactions and proteolytic processing of extracellular matrix proteins via MMP20. This study adds to the list of genes mutated in AI and further highlights the importance of cell–matrix interactions during enamel formation. PMID:24319098

  13. A Novel Homozygous WDR72 Mutation in Two Siblings with Amelogenesis Imperfecta and Mild Short Stature

    PubMed Central

    Kuechler, A.; Hentschel, J.; Kurth, I.; Stephan, B.; Prott, E.-C.; Schweiger, B.; Schuster, A.; Wieczorek, D.; Lüdecke, H.-J.

    2012-01-01

    Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of inherited defects of enamel formation. In isolated AI (no additional segregating features), mutations in at least 7 genes are known so far, causing dominant, recessive or X-linked AI and allowing the identification of the molecular etiology in 40–50% of affected families. We report on 2 siblings (an 11-year-old female and a 7-year-old male) born to consanguineous Turkish parents, with AI and mild, proportionate short stature. Both parents have normal teeth, but mother, maternal grandmother and great-grandfather are/were also of short stature. A spine X-ray performed in the girl excluded brachyolmia. Affymetrix GenomeWide SNP6.0 Array analysis identified no pathogenic copy number changes, but showed sharing of large homozygous regions, including chromosome band 15q21.3 containing the WDR72 gene. WDR72 sequence analysis in both siblings revealed homozygosity for a novel stop mutation in exon 10 (c.997A>T, p.Lys333X) explaining the AI phenotype. Mutations in WDR72 are a very rare cause of autosomal-recessive hypomaturation type of isolated AI. The mutation described in our patients specifies the diagnosis AI IIA3 and represents only the sixth WDR72 mutation reported so far. The WDR72 protein is critical for dental enamel formation, but its exact function is still unknown. PMID:23293580

  14. A missense mutation in ITGB6 causes pitted hypomineralized amelogenesis imperfecta.

    PubMed

    Poulter, James A; Brookes, Steven J; Shore, Roger C; Smith, Claire E L; Abi Farraj, Layal; Kirkham, Jennifer; Inglehearn, Chris F; Mighell, Alan J

    2014-04-15

    We identified a family in which pitted hypomineralized amelogenesis imperfecta (AI) with premature enamel failure segregated in an autosomal recessive fashion. Whole-exome sequencing revealed a missense mutation (c.586C>A, p.P196T) in the I-domain of integrin-β6 (ITGB6), which is consistently predicted to be pathogenic by all available programmes and is the only variant that segregates with the disease phenotype. Furthermore, a recent study revealed that mice lacking a functional allele of Itgb6 display a hypomaturation AI phenotype. Phenotypic characterization of affected human teeth in this study showed areas of abnormal prismatic organization, areas of low mineral density and severe abnormal surface pitting in the tooth's coronal portion. We suggest that the pathogenesis of this form of AI may be due to ineffective ligand binding of ITGB6 resulting in either compromised cell-matrix interaction or compromised ITGB6 activation of transforming growth factor-β (TGF-β) impacting indirectly on ameloblast-ameloblast interactions and proteolytic processing of extracellular matrix proteins via MMP20. This study adds to the list of genes mutated in AI and further highlights the importance of cell-matrix interactions during enamel formation.

  15. Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta.

    PubMed

    Poulter, James A; Murillo, Gina; Brookes, Steven J; Smith, Claire E L; Parry, David A; Silva, Sandra; Kirkham, Jennifer; Inglehearn, Chris F; Mighell, Alan J

    2014-10-15

    Amelogenesis imperfecta (AI) describes a heterogeneous group of inherited dental enamel defects reflecting failure of normal amelogenesis. Ameloblastin (AMBN) is the second most abundant enamel matrix protein expressed during amelogenesis. The pivotal role of AMBN in amelogenesis has been confirmed experimentally using mouse models. However, no AMBN mutations have been associated with human AI. Using autozygosity mapping and exome sequencing, we identified genomic deletion of AMBN exon 6 in a second cousin consanguineous family with three of the six children having hypoplastic AI. The genomic deletion corresponds to an in-frame deletion of 79 amino acids, shortening the protein from 447 to 368 residues. Exfoliated primary teeth (unmatched to genotype) were available from family members. The most severely affected had thin, aprismatic enamel (similar to that reported in mice homozygous for Ambn lacking exons 5 and 6). Other teeth exhibited thicker but largely aprismatic enamel. One tooth had apparently normal enamel. It has been suggested that AMBN may function in bone development. No clinically obvious bone or other co-segregating health problems were identified in the family investigated. This study confirms for the first time that AMBN mutations cause non-syndromic human AI and that mouse models with disrupted Ambn function are valid.

  16. Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta

    PubMed Central

    Poulter, James A.; Murillo, Gina; Brookes, Steven J.; Smith, Claire E. L.; Parry, David A.; Silva, Sandra; Kirkham, Jennifer; Inglehearn, Chris F.; Mighell, Alan J.

    2014-01-01

    Amelogenesis imperfecta (AI) describes a heterogeneous group of inherited dental enamel defects reflecting failure of normal amelogenesis. Ameloblastin (AMBN) is the second most abundant enamel matrix protein expressed during amelogenesis. The pivotal role of AMBN in amelogenesis has been confirmed experimentally using mouse models. However, no AMBN mutations have been associated with human AI. Using autozygosity mapping and exome sequencing, we identified genomic deletion of AMBN exon 6 in a second cousin consanguineous family with three of the six children having hypoplastic AI. The genomic deletion corresponds to an in-frame deletion of 79 amino acids, shortening the protein from 447 to 368 residues. Exfoliated primary teeth (unmatched to genotype) were available from family members. The most severely affected had thin, aprismatic enamel (similar to that reported in mice homozygous for Ambn lacking exons 5 and 6). Other teeth exhibited thicker but largely aprismatic enamel. One tooth had apparently normal enamel. It has been suggested that AMBN may function in bone development. No clinically obvious bone or other co-segregating health problems were identified in the family investigated. This study confirms for the first time that AMBN mutations cause non-syndromic human AI and that mouse models with disrupted Ambn function are valid. PMID:24858907

  17. Crown lengthening procedure in the management of amelogenesis imperfecta

    PubMed Central

    Kalaivani, S.; Manohar, Jenish; Shakunthala, P.; Sujatha, S.; Rajasekaran, S. A.; Karthikeyan, B.; Kalaiselvan, S.

    2015-01-01

    Full mouth rehabilitation includes a promising treatment planning and execution thus fulfilling esthetic, occlusal, and functional parameters maintaining the harmony of the stomatognathic system. Crown lengthening procedures have become an integral component of the esthetic armamentarium and are utilized with increasing frequency to enhance the appearance of restorations placed in the esthetic zone. Crown lengthening plays a role to create healthy relationship of the gingiva and bone levels so as to gain access to more of the tooth which can be restored, if it is badly worn, decayed or fractured, below the gum line. This paper highlights the full mouth crown lengthening procedure performed on a patient with amelogenesis imperfecta. PMID:26538965

  18. Immediate Desensitization in Teeth Affected by Amelogenesis Imperfecta.

    PubMed

    Moreira, Rudá França; Figueiredo, Rossana Gomes; Oliveira, Henrique Eduardo; Fonseca, Ana Christina Lamosa da; Miranda, Mauro Sayão de

    2016-01-01

    The aim of this paper was to describe a clinical case of immediate dental desensitization using a self-etch adhesive system in an adolescent patient diagnosed with amelogenesis imperfecta (AI). AI was associated with severe tooth sensitivity, treated by the application of a universal adhesive system for desensitization of the teeth affected by AI. Reduction of tooth sensitivity was assessed using a visual analog scale during all reevaluations. The technique was effective for reducing tooth sensitivity. It was concluded that the adhesive system for tooth desensitization had an immediate effect and maintained its effectiveness during a 12-month follow-up period.

  19. Amelogenesis imperfecta - lifelong management. Restorative management of the adult patient.

    PubMed

    Patel, M; McDonnell, S T; Iram, S; Chan, M F W-Y

    2013-11-08

    The biggest challenge restorative dentists face in rehabilitating patients with amelogenesis imperfecta (AI) is trying to restore aesthetics, function and occlusal stability while keeping the treatment as conservative as possible. The goals of treatment should be to prolong the life of the patient's own teeth and avoid or delay the need for extractions and subsequent replacement with conventional fixed, removable or implant retained prostheses. In order to achieve these goals a stepwise approach to treatment planning is required starting with the most conservative but aesthetically acceptable treatment. This article discusses the management of AI and presents the various treatment options available for restoring the adult patient who presents to the dentist with AI.

  20. Crown lengthening procedure in the management of amelogenesis imperfecta.

    PubMed

    Kalaivani, S; Manohar, Jenish; Shakunthala, P; Sujatha, S; Rajasekaran, S A; Karthikeyan, B; Kalaiselvan, S

    2015-08-01

    Full mouth rehabilitation includes a promising treatment planning and execution thus fulfilling esthetic, occlusal, and functional parameters maintaining the harmony of the stomatognathic system. Crown lengthening procedures have become an integral component of the esthetic armamentarium and are utilized with increasing frequency to enhance the appearance of restorations placed in the esthetic zone. Crown lengthening plays a role to create healthy relationship of the gingiva and bone levels so as to gain access to more of the tooth which can be restored, if it is badly worn, decayed or fractured, below the gum line. This paper highlights the full mouth crown lengthening procedure performed on a patient with amelogenesis imperfecta.

  1. Amelogenesis Imperfecta, Facial Esthetics and Snap-On Smile.

    PubMed

    Wilson, Lee; Bradshaw, Jonathan P; Marks, Murray K

    2015-01-01

    Amelogenesis imperfecta is a hereditary enamel protein disorder affecting deciduous and secondary crown formation. The prevalence ranges from 1:700 to 1:14,000 depending on the population. These teeth may be hypoplastic, hypomineralized, or hypermineralized and are often discolored, sensitive and caries vulnerable. Patients often present with psychosocial issues due to appearance. Primary teeth are often treated with stainless steel crowns while secondary teeth are treated with full coverage esthetic crowns. The presenting preteen male here was fitted with Snap-On Smile? (www.snaponsmile.com). This treatment option provided cosmetic enhancement of the patient's appearance besides stabilization without altering the primary and secondary dentition during adolescent development.

  2. Conservative treatment for amelogenesis imperfecta: a case report.

    PubMed

    Campos, Roberto Elias; Miranda Valdivia, Andrea Dolores Correia; Santos-Filho, Paulo Cesar de Freitas; Menezes, Murilo de Souza; de Oliveira Junior, Osmir Batista; Soares, Carlos Jose

    2014-01-01

    Amelogenesis imperfecta is a hereditary condition that can alter the thickness, color, and shape of tooth enamel. Recent adhesive materials and techniques have provided less invasive treatment options. This case report presents the treatment of a patient whose anterior teeth had color alterations, white spots, pits, and shape defects. Using a more conservative technique, the mandibular and maxillary anterior teeth were restored using veneer direct composite restorations. After 6 years, the restorations demonstrated no deterioration, and no pathology was seen in association with the rehabilitation.

  3. LAMB3 mutations causing autosomal-dominant amelogenesis imperfecta.

    PubMed

    Kim, J W; Seymen, F; Lee, K E; Ko, J; Yildirim, M; Tuna, E B; Gencay, K; Shin, T J; Kyun, H K; Simmer, J P; Hu, J C-C

    2013-10-01

    Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an in-frame translation termination codon (p.Ser1144*). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome/basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related.

  4. Amelogenesis imperfecta and anterior open bite: Etiological, classification, clinical and management interrelationships

    PubMed Central

    Alachioti, Xanthippi Sofia; Dimopoulou, Eleni; Vlasakidou, Anatoli; Athanasiou, Athanasios E

    2014-01-01

    Although amelogenesis imperfecta is not a common dental pathological condition, its etiological, classification, clinical and management aspects have been addressed extensively in the scientific literature. Of special clinical consideration is the frequent co-existence of amelogenesis imperfecta with the anterior open bite. This paper provides an updated review on amelogenesis imperfecta as well as anterior open bite, in general, and documents the association of these two separate entities, in particular. Diagnosis and treatment of amelogenesis imperfecta patients presenting also with anterior open bite require a lengthy, comprehensive and multidisciplinary approach, which should aim to successfully address all dental, occlusal, developmental, skeletal and soft tissue problems associated with these two serious clinical conditions. PMID:24987656

  5. Occurrence of epidermolysis bullosa along with Amelogenesis imperfecta in female patient of India.

    PubMed

    Javed, A P; Shenai, Prashanth; Chatra, Laxmikanth; Veena, K M; Rao, Prasanna Kumar; Prabhu, Rachana

    2013-11-01

    Epidermolysis bullosa (EB) is an inherited disorder, which is characteristically presented as skin blisters developing in response to minor injury. Junctional variety of EB is also associated with enamel hypoplasia. Amelogenesis imperfecta presents with abnormal formation of the enamel both in deciduous and permanent dentition. This article describes a previously unreported case of Amelogenesis imperfecta with complete loss of enamel in a young female patient with EB.

  6. Clinical findings and long-term managements of patients with amelogenesis imperfecta

    PubMed Central

    Koruyucu, Mine; Bayram, Merve; Tuna, Elif Bahar; Gencay, Koray; Seymen, Figen

    2014-01-01

    The aim of this clinical case series is to present a diagnosis and different treatment methods of patients in different ages with amelogenesis imperfecta (AI) as well as further treatments during a 3-6 years follow-up period. A number of 31 patients (16 female, 15 male with a mean age of 10.77 ± 2.65 years) with AI have been examined for the study group between 2007 and 2010 years. A detailed anamnesis was recorded, followed by a clinical and radiological assessment of oral health. The types of AI classified for each patient according to clinical and radiographic evaluation. The main complaints of patients, presence of dental caries and dental anomalies were noted. Necessary treatments had been planned for the individual cases of AI. A number of 19 patients had hypoplastic (HP) form, and 10 patients showed hypomaturation (HM) form of AI, while one patient showed hypocalcified form of AI and one patient had HM-HP form with taurodontism. Main complaints were chiefly related to dissatisfactory esthetics and dental sensitivity. Caries prevalence index was 93.5%. Mean decayed, missing, filling permanent teeth (DMF) and DMF surface (DMFS) were found as 2.74 ± 1.71 and 6.23 ± 3.99; df (decayed, filling primary teeth) and dfs (decayed, filling primary teeth surface) were found as 3.12 ± 2.85 and 5.24 ± 4.97, respectively. All patients received individual clinical care, including preventive, restorative, and prosthetic treatments. Patients have scheduled for regular follow-up in every 3 months. Composite restorations were used as the most common treatment (25 patients, 80.6%). The treatment plan should be based on patient's age, type of defects and individual needs of the patients. Necessary treatment plan is essential, not only due to functional and aesthetic reasons, but also for the positive psychological impact on young patients. PMID:25512739

  7. Clinical findings and long-term managements of patients with amelogenesis imperfecta.

    PubMed

    Koruyucu, Mine; Bayram, Merve; Tuna, Elif Bahar; Gencay, Koray; Seymen, Figen

    2014-10-01

    The aim of this clinical case series is to present a diagnosis and different treatment methods of patients in different ages with amelogenesis imperfecta (AI) as well as further treatments during a 3-6 years follow-up period. A number of 31 patients (16 female, 15 male with a mean age of 10.77 ± 2.65 years) with AI have been examined for the study group between 2007 and 2010 years. A detailed anamnesis was recorded, followed by a clinical and radiological assessment of oral health. The types of AI classified for each patient according to clinical and radiographic evaluation. The main complaints of patients, presence of dental caries and dental anomalies were noted. Necessary treatments had been planned for the individual cases of AI. A number of 19 patients had hypoplastic (HP) form, and 10 patients showed hypomaturation (HM) form of AI, while one patient showed hypocalcified form of AI and one patient had HM-HP form with taurodontism. Main complaints were chiefly related to dissatisfactory esthetics and dental sensitivity. Caries prevalence index was 93.5%. Mean decayed, missing, filling permanent teeth (DMF) and DMF surface (DMFS) were found as 2.74 ± 1.71 and 6.23 ± 3.99; df (decayed, filling primary teeth) and dfs (decayed, filling primary teeth surface) were found as 3.12 ± 2.85 and 5.24 ± 4.97, respectively. All patients received individual clinical care, including preventive, restorative, and prosthetic treatments. Patients have scheduled for regular follow-up in every 3 months. Composite restorations were used as the most common treatment (25 patients, 80.6%). The treatment plan should be based on patient's age, type of defects and individual needs of the patients. Necessary treatment plan is essential, not only due to functional and aesthetic reasons, but also for the positive psychological impact on young patients.

  8. Esthetic and functional rehabilitation of mutilated dentition and loss of vertical dimension due to amelogenesis imperfecta

    PubMed Central

    Mittal, Shweta; Tewari, Sanjay; Goel, Rajat

    2014-01-01

    Cases of severe attrition are a common finding. Among the congenital anomalies, amelogenesis imperfecta and dentinogenesis imperfecta are important conditions that may cause accelerated wear of teeth. The following case report describes the complete oral rehabilitation of a patient diagnosed with amelogenesis imperfecta. A detailed treatment plan was chalked out which included proper oral hygiene measures, restoration of carious teeth and endodontic treatment followed by foundation restorations of teeth that were crucial for the final prostheses. Patient was given transitional restorations for about 6 weeks with the aim of regaining the lost vertical dimensions. Final rehabilitation was done by fixed dental prostheses. PMID:25565735

  9. Esthetic and functional rehabilitation of mutilated dentition and loss of vertical dimension due to amelogenesis imperfecta.

    PubMed

    Mittal, Shweta; Tewari, Sanjay; Goel, Rajat

    2014-04-01

    Cases of severe attrition are a common finding. Among the congenital anomalies, amelogenesis imperfecta and dentinogenesis imperfecta are important conditions that may cause accelerated wear of teeth. The following case report describes the complete oral rehabilitation of a patient diagnosed with amelogenesis imperfecta. A detailed treatment plan was chalked out which included proper oral hygiene measures, restoration of carious teeth and endodontic treatment followed by foundation restorations of teeth that were crucial for the final prostheses. Patient was given transitional restorations for about 6 weeks with the aim of regaining the lost vertical dimensions. Final rehabilitation was done by fixed dental prostheses.

  10. Dental rehabilitation of amelogenesis imperfecta using thermoformed templates.

    PubMed

    Sockalingam, Snmp

    2011-01-01

    Amelogenesis imperfecta represents a group of dental developmental conditions that are genomic in origin. Hypoplastic AI, hypomineralised AI or both in combination were the most common types seen clinically. This paper describes oral rehabilitation of a 9-year-old Malay girl with inherited hypoplastic AI using transparent thermoforming templates. The defective surface areas were reconstructed to their original dimensions on stone cast models of the upper and lower arches using composite, and transparent thermoform templates were fabricated on the models. The templates were used as crown formers to reconstruct the defective teeth clinically using esthetically matching composite. The usage of the templates allowed direct light curing of the composite, accurate reproducibility of the anatomic contours of the defective teeth, reduced chair-side time and easy contouring and placement of homogenous thickness of composite in otherwise inaccessible sites of the affected teeth.

  11. Bilateral nephrocalcinosis and amelogenesis imperfecta: A case report.

    PubMed

    Patel, Alok; Jagtap, Chetana; Bhat, Chetan; Shah, Rohan

    2015-01-01

    Amelogenesis imperfecta (AI) is a group of hereditary disorders that affect the quality and/or quantity of dental enamel. This paper describes the clinicopathological features of a patient who was born of nonconsanguineous parents and who presented with oral alterations, including yellow and misshapen teeth, intrapulpal calcifications, delayed tooth eruption, and gum enlargement. Scanning electron microscopy of the teeth revealed hypoplastic enamel, and a renal ultrasound detected bilateral nephrocalcinosis, leading to a diagnosis of AI and nephrocalcinosis syndrome. Since nephrocalcinosis is often asymptomatic and can be associated with impaired renal function, dentists who see children with a generalized and thin hypoplastic AI should consider a renal ultrasound scan and referral to a Nephrologist. Children with nephrocalcinosis should also be considered for a dental check.

  12. Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes.

    PubMed

    Prasad, M K; Laouina, S; El Alloussi, M; Dollfus, H; Bloch-Zupan, A

    2016-12-01

    Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis.

  13. Scanning electron microscopy and calcification in amelogenesis imperfecta in anterior and posterior human teeth.

    PubMed

    Sánchez-Quevedo, M C; Ceballos, G; García, J M; Rodríguez, I A; Gómez de Ferraris, M E; Campos, A

    2001-07-01

    Teeth fragments from members of a family clinically and genetically diagnosed as having amelogenesis imperfecta were studied by scanning electron microscopy and X-ray microprobe analysis to establish the morphological patterns and the quantitative concentration of calcium in the enamel of anterior (canine, incisor) and posterior (premolar and molar) teeth. The prism patterns in the enamel of teeth from both regions were parallel or irregularly decussate, with occasional filamentous prisms accompanied by small, irregularly rounded formations. Prismless enamel showed the R- and P-type patterns. Calcium levels in enamel of amelogenesis imperfecta and control teeth differed significantly between anterior and posterior teeth, indicating that the factors that influence normal mineralization in different regions of the dental arch are not altered in the process of amelogenesis imperfecta.

  14. Enamel renal syndrome with associated amelogenesis imperfecta, nephrolithiasis, and hypocitraturia: A case report.

    PubMed

    Bhesania, Dhvani; Arora, Ankit; Kapoor, Sonali

    2015-09-01

    Numerous cases of enamel renal syndrome have been previously reported. Various terms, such as enamel renal syndrome, amelogenesis imperfecta and gingival fibromatosis syndrome, and enamel-renal-gingival syndrome, have been used for patients presenting with the dental phenotype characteristic of this condition, nephrocalcinosis or nephrolithiasis, and gingival findings. This report describes a case of amelogenesis imperfecta of the enamel agenesis variety with nephrolithiasis in a 21-year-old male patient who complained of small teeth. The imaging modalities employed were conventional radiography, cone-beam computed tomography, and renal sonography. Such cases are first encountered by dentists, as other organ or metabolic diseases are generally hidden. Hence, cases of amelogenesis imperfecta should be subjected to advanced diagnostic modalities, incorporating both dental and medical criteria, in order to facilitate comprehensive long-term management.

  15. Diagnosis and esthetic functional rehabilitation of a patient with amelogenesis imperfecta.

    PubMed

    Oliveira, Ilione Kruschewsky Costa Sousa; Fonseca, Jussara de Fatima Barbosa; do Amaral, Flavia Lucisano Botelho; Pecorari, Vanessa Gallego Arias; Basting, Roberta Tarkany; França, Fabiana Mantovani Gomes

    2011-06-01

    Amelogenesis imperfecta is a hereditary disease that causes structural anomalies in dental enamel of both the primary and permanent dentition. The anomaly may present a variety of clinical forms and appearances, with its main characteristics being the loss of tooth structure, compromised esthetic appearance, and dental sensitivity. The aim of this study was to present the clinical report of a 16-year-old patient with severely compromised esthetics as a result of amelogenesis imperfecta of the hypocalcified type who was rehabilitated with composite resin and ceramic crowns.

  16. Target gene analyses of 39 amelogenesis imperfecta kindreds

    PubMed Central

    Chan, Hui-Chen; Estrella, Ninna M. R. P.; Milkovich, Rachel N.; Kim, Jung-Wook; Simmer, James P.; Hu, Jan C-C.

    2012-01-01

    Previously, mutational analyses identified six disease-causing mutations in 24 amelogenesis imperfecta (AI) kindreds. We have since expanded the number of AI kindreds to 39, and performed mutation analyses covering the coding exons and adjoining intron sequences for the six proven AI candidate genes [amelogenin (AMELX), enamelin (ENAM), family with sequence similarity 83, member H (FAM83H), WD repeat containing domain 72 (WDR72), enamelysin (MMP20), and kallikrein-related peptidase 4 (KLK4)] and for ameloblastin (AMBN) (a suspected candidate gene). All four of the X-linked AI families (100%) had disease-causing mutations in AMELX, suggesting that AMELX is the only gene involved in the aetiology of X-linked AI. Eighteen families showed an autosomal-dominant pattern of inheritance. Disease-causing mutations were identified in 12 (67%): eight in FAM83H, and four in ENAM. No FAM83H coding-region or splice-junction mutations were identified in three probands with autosomal-dominant hypocalcification AI (ADHCAI), suggesting that a second gene may contribute to the aetiology of ADHCAI. Six families showed an autosomal-recessive pattern of inheritance, and disease-causing mutations were identified in three (50%): two in MMP20, and one in WDR72. No disease-causing mutations were found in 11 families with only one affected member. We conclude that mutation analyses of the current candidate genes for AI have about a 50% chance of identifying the disease-causing mutation in a given kindred. PMID:22243262

  17. Target gene analyses of 39 amelogenesis imperfecta kindreds.

    PubMed

    Chan, Hui-Chen; Estrella, Ninna M R P; Milkovich, Rachel N; Kim, Jung-Wook; Simmer, James P; Hu, Jan C-C

    2011-12-01

    Previously, mutational analyses identified six disease-causing mutations in 24 amelogenesis imperfecta (AI) kindreds. We have since expanded the number of AI kindreds to 39, and performed mutation analyses covering the coding exons and adjoining intron sequences for the six proven AI candidate genes [amelogenin (AMELX), enamelin (ENAM), family with sequence similarity 83, member H (FAM83H), WD repeat containing domain 72 (WDR72), enamelysin (MMP20), and kallikrein-related peptidase 4 (KLK4)] and for ameloblastin (AMBN) (a suspected candidate gene). All four of the X-linked AI families (100%) had disease-causing mutations in AMELX, suggesting that AMELX is the only gene involved in the aetiology of X-linked AI. Eighteen families showed an autosomal-dominant pattern of inheritance. Disease-causing mutations were identified in 12 (67%): eight in FAM83H, and four in ENAM. No FAM83H coding-region or splice-junction mutations were identified in three probands with autosomal-dominant hypocalcification AI (ADHCAI), suggesting that a second gene may contribute to the aetiology of ADHCAI. Six families showed an autosomal-recessive pattern of inheritance, and disease-causing mutations were identified in three (50%): two in MMP20, and one in WDR72. No disease-causing mutations were found in 11 families with only one affected member. We conclude that mutation analyses of the current candidate genes for AI have about a 50% chance of identifying the disease-causing mutation in a given kindred.

  18. Minimally invasive rehabilitation of a patient with amelogenesis imperfecta.

    PubMed

    Büchi, Dominik; Fehmer, Vincent; Sailer, Irene; Wolleb, Karin; Jung, Ronald

    2014-01-01

    This case report describes a minimally invasive step-by-step approach to treat a patient with amelogenesis imperfecta. This is a genetic developmental disorder of the dental enamel, which clinically manifests as white and dark discolorations of the teeth. The clinical examination did not reveal the true depth of the staining. Therefore, a step-wise treatment approach was chosen. The first step consisted of a home bleaching procedure, which led to a slight improvement of the esthetic appearance, but the stains were still clearly visible. The next step was the application of a microabrasion technique. This led to further improvement, but not to a satisfactory result for this patient who had high esthetic expectations. Thus, the third step was undertaken: it was planned to restore the maxillary incisors and canines with ceramic veneers. The dental technician prepared a wax-up, which served as a basis for a clinical mock-up. After discussing the mock-up and the treatment plan with the patient, crown lengthening was performed on teeth 11 and 23 to improve the pink esthetics. Subsequently, the teeth were prepared in a minimally invasive way and a final impression was taken. Following try-in, the six veneers were inserted with resin cement.

  19. Dental management of amelogenesis imperfecta patients: a primer on genotype-phenotype correlations.

    PubMed

    Ng, F K; Messer, L B

    2009-01-01

    Amelogenesis imperfecta (AI) represents a group of hereditary conditions which affects enamel formation in the primary and permanent dentitions. Mutations in genes critical for amelogenesis result in diverse phenotypes characterized by variably thin and/or defective enamel. To date, mutations in 5 genes are known to cause AI in humans. Understanding the molecular etiologies and associated inheritance patterns can assist in the early diagnosis of this condition. Recognition of genotype-phenotype correlations will allow clinicians to guide genetic testing and select appropriate management strategies for patients who express different phenotypes. The purpose of this paper was to provide a narrative review of the current literature on amelogenesis imperfecta, particularly regarding recent advances in the identification of candidate genes and the patterns of inheritance.

  20. Novel MMP20 and KLK4 Mutations in Amelogenesis Imperfecta.

    PubMed

    Seymen, F; Park, J-C; Lee, K-E; Lee, H-K; Lee, D-S; Koruyucu, M; Gencay, K; Bayram, M; Tuna, E B; Lee, Z H; Kim, Y-J; Kim, J-W

    2015-08-01

    In order to achieve highly mineralized tooth enamel, enamel proteinases serve the important function of removing the remaining organic matrix in the mineralization and maturation of the enamel matrix. Mutations in the kallikrein 4 (KLK4), enamelysin (MMP20), and WDR72 genes have been identified as causing hypomaturation enamel defects in an autosomal-recessive hereditary pattern. In this report, 2 consanguineous families with a hypomaturation-type enamel defect were recruited, and mutational analysis was performed to determine the molecular genetic etiology of the disease. Whole exome sequencing and autozygosity mapping identified novel homozygous mutations in the KLK4 (c.620_621delCT, p.Ser207Trpfs*38) and MMP20 (c.1054G>A, p.Glu352Lys) genes. Further analysis on the effect of the mutations on the translation, secretion, and function of KLK4 and MMP20 revealed that mutant KLK4 was degraded intracellularly and became inactive while mutant MMP20 was expressed at a normal level but secreted only minimally with proteolytic function.

  1. Recessive Mutations in ACPT, Encoding Testicular Acid Phosphatase, Cause Hypoplastic Amelogenesis Imperfecta.

    PubMed

    Seymen, Figen; Kim, Youn Jung; Lee, Ye Ji; Kang, Jenny; Kim, Tak-Heun; Choi, Hwajung; Koruyucu, Mine; Kasimoglu, Yelda; Tuna, Elif Bahar; Gencay, Koray; Shin, Teo Jeon; Hyun, Hong-Keun; Kim, Young-Jae; Lee, Sang-Hoon; Lee, Zang Hee; Zhang, Hong; Hu, Jan C-C; Simmer, James P; Cho, Eui-Sic; Kim, Jung-Wook

    2016-11-03

    Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders affecting tooth enamel. The affected enamel can be hypoplastic and/or hypomineralized. In this study, we identified ACPT (testicular acid phosphatase) biallelic mutations causing non-syndromic, generalized hypoplastic autosomal-recessive amelogenesis imperfecta (AI) in individuals from six apparently unrelated Turkish families. Families 1, 4, and 5 were affected by the homozygous ACPT mutation c.713C>T (p.Ser238Leu), family 2 by the homozygous ACPT mutation c.331C>T (p.Arg111Cys), family 3 by the homozygous ACPT mutation c.226C>T (p.Arg76Cys), and family 6 by the compound heterozygous ACPT mutations c.382G>C (p.Ala128Pro) and 397G>A (p.Glu133Lys). Analysis of the ACPT crystal structure suggests that these mutations damaged the activity of ACPT by altering the sizes and charges of key amino acid side chains, limiting accessibility of the catalytic core, and interfering with homodimerization. Immunohistochemical analysis confirmed localization of ACPT in secretory-stage ameloblasts. The study results provide evidence for the crucial function of ACPT during amelogenesis.

  2. Amelogenesis imperfecta with multiple impacted teeth and skeletal class III malocclusion: complete mouth rehabilitation of a young adult.

    PubMed

    Patil, Pravinkumar G; Patil, Smita P

    2014-01-01

    Amelogenesis imperfecta is an autosomal dominant disorder. It is a group of hereditary diseases showing abnormal enamel density and crown malformation. This clinical report describes the oral rehabilitation of a young adult diagnosed with a variant of hypoplastic amelogenesis imperfecta with multiple impacted teeth and skeletal class III malocclusion. The treatment procedures of teeth extractions, endodontic treatment of remaining teeth followed by post and core restorations, esthetic and functional crown lengthening, and metal ceramic fixed dental prostheses were performed sequentially in the maxillary arch. The mandibular arch was restored with an overdenture. One-year follow-up revealed satisfactory results.

  3. Chairside treatment of amelogenesis imperfecta, including establishment of a new vertical dimension with resin nanoceramic and intraoral scanning.

    PubMed

    Zimmermann, Moritz; Koller, Christina; Hickel, Reinhard; Kühnisch, Jan

    2016-09-01

    Amelogenesis imperfecta is a hereditary disease affecting the structural development of tooth substance. This clinical report describes a 1-visit chairside treatment of an 8-year-old patient with amelogenesis imperfecta, using computer-aided design and computer-aided manufacturing (CAD-CAM) technology. Intraoral scanning was performed using the Cerec Omnicam. Thirteen resin nanoceramic crowns (Lava Ultimate) were fabricated chairside by using a Cerec MCXL milling unit and seated adhesively. The patient's treatment included establishing a new occlusal vertical dimension and new centric relationship. Reevaluation after 6 months showed a stable situation.

  4. Amelogenesis Imperfecta and Generalized Gingival Overgrowth Resembling Hereditary Gingival Fibromatosis in Siblings: A Case Report

    PubMed Central

    Yaprak, Emre; Subaşı, Meryem Gülce; Avunduk, Mustafa; Aykent, Filiz

    2012-01-01

    Amelogenesis imperfecta (AI) is a group of hereditary disorders primarily characterized by developmental abnormalities in the quantity and/or quality of enamel. There are some reports suggesting an association between AI and generalized gingival enlargement. This paper describes the clinical findings and oral management of two siblings presenting both AI and hereditary gingival fibromatosis (HGF) like generalized gingival enlargements. The treatment of gingival enlargements by periodontal flap surgery was successful in the management of the physiologic gingival form for both patients in the 3-year follow-up period. Prosthetic treatment was also satisfactory for the older patient both aesthetically and functionally. PMID:23091740

  5. Interdisciplinary treatment of a patient with amelogenesis imperfecta, a skeletal Class III relationship, and an anterior open bite.

    PubMed

    Marşan, Gülnaz; Aksu, Irem Sakarya; Kurt, Hanefi; Kuvat, Samet Vasfi; Cura, Nil

    2010-01-01

    An adult woman with amelogenesis imperfecta, a skeletal Class III relationship, long face syndrome, and a severe anterior open bite received interdisciplinary treatment (orthodontics, orthognathic surgery, and prosthodontics). Presurgical orthodontic treatment was followed by a maxillary posterior impaction with anterior advancement and a mandibular setback. After surgery, the patient received ceramic crowns. Function and esthetics were successfully re-established.

  6. Restoring function and esthetics in a patient with amelogenesis imperfecta: a case report.

    PubMed

    Sengun, Abdulkadir; Ozer, Füsun

    2002-03-01

    Amelogenesis imperfecta is a hereditary disorder that affects enamel on primary and permanent teeth. It is a rare dental disease but represents a major restorative challenge for the dentist. A 14-year-old boy presented with sensitive, discolored, and mutilated teeth and a decreased vertical dimension of occlusion. The aim of treatment was to reduce dental sensitivity, to restore esthetics, and to correct the vertical dimension of occlusion. To modify the occlusion, and to protect the dentin from chemical and thermal attacks, nickel-chrome onlays were placed on the molars. To improve the esthetics of the incisors and premolars, resin composite restorations were applied. The patient was regularly recalled during the postoperative period. Radiographic and clinical examinations 10 months posttreatment revealed no evidence of disorders associated with the restored teeth or their supporting structures.

  7. Mutations in CNNM4 cause recessive cone-rod dystrophy with amelogenesis imperfecta.

    PubMed

    Polok, Bozena; Escher, Pascal; Ambresin, Aude; Chouery, Eliane; Bolay, Sylvain; Meunier, Isabelle; Nan, Francis; Hamel, Christian; Munier, Francis L; Thilo, Bernard; Mégarbané, André; Schorderet, Daniel F

    2009-02-01

    Cone-rod dystrophies are inherited dystrophies of the retina characterized by the accumulation of deposits mainly localized to the cone-rich macular region of the eye. Dystrophy can be limited to the retina or be part of a syndrome. Unlike nonsyndromic cone-rod dystrophies, syndromic cone-rod dystrophies are genetically heterogeneous with mutations in genes encoding structural, cell-adhesion, and transporter proteins. Using a genome-wide single-nucleotide polymorphism (SNP) haplotype analysis to fine map the locus and a gene-candidate approach, we identified homozygous mutations in the ancient conserved domain protein 4 gene (CNNM4) that either generate a truncated protein or occur in highly conserved regions of the protein. Given that CNNM4 is implicated in metal ion transport, cone-rod dystrophy and amelogenesis imperfecta may originate from abnormal ion homeostasis.

  8. Full Mouth Rehabilitation of a Patient with Amelogenesis Imperfecta: A Case Report

    PubMed Central

    Rajesh, P; Prasad, Maruthi; Haldal, Sindhu

    2014-01-01

    Amelogenesis imperfecta (AI) is a hereditary disorder expressing a group of conditions which cause developmental alterations in the structure of enamel. This disorder has an adverse impact on oral health and also hampers the quality of life of the individual causing physiologic problems. The treatment of such patients would not only upgrade their quality-of-life, but also improve their self-esteem. The correction of such severely worn out dentition may require extensive restorative treatment to achieve appropriate results. It is important to identify the factors that contribute to the excessive wear and loss of vertical dimension. The correction of the defects has to be done without violating the biologic or mechanical principles. Full mouth rehabilitation in such patients improves esthetics, function and comfort. The following case report presents a systematic approach in rehabilitating a case of AI hypoplastic type using full mouth metal reinforced porcelain restorations. PMID:25214738

  9. Full mouth rehabilitation of a patient with amelogenesis imperfecta: a case report.

    PubMed

    Rajesh, P; Prasad, Maruthi; Haldal, Sindhu

    2014-07-01

    Amelogenesis imperfecta (AI) is a hereditary disorder expressing a group of conditions which cause developmental alterations in the structure of enamel. This disorder has an adverse impact on oral health and also hampers the quality of life of the individual causing physiologic problems. The treatment of such patients would not only upgrade their quality-of-life, but also improve their self-esteem. The correction of such severely worn out dentition may require extensive restorative treatment to achieve appropriate results. It is important to identify the factors that contribute to the excessive wear and loss of vertical dimension. The correction of the defects has to be done without violating the biologic or mechanical principles. Full mouth rehabilitation in such patients improves esthetics, function and comfort. The following case report presents a systematic approach in rehabilitating a case of AI hypoplastic type using full mouth metal reinforced porcelain restorations.

  10. Exclusion of known gene for enamel development in two Brazilian families with amelogenesis imperfecta.

    PubMed

    Santos, Maria C L G; Hart, P Suzanne; Ramaswami, Mukundhan; Kanno, Cláudia M; Hart, Thomas C; Line, Sergio R P

    2007-01-31

    Amelogenesis imperfecta (AI) is a genetically heterogeneous group of diseases that result in defective development of tooth enamel. Mutations in several enamel proteins and proteinases have been associated with AI. The object of this study was to evaluate evidence of etiology for the six major candidate gene loci in two Brazilian families with AI. Genomic DNA was obtained from family members and all exons and exon-intron boundaries of the ENAM, AMBN, AMELX, MMP20, KLK4 and Amelotin gene were amplified and sequenced. Each family was also evaluated for linkage to chromosome regions known to contain genes important in enamel development. The present study indicates that the AI in these two families is not caused by any of the known loci for AI or any of the major candidate genes proposed in the literature. These findings indicate extensive genetic heterogeneity for non-syndromic AI.

  11. Novel ENAM and LAMB3 mutations in Chinese families with hypoplastic amelogenesis imperfecta.

    PubMed

    Wang, Xin; Zhao, Yuming; Yang, Yuan; Qin, Man

    2015-01-01

    Amelogenesis imperfecta is a group of inherited diseases affecting the quality and quantity of dental enamel. To date, mutations in more than ten genes have been associated with non-syndromic amelogenesis imperfecta (AI). Among these, ENAM and LAMB3 mutations are known to be parts of the etiology of hypoplastic AI in human cases. When both alleles of LAMB3 are defective, it could cause junctional epidermolysis bullosa (JEB), while with only one mutant allele in the C-terminus of LAMB3, it could result in severe hypoplastic AI without skin fragility. We enrolled three Chinese families with hypoplastic autosomal-dominant AI. Despite the diagnosis falling into the same type, the characteristics of their enamel hypoplasia were different. Screening of ENAM and LAMB3 genes was performed by direct sequencing of genomic DNA from blood samples. Disease-causing mutations were identified and perfectly segregated with the enamel defects in three families: a 19-bp insertion mutation in the exon 7 of ENAM (c.406_407insTCAAAAAAGCCGACCACAA, p.K136Ifs*16) in Family 1, a single-base deletion mutation in the exon 5 of ENAM (c. 139delA, p. M47Cfs*11) in Family 2, and a LAMB3 nonsense mutation in the last exon (c.3466C>T, p.Q1156X) in Family 3. Our results suggest that heterozygous mutations in ENAM and LAMB3 genes can cause hypoplastic AI with markedly different phenotypes in Chinese patients. And these findings extend the mutation spectrum of both genes and can be used for mutation screening of AI in the Chinese population.

  12. Rehabilitation of a patient with amelogenesis imperfecta using porcelain veneers and CAD/CAM polymer restorations: A clinical report.

    PubMed

    Saeidi Pour, Reza; Edelhoff, Daniel; Prandtner, Otto; Liebermann, Anja

    2015-01-01

    The complete dental rehabilitation of patients with a vertical dimension loss (VDL) caused by structural enamel deficits associated with amelogenesis imperfecta (AI) represents a difficult challenge for restorative teams. Accurate analysis and treatment planning that includes esthetic and functional evaluations and adequate material selection are important prerequisites for successful results. Long-term provisional restorations play an important role in exploring and elucidating the patients' esthetic demands and functional needs. Restorative treatment options can vary from requiring only oral hygiene instructions to extensive dental restorations that include composite fillings, ceramic veneers, metal-ceramic, or all-ceramic crowns. This case report describes a full-mouth rehabilitation of a patient with amelogenesis imperfecta including the case planning, bite replacement, preparation, and restoration setting steps with an experimental CAD/CAM polymer and porcelain veneers.

  13. Mutations in the pH-Sensing G-protein-Coupled Receptor GPR68 Cause Amelogenesis Imperfecta.

    PubMed

    Parry, David A; Smith, Claire E L; El-Sayed, Walid; Poulter, James A; Shore, Roger C; Logan, Clare V; Mogi, Chihiro; Sato, Koichi; Okajima, Fumikazu; Harada, Akihiro; Zhang, Hong; Koruyucu, Mine; Seymen, Figen; Hu, Jan C-C; Simmer, James P; Ahmed, Mushtaq; Jafri, Hussain; Johnson, Colin A; Inglehearn, Chris F; Mighell, Alan J

    2016-10-06

    Amelogenesis is the process of dental enamel formation, leading to the deposition of the hardest tissue in the human body. This process requires the intricate regulation of ion transport and controlled changes to the pH of the developing enamel matrix. The means by which the enamel organ regulates pH during amelogenesis is largely unknown. We identified rare homozygous variants in GPR68 in three families with amelogenesis imperfecta, a genetically and phenotypically heterogeneous group of inherited conditions associated with abnormal enamel formation. Each of these homozygous variants (a large in-frame deletion, a frameshift deletion, and a missense variant) were predicted to result in loss of function. GPR68 encodes a proton-sensing G-protein-coupled receptor with sensitivity in the pH range that occurs in the developing enamel matrix during amelogenesis. Immunohistochemistry of rat mandibles confirmed localization of GPR68 in the enamel organ at all stages of amelogenesis. Our data identify a role for GPR68 as a proton sensor that is required for proper enamel formation.

  14. ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta

    PubMed Central

    Wang, Shih-Kai; Choi, Murim; Richardson, Amelia S.; Reid, Bryan M.; Lin, Brent P.; Wang, Susan J.; Kim, Jung-Wook; Simmer, James P.; Hu, Jan C.-C.

    2014-01-01

    Integrins are cell-surface adhesion receptors that bind to extracellular matrices (ECM) and mediate cell–ECM interactions. Some integrins are known to play critical roles in dental enamel formation. We recruited two Hispanic families with generalized hypoplastic amelogenesis imperfecta (AI). Analysis of whole-exome sequences identified three integrin beta 6 (ITGB6) mutations responsible for their enamel malformations. The female proband of Family 1 was a compound heterozygote with an ITGB6 transition mutation in Exon 4 (g.4545G > A c.427G > A p.Ala143Thr) and an ITGB6 transversion mutation in Exon 6 (g.27415T > A c.825T > A p.His275Gln). The male proband of Family 2 was homozygous for an ITGB6 transition mutation in Exon 11 (g.73664C > T c.1846C > T p.Arg616*) and hemizygous for a transition mutation in Exon 6 of Nance–Horan Syndrome (NHS Xp22.13; g.355444T > C c.1697T > C p.Met566Thr). These are the first disease-causing ITGB6 mutations to be reported. Immunohistochemistry of mouse mandibular incisors localized ITGB6 to the distal membrane of differentiating ameloblasts and pre-ameloblasts, and then ITGB6 appeared to be internalized by secretory stage ameloblasts. ITGB6 expression was strongest in the maturation stage and its localization was associated with ameloblast modulation. Our findings demonstrate that early and late amelogenesis depend upon cell–matrix interactions. Our approach (from knockout mouse phenotype to human disease) demonstrates the power of mouse reverse genetics in mutational analysis of human genetic disorders and attests to the need for a careful dental phenotyping in large-scale knockout mouse projects. PMID:24305999

  15. ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta.

    PubMed

    Wang, Shih-Kai; Choi, Murim; Richardson, Amelia S; Reid, Bryan M; Lin, Brent P; Wang, Susan J; Kim, Jung-Wook; Simmer, James P; Hu, Jan C-C

    2014-04-15

    Integrins are cell-surface adhesion receptors that bind to extracellular matrices (ECM) and mediate cell-ECM interactions. Some integrins are known to play critical roles in dental enamel formation. We recruited two Hispanic families with generalized hypoplastic amelogenesis imperfecta (AI). Analysis of whole-exome sequences identified three integrin beta 6 (ITGB6) mutations responsible for their enamel malformations. The female proband of Family 1 was a compound heterozygote with an ITGB6 transition mutation in Exon 4 (g.4545G > A c.427G > A p.Ala143Thr) and an ITGB6 transversion mutation in Exon 6 (g.27415T > A c.825T > A p.His275Gln). The male proband of Family 2 was homozygous for an ITGB6 transition mutation in Exon 11 (g.73664C > T c.1846C > T p.Arg616*) and hemizygous for a transition mutation in Exon 6 of Nance-Horan Syndrome (NHS Xp22.13; g.355444T > C c.1697T > C p.Met566Thr). These are the first disease-causing ITGB6 mutations to be reported. Immunohistochemistry of mouse mandibular incisors localized ITGB6 to the distal membrane of differentiating ameloblasts and pre-ameloblasts, and then ITGB6 appeared to be internalized by secretory stage ameloblasts. ITGB6 expression was strongest in the maturation stage and its localization was associated with ameloblast modulation. Our findings demonstrate that early and late amelogenesis depend upon cell-matrix interactions. Our approach (from knockout mouse phenotype to human disease) demonstrates the power of mouse reverse genetics in mutational analysis of human genetic disorders and attests to the need for a careful dental phenotyping in large-scale knockout mouse projects.

  16. Endoplasmic reticulum stress in amelogenesis imperfecta and phenotypic rescue using 4-phenylbutyrate

    PubMed Central

    Brookes, Steven J.; Barron, Martin J.; Boot-Handford, Ray; Kirkham, Jennifer; Dixon, Michael J.

    2014-01-01

    Inherited diseases caused by genetic mutations can arise due to loss of protein function. Alternatively, mutated proteins may mis-fold, impairing endoplasmic reticulum (ER) trafficking, causing ER stress and triggering the unfolded protein response (UPR). The UPR attempts to restore proteostasis but if unsuccessful drives affected cells towards apoptosis. Previously, we reported that in mice, the p.Tyr64His mutation in the enamel extracellular matrix (EEM) protein amelogenin disrupts the secretory pathway in the enamel-forming ameloblasts, resulting in eruption of malformed tooth enamel that phenocopies human amelogenesis imperfecta (AI). Defective amelogenin post-secretory self-assembly and processing within the developing EEM has been suggested to underlie the pathogenesis of X chromosome-linked AI. Here, we challenge this concept by showing that AI pathogenesis associated with the p.Tyr64His amelogenin mutation involves ameloblast apoptosis induced by ER stress. Furthermore, we show that 4-phenylbutyrate can rescue the enamel phenotype in affected female mice by promoting cell survival over apoptosis such that they are able to complete enamel formation despite the presence of the mutation, offering a potential therapeutic option for patients with this form of AI and emphasizing the importance of ER stress in the pathogenesis of this inherited conformational disease. PMID:24362885

  17. Aesthetic and Functional Rehabilitation of the Primary Dentition Affected by Amelogenesis Imperfecta

    PubMed Central

    Marquezin, Maria Carolina Salomé; Zancopé, Bruna Raquel; Pacheco, Larissa Ferreira; Gavião, Maria Beatriz Duarte; Pascon, Fernanda Miori

    2015-01-01

    The objective of this case report was to describe the oral rehabilitation of a five-year-old boy patient diagnosed with amelogenesis imperfecta (AI) in the primary dentition. AI is a group of hereditary disorders that affects the enamel structure. The patient was brought to the dental clinic complaining of tooth hypersensitivity during meals. The medical history and clinical examination were used to arrive at the diagnosis of AI. The treatment was oral rehabilitation of the primary molars with stainless steel crowns and resin-filled celluloid forms. The main objectives of the selected treatment were to enhance the esthetics, restore masticatory function, and eliminate the teeth sensitivity. The child was monitored in the pediatric dentistry clinic at four-month intervals until the mixed dentition stage. Treatment not only restored function and esthetic, but also showed a positive psychological impact and thereby improved perceived quality of life. The preventive, psychological, and curative measures of a young child with AI were successful. This result can encourage the clinicians to seek a cost-effective technique such as stainless steel crowns, and resin-filled celluloid forms to reestablish the oral functions and improve the child's psychosocial development. PMID:25705526

  18. A new locus for autosomal dominant amelogenesis imperfecta on chromosome 8q24.3.

    PubMed

    Mendoza, Gustavo; Pemberton, Trevor J; Lee, Kwanghyuk; Scarel-Caminaga, Raquel; Mehrian-Shai, Ruty; Gonzalez-Quevedo, Catalina; Ninis, Vasiliki; Hartiala, Jaana; Allayee, Hooman; Snead, Malcolm L; Leal, Suzanne M; Line, Sergio R P; Patel, Pragna I

    2007-01-01

    Amelogenesis imperfecta (AI) is a collective term used to describe phenotypically diverse forms of defective tooth enamel development. AI has been reported to exhibit a variety of inheritance patterns, and several loci have been identified that are associated with AI. We have performed a genome-wide scan in a large Brazilian family segregating an autosomal dominant form of AI and mapped a novel locus to 8q24.3. A maximum multipoint LOD score of 7.5 was obtained at marker D8S2334 (146,101,309 bp). The disease locus lies in a 1.9 cM (2.1 Mb) region according to the Rutgers Combined Linkage-Physical map, between a VNTR marker (at 143,988,705 bp) and the telomere (146,274,826 bp). Ten candidate genes were identified based on gene ontology and microarray-facilitated gene selection using the expression of murine orthologues in dental tissue, and examined for the presence of a mutation. However, no causative mutation was identified.

  19. Variation in dental and skeletal open bite malocclusion in humans with amelogenesis imperfecta.

    PubMed

    Ravassipour, Darren B; Powell, Cynthia M; Phillips, Ceib L; Hart, P Suzanne; Hart, Thomas C; Boyd, Courtney; Wright, J Tim

    2005-07-01

    The amelogenesis imperfectas (AI) are a diverse group of genetic disorders primarily affecting the quality and or quantity of enamel, however, affected individuals often have an open bite malocclusion. Three main AI types are recognized based on the perceived developmental mechanisms involved and the enamel phenotype. The purpose of this investigation was to evaluate the association of the AI enamel defect with craniofacial features characteristic of an open bite malocclusion. The sample consisted of 54 AI affected and 34 unaffected family members from 18 different kindreds. Lateral cephalograms were digitized and measurements evaluated for vertical plane alterations using Z-scores. Forty two percent of AI affected individuals and 12% of unaffected family members had dental or skeletal open bite malocclusions. Skeletal open bite malocclusion was variably expressed in AI affected individuals. The enamel phenotype severity did not necessarily correspond with the presence or severity of open bite malocclussion. Open bite malocclusion occurred in individuals with AI caused by mutations in the AMELX and ENAM genes even though these genes are considered to be predominantly or exclusively expressed in teeth. Affected AI individuals with cephalometric values meeting our criteria of skeletal open bite malocclusion were observed in all three major AI types. The pathophysiological relationship between AI associated enamel defects and open bite malocclusion remains unknown.

  20. Multidisciplinary Approach for Restoring Function and Esthetics in a Patient with Amelogenesis Imperfecta: A Clinical Report

    PubMed Central

    Kamble, Vaibhav D; Parkhedkar, Rambhau D

    2013-01-01

    Amelogenesis Imperfecta (AI) is a genetically determined and enamel mineralization defect reported, depicted as “Hereditary brown teeth.” AI is characterized as a clinical entity and its clinical manifestations, histological appearance, and genetic pattern are characterized by their heterogeneity. The need for prosthodontic management of this group of patients varies. Some patients need oral hygiene instructions only, whereas others need extensive dental treatment that includes composite restorations, metal ceramic crowns, all ceramic crowns, porcelain veneers. A 20-year-old male patient presented with sensitive, discoloured, and mutilated teeth, with a decreased vertical dimension of occlusion. The 4-year recall examination revealed no pathology associated with the full mouth rehabilitation, and the patient’s aesthetic and functional expectations were satisfied. The rehabilitation included all-ceramic crowns on anterior teeth and metal-ceramic crowns on posterior teeth following endodontic treatment and a crown-lengthening procedure for eliminating tooth sensitivity, improving the aesthetics and occlusion, and for restoring function. PMID:24551735

  1. Amelogenesis Imperfecta: Rehabilitation and Brainstorming on the Treatment Outcome after the First Year

    PubMed Central

    İzgi, Ayça Deniz; Kale, Ediz; Niğiz, Remzi

    2015-01-01

    Amelogenesis imperfecta (AI) affects enamel on primary and permanent dentition. This hereditary disorder is characterized by loss of enamel, poor esthetics, and hypersensitivity. Functional and cosmetic rehabilitation is challenging with variety of treatment options. This report presents the treatment of an AI patient using conventional fixed dentures and discusses issues related to posttreatment complications and prosthetic treatment outcome after 1 year of follow-up. A 19-year-old male AI patient with impaired self-esteem presented with hypersensitive, discolored, and mutilated teeth. Clinical examination revealed compromised occlusion and anterior open-bite. After hygiene maintenance full-coverage porcelain-fused-to-metal fixed restorations were indicated and applied. At the end of the treatment acceptable functional and esthetic results could be achieved. However, nearly a year after treatment a gingival inflammation in the esthetic zone complicated the outcome. Insufficient oral hygiene was to be blamed. Tooth sensitivity present from early childhood in these patients may prevent oral hygiene from becoming a habit. The relaxation due to relieve of hypersensitivity after treatment makes oral hygiene learning difficult. Continuous oral hygiene maintenance motivation may be crucial for the success of the treatment of AI patients. Treatment of AI patients should be carefully planned and an acceptable risk-benefit balance should be established. PMID:26783475

  2. Deletion of amelotin exons 3–6 is associated with amelogenesis imperfecta

    PubMed Central

    Smith, Claire E.L.; Murillo, Gina; Brookes, Steven J.; Poulter, James A.; Silva, Sandra; Kirkham, Jennifer; Inglehearn, Chris F.; Mighell, Alan J.

    2016-01-01

    Amelogenesis imperfecta (AI) is a heterogeneous group of genetic conditions that result in defective dental enamel formation. Amelotin (AMTN) is a secreted protein thought to act as a promoter of matrix mineralization in the final stage of enamel development, and is strongly expressed, almost exclusively, in maturation stage ameloblasts. Amtn overexpression and Amtn knockout mouse models have defective enamel with no other associated phenotypes, highlighting AMTN as an excellent candidate gene for human AI. However, no AMTN mutations have yet been associated with human AI. Using whole exome sequencing, we identified an 8,678 bp heterozygous genomic deletion encompassing exons 3-6 of AMTN in a Costa Rican family segregating dominant hypomineralised AI. The deletion corresponds to an in-frame deletion of 92 amino acids, shortening the protein from 209 to 117 residues. Exfoliated primary teeth from an affected family member had enamel that was of a lower mineral density compared to control enamel and exhibited structural defects at least some of which appeared to be associated with organic material as evidenced using elemental analysis. This study demonstrates for the first time that AMTN mutations cause non-syndromic human AI and explores the human phenotype, comparing it with that of mice with disrupted Amtn function. PMID:27412008

  3. Endoplasmic reticulum stress in amelogenesis imperfecta and phenotypic rescue using 4-phenylbutyrate.

    PubMed

    Brookes, Steven J; Barron, Martin J; Boot-Handford, Ray; Kirkham, Jennifer; Dixon, Michael J

    2014-05-01

    Inherited diseases caused by genetic mutations can arise due to loss of protein function. Alternatively, mutated proteins may mis-fold, impairing endoplasmic reticulum (ER) trafficking, causing ER stress and triggering the unfolded protein response (UPR). The UPR attempts to restore proteostasis but if unsuccessful drives affected cells towards apoptosis. Previously, we reported that in mice, the p.Tyr64His mutation in the enamel extracellular matrix (EEM) protein amelogenin disrupts the secretory pathway in the enamel-forming ameloblasts, resulting in eruption of malformed tooth enamel that phenocopies human amelogenesis imperfecta (AI). Defective amelogenin post-secretory self-assembly and processing within the developing EEM has been suggested to underlie the pathogenesis of X chromosome-linked AI. Here, we challenge this concept by showing that AI pathogenesis associated with the p.Tyr64His amelogenin mutation involves ameloblast apoptosis induced by ER stress. Furthermore, we show that 4-phenylbutyrate can rescue the enamel phenotype in affected female mice by promoting cell survival over apoptosis such that they are able to complete enamel formation despite the presence of the mutation, offering a potential therapeutic option for patients with this form of AI and emphasizing the importance of ER stress in the pathogenesis of this inherited conformational disease.

  4. Simple recessive mutation in ENAM is associated with amelogenesis imperfecta in Italian Greyhounds.

    PubMed

    Gandolfi, Barbara; Liu, Hongwei; Griffioen, Layle; Pedersen, Niels C

    2013-08-01

    We report a familial enamel hypoplasia in Italian Greyhounds resembling non-syndromic autosomal recessive amelogenesis imperfecta (AI) of humans. The condition uniformly affects deciduous and permanent teeth and is manifested by enamel roughening/thinning and brownish mottling. Affected teeth are often small and pointed with increased gaps. However, basic tooth structure is usually maintained throughout life, and fractures and dental cavities are not a serious problem as in humans. No tissues or organs other than teeth were affected by this mutation, and there was no relationship between enamel hypoplasia and either autoimmunity or periodontal disease, which also are prevalent in the breed. The enamel hypoplasia was associated with a 5-bp deletion in exon 10 of the enamelin (ENAM) gene. The prevalence of the enamel defect in Italian Greyhounds was 14%, and 30% of dogs with normal teeth were carriers. Genome analyses suggest that the trait is under inadvertent positive selection. Based on the deletion detected in the ENAM gene, a genetic test was developed for identifying mutation carriers, which would enable breeders to manage the trait.

  5. A Randomized Controlled Trial of Crown Therapy in Young Individuals with Amelogenesis Imperfecta.

    PubMed

    Pousette Lundgren, G; Morling Vestlund, G I; Trulsson, M; Dahllöf, G

    2015-08-01

    Amelogenesis imperfecta (AI) is a rare, genetically determined defect in enamel mineralization. Existing treatment recommendations suggest resin-composite restorations until adulthood, although such restorations have a limited longevity. New crown materials allow for minimal preparation techniques. The aim of this study was to compare the quality and longevity of 2 crown types-Procera and IPS e.max Press-in adolescents and young adults with AI. A secondary aim was to document adverse events. We included 27 patients (11 to 22 y of age) with AI in need of crown therapy in a randomized controlled trial using a split-mouth technique. After placing 119 Procera crowns and 108 IPS e.max Press crowns following randomization, we recorded longevity, quality, adverse events, and tooth sensitivity. After 2 y, 97% of the crowns in both crown groups had excellent or acceptable quality. We found no significant differences in quality between Procera and IPS e.max Press crowns. Tooth sensitivity was significantly reduced after crown therapy (P < 0.001). Endodontic complications occurred in 3% of crowns. The results show that it is possible to perform crown therapy with excellent results and without severe complications in young patients with AI. The study is registered at http://www.controlled-trials.com (ISRCTN70438627).

  6. The Use of Mouse Models to Investigate Shear Bond Strength in Amelogenesis Imperfecta

    PubMed Central

    Pugach, M.K.; Ozer, F.; Li, Y.; Sheth, K.; Beasley, R.; Resnick, A.; Daneshmehr, L.; Kulkarni, A.B.; Bartlett, J.D.; Gibson, C.W.; Lindemeyer, R.G.

    2011-01-01

    Patients with amelogenesis imperfecta (AI) have defective enamel; therefore, bonded restorations of patients with AI have variable success rates. To distinguish which cases of AI may have good clinical outcomes with bonded materials, we evaluated etching characteristics and bond strength of enamel in mouse models, comparing wild-type (WT) with those having mutations in amelogenin (Amelx) and matrix metalloproteinase-20 (Mmp20), which mimic 2 forms of human AI. Etched enamel surfaces were compared for roughness by scanning electron microscopy (SEM) images. Bonding was compared through shear bond strength (SBS) studies with 2 different systems (etch-and-rinse and self-etch). Etched enamel surfaces of incisors from Amelx knock-out (AmelxKO) mice appeared randomly organized and non-uniform compared with WT. Etching of Mmp20KO surfaces left little enamel, and the etching pattern was indistinguishable from unetched surfaces. SBS results were significantly different when AmelxKO and Mmp20KO enamel surfaces were compared. A significant increase in SBS was measured for all samples when the self-etch system was compared with the etch-and-rinse system. We have developed a novel system for testing shear bond strength of mouse incisors with AI variants, and analysis of these data may have important clinical implications for the treatment of patients with AI. PMID:21917602

  7. Perturbed Amelogenin Secondary Structure Leads to Uncontrolled Aggregation in Amelogenesis Imperfecta Mutant Proteins*

    PubMed Central

    Lakshminarayanan, Rajamani; Bromley, Keith M.; Lei, Ya-Ping; Snead, Malcolm L.; Moradian-Oldak, Janet

    2010-01-01

    Mutations in amelogenin sequence result in defective enamel, and the diverse group of genetically altered conditions is collectively known as amelogenesis imperfecta (AI). Despite numerous studies, the detailed molecular mechanism of defective enamel formation is still unknown. In this study, we have examined the biophysical properties of a recombinant murine amelogenin (rM180) and two point mutations identified from human DNA sequences in two cases of AI (T21I and P41T). At pH 5.8 and 25 °C, wild type (WT) rM180 and mutant P41T existed as monomers, and mutant T21I formed lower order oligomers. CD, dynamic light scattering, and fluorescence studies indicated that rM180 and P41T can be classified as a premolten globule-like subclass protein at 25 °C. Thermal denaturation and refolding monitored by CD ellipticity at 224 nm indicated the presence of a strong hysteresis in mutants compared with WT. Variable temperature tryptophan fluorescence and dynamic light scattering studies showed that WT transformed to a partially folded conformation upon heating and remained stable. The partially folded conformation formed by P41T, however, readily converted into a heterogeneous population of aggregates. T21I existed in an oligomeric state at room temperature and, upon heating, rapidly formed large aggregates over a very narrow temperature range. Thermal denaturation and refolding studies indicated that the mutants are less stable and exhibit poor refolding ability compared with WT rM180. Our results suggest that alterations in self-assembly of amelogenin are a consequence of destabilization of the intrinsic disorder. Therefore, we propose that, like a number of other human diseases, AI appears to be due to the destabilization of the secondary structure as a result of amelogenin mutations. PMID:20929860

  8. Amelogenesis Imperfecta in Two Families with Defined AMELX Deletions in ARHGAP6

    PubMed Central

    Hu, Jan C.-C.; Chan, Hui-Chen; Simmer, Stephen G.; Seymen, Figen; Richardson, Amelia S.; Hu, Yuanyuan; Milkovich, Rachel N.; Estrella, Ninna M. R. P.; Yildirim, Mine; Bayram, Merve; Chen, Chiung-Fen; Simmer, James P.

    2012-01-01

    Amelogenesis imperfecta (AI) is a group of inherited conditions featuring isolated enamel malformations. About 5% of AI cases show an X-linked pattern of inheritance, which are caused by mutations in AMELX. In humans there are two, non-allelic amelogenin genes: AMELX (Xp22.3) and AMELY (Yp11.2). About 90% of amelogenin expression is from AMELX, which is nested within intron 1 of the gene encoding Rho GTPase activating protein 6 (ARHGAP6). We recruited two AI families and determined that their disease-causing mutations were partial deletions in ARHGAP6 that completely deleted AMELX. Affected males in both families had a distinctive enamel phenotype resembling “snow-capped” teeth. The 96,240 bp deletion in family 1 was confined to intron 1 of ARHGAP6 (g.302534_398773del96240), but removed alternative ARHGAP6 promoters 1c and 1d. Analyses of developing teeth in mice showed that ARHGAP6 is not expressed from these promoters in ameloblasts. The 52,654 bp deletion in family 2 (g.363924_416577del52654insA) removed ARHGAP6 promoter 1d and exon 2, precluding normal expression of ARHGAP6. The male proband of family 2 had slightly thinner enamel with greater surface roughness, but exhibited the same pattern of enamel malformations characteristic of males in family 1, which themselves showed minor variations in their enamel phenotypes. We conclude that the enamel defects in both families were caused by amelogenin insufficiency, that deletion of AMELX results in males with a characteristic snow-capped enamel phenotype, and failed ARHGAP6 expression did not appreciably alter the severity of enamel defects when AMELX was absent. PMID:23251683

  9. Phenotype-genotype correlations in mouse models of amelogenesis imperfecta caused by Amelx and Enam mutations.

    PubMed

    Coxon, Thomas Liam; Brook, Alan Henry; Barron, Martin John; Smith, Richard Nigel

    2012-01-01

    Mutations in human and in mouse orthologous genes Amelx and Enam result in a diverse range of enamel defects. In this study we aimed to investigate the phenotype-genotype correlation between the mutants and the wild-type controls in mouse models of amelogenesis imperfecta using novel measurement approaches. Ten hemi-mandibles and incisors were dissected from each group of Amelx(WT), Amelx(X/Y64H), Amelx(Y/Y64H), Amelx(Y64H/Y64H), and Enam(WT), Enam(Rgsc395) heterozygous and Enam(Rgsc395) homozygous mice. Their macro-morphology, colour and micro-topography were assessed using bespoke 2D and 3D image analysis systems and customized colour and whiteness algorithms. The novel methods identified significant differences (p ≤ 0.05) between the Amelx groups for mandible and incisor size and enamel colour and between the Enam groups for incisor size and enamel colour. The Amelx(WT) mice had the largest mandibles and incisors, followed in descending order of size by the Amelx(X/Y64H), Amelx(Y/Y64H) and Amelx(Y64H/Y64H) mice. Within the Enam groups the Enam(WT) incisors were largest and the Enam(Rgsc395) heterozygous mice were smallest. The effect on tooth morphology was also reflected by the severity of the enamel defects in the colour and whiteness assessment. Amelogenin affected mandible morphology and incisor enamel formation, while enamelin only affected incisors, supporting the multifunctional role of amelogenin. The enamelin mutation was associated with earlier forming enamel defects. The study supported the critical involvement of amelogenin and enamelin in enamel mineralization.

  10. Amelogenesis imperfecta and other biomineralization defects in Fam20a and Fam20c null mice.

    PubMed

    Vogel, P; Hansen, G M; Read, R W; Vance, R B; Thiel, M; Liu, J; Wronski, T J; Smith, D D; Jeter-Jones, S; Brommage, R

    2012-11-01

    The FAM20 family of secreted proteins consists of three members (FAM20A, FAM20B, and FAM20C) recently linked to developmental disorders suggesting roles for FAM20 proteins in modulating biomineralization processes. The authors report here findings in knockout mice having null mutations affecting each of the three FAM20 proteins. Both Fam20a and Fam20c null mice survived to adulthood and showed biomineralization defects. Fam20b (-/-) embryos showed severe stunting and increased mortality at E13.5, although early lethality precluded detailed investigations. Physiologic calcification or biomineralization of extracellular matrices is a normal process in the development and functioning of various tissues (eg, bones and teeth). The lesions that developed in teeth, bones, or blood vessels after functional deletion of either Fam20a or Fam20c support a significant role for their encoded proteins in modulating biomineralization processes. Severe amelogenesis imperfecta (AI) was present in both Fam20a and Fam20c null mice. In addition, Fam20a (-/-) mice developed disseminated calcifications of muscular arteries and intrapulmonary calcifications, similar to those of fetuin-A deficient mice, although they were normocalcemic and normophosphatemic, with normal dentin and bone. Fam20a gene expression was detected in ameloblasts, odontoblasts, and the parathyroid gland, with local and systemic effects suggesting both local and/or systemic effects for FAM20A. In contrast, Fam20c (-/-) mice lacked ectopic calcifications but were severely hypophosphatemic and developed notable lesions in both dentin and bone to accompany the AI. The bone and dentin lesions, plus the marked hypophosphatemia and elevated serum alkaline phosphatase and FGF23 levels, are indicative of autosomal recessive hypophosphatemic rickets/osteomalacia in Fam20c (-/-) mice.

  11. Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression.

    PubMed

    Xie, Xiaohua; Liu, Chao; Zhang, Hua; Jani, Priyam H; Lu, Yongbo; Wang, Xiaofang; Zhang, Bin; Qin, Chunlin

    2016-05-05

    Amelogenesis Imperfecta (AI) can be caused by the deficiencies of enamel matrix proteins, molecules responsible for the transportation and secretion of enamel matrix components, and proteases processing enamel matrix proteins. In the present study, we discovered the double deletion of bone morphogenetic protein 2 (Bmp2) and bone morphogenetic protein 4 (Bmp4) in the dental epithelium by K14-cre resulted in hypoplastic enamel and reduced density in X-ray radiography as well as shortened enamel rods under scanning electron microscopy. Such enamel phenotype was consistent with the diagnosis of hypoplastic amelogenesis imperfecta. Histological and molecular analyses revealed that the removal of matrix proteins in the mutant enamel was drastically delayed, which was coincided with the greatly reduced expression of matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4). Although the expression of multiple enamel matrix proteins was down-regulated in the mutant ameloblasts, the cleavage of ameloblastin was drastically impaired. Therefore, we attributed the AI primarily to the reduction of MMP20 and KLK4. Further investigation found that BMP/Smad4 signaling pathway was down-regulated in the K14-cre;Bmp2(f/f);Bmp4(f/f)ameloblasts, suggesting that the reduced MMP20 and KLK4 expression may be due to the attenuated epithelial BMP/Smad4 signaling.

  12. Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression

    PubMed Central

    Xie, Xiaohua; Liu, Chao; Zhang, Hua; Jani, Priyam H.; Lu, Yongbo; Wang, Xiaofang; Zhang, Bin; Qin, Chunlin

    2016-01-01

    Amelogenesis Imperfecta (AI) can be caused by the deficiencies of enamel matrix proteins, molecules responsible for the transportation and secretion of enamel matrix components, and proteases processing enamel matrix proteins. In the present study, we discovered the double deletion of bone morphogenetic protein 2 (Bmp2) and bone morphogenetic protein 4 (Bmp4) in the dental epithelium by K14-cre resulted in hypoplastic enamel and reduced density in X-ray radiography as well as shortened enamel rods under scanning electron microscopy. Such enamel phenotype was consistent with the diagnosis of hypoplastic amelogenesis imperfecta. Histological and molecular analyses revealed that the removal of matrix proteins in the mutant enamel was drastically delayed, which was coincided with the greatly reduced expression of matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4). Although the expression of multiple enamel matrix proteins was down-regulated in the mutant ameloblasts, the cleavage of ameloblastin was drastically impaired. Therefore, we attributed the AI primarily to the reduction of MMP20 and KLK4. Further investigation found that BMP/Smad4 signaling pathway was down-regulated in the K14-cre;Bmp2f/f;Bmp4f/fameloblasts, suggesting that the reduced MMP20 and KLK4 expression may be due to the attenuated epithelial BMP/Smad4 signaling. PMID:27146352

  13. Mutations in C4orf26, encoding a peptide with in vitro hydroxyapatite crystal nucleation and growth activity, cause amelogenesis imperfecta.

    PubMed

    Parry, David A; Brookes, Steven J; Logan, Clare V; Poulter, James A; El-Sayed, Walid; Al-Bahlani, Suhaila; Al Harasi, Sharifa; Sayed, Jihad; Raïf, El Mostafa; Shore, Roger C; Dashash, Mayssoon; Barron, Martin; Morgan, Joanne E; Carr, Ian M; Taylor, Graham R; Johnson, Colin A; Aldred, Michael J; Dixon, Michael J; Wright, J Tim; Kirkham, Jennifer; Inglehearn, Chris F; Mighell, Alan J

    2012-09-07

    Autozygosity mapping and clonal sequencing of an Omani family identified mutations in the uncharacterized gene, C4orf26, as a cause of recessive hypomineralized amelogenesis imperfecta (AI), a disease in which the formation of tooth enamel fails. Screening of a panel of 57 autosomal-recessive AI-affected families identified eight further families with loss-of-function mutations in C4orf26. C4orf26 encodes a putative extracellular matrix acidic phosphoprotein expressed in the enamel organ. A mineral nucleation assay showed that the protein's phosphorylated C terminus has the capacity to promote nucleation of hydroxyapatite, suggesting a possible function in enamel mineralization during amelogenesis.

  14. Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta

    PubMed Central

    Huckert, Mathilde; Stoetzel, Corinne; Morkmued, Supawich; Laugel-Haushalter, Virginie; Geoffroy, Véronique; Muller, Jean; Clauss, François; Prasad, Megana K.; Obry, Frédéric; Raymond, Jean Louis; Switala, Marzena; Alembik, Yves; Soskin, Sylvie; Mathieu, Eric; Hemmerlé, Joseph; Weickert, Jean-Luc; Dabovic, Branka Brukner; Rifkin, Daniel B.; Dheedene, Annelies; Boudin, Eveline; Caluseriu, Oana; Cholette, Marie-Claude; Mcleod, Ross; Antequera, Reynaldo; Gellé, Marie-Paule; Coeuriot, Jean-Louis; Jacquelin, Louis-Frédéric; Bailleul-Forestier, Isabelle; Manière, Marie-Cécile; Van Hul, Wim; Bertola, Debora; Dollé, Pascal; Verloes, Alain; Mortier, Geert; Dollfus, Hélène; Bloch-Zupan, Agnès

    2015-01-01

    Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder. PMID:25669657

  15. Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta.

    PubMed

    Huckert, Mathilde; Stoetzel, Corinne; Morkmued, Supawich; Laugel-Haushalter, Virginie; Geoffroy, Véronique; Muller, Jean; Clauss, François; Prasad, Megana K; Obry, Frédéric; Raymond, Jean Louis; Switala, Marzena; Alembik, Yves; Soskin, Sylvie; Mathieu, Eric; Hemmerlé, Joseph; Weickert, Jean-Luc; Dabovic, Branka Brukner; Rifkin, Daniel B; Dheedene, Annelies; Boudin, Eveline; Caluseriu, Oana; Cholette, Marie-Claude; Mcleod, Ross; Antequera, Reynaldo; Gellé, Marie-Paule; Coeuriot, Jean-Louis; Jacquelin, Louis-Frédéric; Bailleul-Forestier, Isabelle; Manière, Marie-Cécile; Van Hul, Wim; Bertola, Debora; Dollé, Pascal; Verloes, Alain; Mortier, Geert; Dollfus, Hélène; Bloch-Zupan, Agnès

    2015-06-01

    Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder.

  16. Interdisciplinary Full Mouth Rehabilitation of a Patient with Amelogenesis Imperfecta: A Case Report with 8 Years Follow-up.

    PubMed

    Sreedevi, S; Sanjeev, R; Ephraim, Rena; Joseph, Mathai

    2014-01-01

    This case report deals with the interdisciplinary approach of a 28-year-old lady with Amelogenesis imperfecta of the hypoplastic kind. The patient came with a chief illness of worn out teeth, unsatisfactory esthetics and severe sensitivity of teeth. Her family history revealed a related situation in her father's brother and her sister. On clinical assessment, the crowns of all teeth were worn out. The plan of the treatment was to protect as much tooth structure, restore the vertical dimension, and improve esthetics and masticatory function. The treatment procedures involved prosthodontic, endodontic, and periodontic interventions. After recording the vertical height, endodontic treatment and crown lengthening were performed with respect to the lower anteriors. The lost vertical height was regained in stages by insertion of full coverage crowns for all the teeth. The patient's esthetic and functional needs were met with systematic and sequential interdisciplinary treatment approach.

  17. Whole-Exome sequencing identifies FAM20A mutations as a cause of amelogenesis imperfecta and gingival hyperplasia syndrome.

    PubMed

    O'Sullivan, James; Bitu, Carolina C; Daly, Sarah B; Urquhart, Jill E; Barron, Martin J; Bhaskar, Sanjeev S; Martelli-Júnior, Hercilio; dos Santos Neto, Pedro Eleuterio; Mansilla, Maria A; Murray, Jeffrey C; Coletta, Ricardo D; Black, Graeme C M; Dixon, Michael J

    2011-05-13

    Amelogenesis imperfecta (AI) describes a clinically and genetically heterogeneous group of disorders of biomineralization resulting from failure of normal enamel formation. AI is found as an isolated entity or as part of a syndrome, and an autosomal-recessive syndrome associating AI and gingival hyperplasia was recently reported. Using whole-exome sequencing, we identified a homozygous nonsense mutation in exon 2 of FAM20A that was not present in the Single Nucleotide Polymorphism database (dbSNP), the 1000 Genomes database, or the Centre d'Etude du Polymorphisme Humain (CEPH) Diversity Panel. Expression analyses indicated that Fam20a is expressed in ameloblasts and gingivae, providing biological plausibility for mutations in FAM20A underlying the pathogenesis of this syndrome.

  18. Interdisciplinary Full Mouth Rehabilitation of a Patient with Amelogenesis Imperfecta: A Case Report with 8 Years Follow-up

    PubMed Central

    Sreedevi, S; Sanjeev, R; Ephraim, Rena; Joseph, Mathai

    2014-01-01

    This case report deals with the interdisciplinary approach of a 28-year-old lady with Amelogenesis imperfecta of the hypoplastic kind. The patient came with a chief illness of worn out teeth, unsatisfactory esthetics and severe sensitivity of teeth. Her family history revealed a related situation in her father’s brother and her sister. On clinical assessment, the crowns of all teeth were worn out. The plan of the treatment was to protect as much tooth structure, restore the vertical dimension, and improve esthetics and masticatory function. The treatment procedures involved prosthodontic, endodontic, and periodontic interventions. After recording the vertical height, endodontic treatment and crown lengthening were performed with respect to the lower anteriors. The lost vertical height was regained in stages by insertion of full coverage crowns for all the teeth. The patient’s esthetic and functional needs were met with systematic and sequential interdisciplinary treatment approach. PMID:25628493

  19. Loss of epithelial FAM20A in mice causes amelogenesis imperfecta, tooth eruption delay and gingival overgrowth

    PubMed Central

    Li, Li-Li; Liu, Pei-Hong; Xie, Xiao-Hua; Ma, Su; Liu, Chao; Chen, Li; Qin, Chun-Lin

    2016-01-01

    FAM20A has been studied to a very limited extent. Mutations in human FAM20A cause amelogenesis imperfecta, gingival fibromatosis and kidney problems. It would be desirable to systemically analyse the expression of FAM20A in dental tissues and to assess the pathological changes when this molecule is specifically nullified in individual tissues. Recently, we generated mice with a Fam20A-floxed allele containing the beta-galactosidase reporter gene. We analysed FAM20A expression in dental tissues using X-Gal staining, immunohistochemistry and in situ hybridization, which showed that the ameloblasts in the mouse mandibular first molar began to express FAM20A at 1 day after birth, and the reduced enamel epithelium in erupting molars expressed a significant level of FAM20A. By breeding K14-Cre mice with Fam20Aflox/flox mice, we created K14-Cre;Fam20Aflox/flox (conditional knock out, cKO) mice, in which Fam20A was inactivated in the epithelium. We analysed the dental tissues of cKO mice using X-ray radiography, histology and immunohistochemistry. The molar enamel matrix in cKO mice was much thinner than normal and was often separated from the dentinoenamel junction. The Fam20A-deficient ameloblasts were non-polarized and disorganized and were detached from the enamel matrix. The enamel abnormality in cKO mice was consistent with the diagnosis of amelogenesis imperfecta. The levels of enamelin and matrix metalloproteinase 20 were lower in the ameloblasts and enamel of cKO mice than the normal mice. The cKO mice had remarkable delays in the eruption of molars and hyperplasia of the gingival epithelium. The findings emphasize the essential roles of FAM20A in the development of dental and oral tissues. PMID:27281036

  20. Loss of epithelial FAM20A in mice causes amelogenesis imperfecta, tooth eruption delay and gingival overgrowth.

    PubMed

    Li, Li-Li; Liu, Pei-Hong; Xie, Xiao-Hua; Ma, Su; Liu, Chao; Chen, Li; Qin, Chun-Lin

    2016-06-30

    FAM20A has been studied to a very limited extent. Mutations in human FAM20A cause amelogenesis imperfecta, gingival fibromatosis and kidney problems. It would be desirable to systemically analyse the expression of FAM20A in dental tissues and to assess the pathological changes when this molecule is specifically nullified in individual tissues. Recently, we generated mice with a Fam20A-floxed allele containing the beta-galactosidase reporter gene. We analysed FAM20A expression in dental tissues using X-Gal staining, immunohistochemistry and in situ hybridization, which showed that the ameloblasts in the mouse mandibular first molar began to express FAM20A at 1 day after birth, and the reduced enamel epithelium in erupting molars expressed a significant level of FAM20A. By breeding K14-Cre mice with Fam20A(flox/flox) mice, we created K14-Cre;Fam20A(flox/flox) (conditional knock out, cKO) mice, in which Fam20A was inactivated in the epithelium. We analysed the dental tissues of cKO mice using X-ray radiography, histology and immunohistochemistry. The molar enamel matrix in cKO mice was much thinner than normal and was often separated from the dentinoenamel junction. The Fam20A-deficient ameloblasts were non-polarized and disorganized and were detached from the enamel matrix. The enamel abnormality in cKO mice was consistent with the diagnosis of amelogenesis imperfecta. The levels of enamelin and matrix metalloproteinase 20 were lower in the ameloblasts and enamel of cKO mice than the normal mice. The cKO mice had remarkable delays in the eruption of molars and hyperplasia of the gingival epithelium. The findings emphasize the essential roles of FAM20A in the development of dental and oral tissues.

  1. Mutations in CNNM4 Cause Jalili Syndrome, Consisting of Autosomal-Recessive Cone-Rod Dystrophy and Amelogenesis Imperfecta

    PubMed Central

    Parry, David A.; Mighell, Alan J.; El-Sayed, Walid; Shore, Roger C.; Jalili, Ismail K.; Dollfus, Hélène; Bloch-Zupan, Agnes; Carlos, Roman; Carr, Ian M.; Downey, Louise M.; Blain, Katharine M.; Mansfield, David C.; Shahrabi, Mehdi; Heidari, Mansour; Aref, Parissa; Abbasi, Mohsen; Michaelides, Michel; Moore, Anthony T.; Kirkham, Jennifer; Inglehearn, Chris F.

    2009-01-01

    The combination of recessively inherited cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) was first reported by Jalili and Smith in 1988 in a family subsequently linked to a locus on chromosome 2q11, and it has since been reported in a second small family. We have identified five further ethnically diverse families cosegregating CRD and AI. Phenotypic characterization of teeth and visual function in the published and new families reveals a consistent syndrome in all seven families, and all link or are consistent with linkage to 2q11, confirming the existence of a genetically homogenous condition that we now propose to call Jalili syndrome. Using a positional-candidate approach, we have identified mutations in the CNNM4 gene, encoding a putative metal transporter, accounting for the condition in all seven families. Nine mutations are described in all, three missense, three terminations, two large deletions, and a single base insertion. We confirmed expression of Cnnm4 in the neural retina and in ameloblasts in the developing tooth, suggesting a hitherto unknown connection between tooth biomineralization and retinal function. The identification of CNNM4 as the causative gene for Jalili syndrome, characterized by syndromic CRD with AI, has the potential to provide new insights into the roles of metal transport in visual function and biomineralization. PMID:19200525

  2. Noninvasive and Multidisciplinary Approach to the Functional and Esthetic Rehabilitation of Amelogenesis Imperfecta: A Pediatric Case Report

    PubMed Central

    de Souza, Juliana Feltrin; Fragelli, Camila Maria Bullio; Paschoal, Marco Aurélio Benini; Campos, Edson Alves; Cunha, Leonardo Fernandes; Losso, Estela Maris; Cordeiro, Rita de Cássia Loiola

    2014-01-01

    Case Report. An 8-year-old girl with amelogenesis imperfecta (AI) reported unsatisfactory aesthetics, difficulty in mastication, and dental hypersensitivity. The intraoral examination observed mixed dentition, malocclusion in anteroposterior relationships, anterior open bite, and dental asymmetry. A hypoplastic form of AI was diagnosed in the permanent dentition. A multidisciplinary planning was performed and divided into preventive, orthopedic, and rehabilitation stages. Initially, preventive treatment was implemented, with fluoride varnish applications, in order to protect the fragile enamel and reduce the dental sensitivity. In the second stage, the patient received an interceptive orthopedic treatment to improve cross-relationship of the arches during six months. Finally, the rehabilitation treatment was executed to establish the vertical dimension. In the posterior teeth, indirect composite resin crowns were performed with minimally invasive dental preparation. Direct composite resin restorations were used to improve the appearance of anterior teeth. Follow-Up. The follow-up was carried out after 3, 6, 12, and 18 months. After 18 months of follow-up, The restoration of integrity, oral hygiene, and patient satisfaction were observed . Conclusion. Successful reduction of the dental hypersensitivity and improvement of the aesthetic and functional aspects as well as quality of life were observed. PMID:25061528

  3. Full-mouth adhesive rehabilitation in a case of amelogenesis imperfecta: a 5-year follow-up case report.

    PubMed

    Gerdolle, David; Mortier, Eric; Richard, Adeline; Vailati, Francesca

    2015-01-01

    Amelogenesis imperfecta (AI) is a hereditary disorder caused by mutations of genes primarily involved in the enamel formation. Several different types of AI have been identified, based on the phenotype and on the mode of inheritance. Regardless of the type, the dental treatment tends to be the same, favoring the complete removal of the compromised enamel late in the patient's life. With the new dentistry guidelines that orient clinicians towards minimal invasiveness, it should be mandatory to intercept patients affected by AI earlier, not only to protect the dentition from further degradation but also to help patients improve their self-esteem. This article examines the restorative dentistry performed on a 24-year-old Caucasian female suffering from the hypoplastic type of AI, using only adhesive procedures. Due to the complex needs of the patient, an interdisciplinary approach was followed, involving orthodontics, periodontics, and restorative dentistry. A full-mouth adhesive rehabilitation was achieved by means of direct composite restorations, veneer/onlays and facial/palatal veneers. No elective endodontic therapy was necessary for restorative purposes. The esthetics, mechanics, and biological success were achieved and maintained. The bond to the enamel did not show signs of degradation (eg, discoloration or infiltration) even after 5 years of function. This is encouraging as it shows that adhesive techniques may be a reliable approach even in the presence of a compromised enamel layer.

  4. Amelogenesis Imperfecta and Early Restorative Crown Therapy: An Interview Study with Adolescents and Young Adults on Their Experiences

    PubMed Central

    Wickström, Anette; Hasselblad, Tove; Dahllöf, Göran

    2016-01-01

    Patients with Amelogenesis imperfecta (AI) can present with rapid tooth loss or fractures of enamel as well as alterations in enamel thickness, color, and shape; factors that may compromise aesthetic appearance and masticatory function. The aim was to explore the experiences and perceptions of adolescents and young adults living with AI and receiving early prosthetic therapy. Seven patients with severe AI aged 16 to 23 years who underwent porcelain crown therapy participated in one-to-one individual interviews. The interviews followed a topic guide consisting of open-ended questions related to experiences of having AI. Transcripts from the interviews were analyzed using thematic analysis. The analysis process identified three main themes: Disturbances in daily life, Managing disturbances, and Normalization of daily life. These themes explain the experiences of patients living with enamel disturbances caused by AI and receiving early crown therapy. Experiences include severe pain and sensitivity problems, feelings of embarrassment, and dealing with dental staff that lack knowledge and understanding of their condition. The patients described ways to manage their disturbances and to reduce pain when eating or drinking, and strategies for meeting other people. After definitive treatment with porcelain crown therapy, they described feeling like a normal patient. In conclusion the results showed that adolescents and young adults describe a profound effect of AI on several aspects of their daily life. PMID:27359125

  5. Amelogenesis Imperfecta Caused by N-Terminal Enamelin Point Mutations in Mice and Men is driven by Endoplasmic Reticulum Stress.

    PubMed

    Brookes, Steven J; Barron, Martin J; Smith, Claire E L; Poulter, James A; Mighell, Alan J; Inglehearn, Chris F; Brown, Catriona J; Rodd, Helen; Kirkham, Jennifer; Dixon, Michael J

    2017-03-11

    "Amelogenesis imperfecta" (AI) describes a group of inherited diseases of dental enamel that have major clinical impact. Here, we identify the aetiology driving AI in mice carrying a p.S55I mutation in enamelin; one of the most commonly mutated proteins underlying AI in humans. Our data indicate that the mutation inhibits the ameloblast secretory pathway leading to ER stress and an activated unfolded protein response (UPR). Initially, with the support of the UPR acting in pro-survival mode, Enamp.S55I heterozygous mice secreted structurally normal enamel. However, enamel secreted thereafter was structurally abnormal; presumably due to the UPR modulating ameloblast behaviour and function in an attempt to relieve ER stress. Homozygous mutant mice failed to produce enamel. We also identified a novel heterozygous ENAMp.L31R mutation causing AI in humans. We hypothesise that ER stress is the aetiological factor in this case of human AI as it shared the characteristic phenotype described above for the Enamp.S55I mouse. We previously demonstrated that AI in mice carrying the Amelxp.Y64H mutation is a proteinopathy. The current data indicate that AI in Enamp.S55I mice is also a proteinopathy, and based on comparative phenotypic analysis, we suggest that human AI resulting from the ENAMp.L31R mutation is another proteinopathic disease. Identifying a common aetiology for AI resulting from mutations in two different genes opens the way for developing pharmaceutical interventions designed to relieve ER stress or modulate the UPR during enamel development to ameliorate the clinical phenotype.

  6. Complex morphological and molecular genetic examination of amelogenesis imperfecta: a case presentation of two Czech siblings with a non-syndrome form of the disease.

    PubMed

    Kripnerova, Tereza; Krulisova, Veronika; Ptakova, Nikola; Macek, Milan; Dostalova, Tatjana

    2014-01-01

    Amelogenesis imperfecta (AI) is an overarching term for a group of rare inherited disorders of hard tooth tissues. It is characterized by various defects in proper enamel formation. AI is a severe disorder that affects both the aesthetics and function of the dentition, with affected teeth increasingly suffering from dental caries. Therefore, early diagnosis and lifelong stomatological interventions are important. Due to the complex nature of AI family history, stomatological, radiographic, and molecular genetic examinations should be part of the diagnostic portfolio. Additionally, we utilized new visualization methods for the assessment of teeth demineralization. We present a case report of two affected Czech sisters (6 and 8 years old) with clinically defined AI. These are the first Czech cases in which comprehensive clinical and genetic analysis had been carried out and reflect the complex clinical nature, positive treatment options, and limitations of candidate-gene molecular genetic testing.

  7. Enamel defects in extracted and exfoliated teeth from patients with Amelogenesis Imperfecta, measured using the extended enamel defects index and image analysis

    PubMed Central

    Smith, R.N.; Elcock, C.; Abdellatif, A.; Bäckman, B.; Russell, J.M.; Brook, A.H.

    2009-01-01

    Aims To enhance the phenotypic description and quantification of enamel defects from a North Sweden sample of extracted and exfoliated teeth originating from families with Amelogenesis Imperfecta by use of the extended enamel defects index (EDI) and image analysis to demonstrate the comparable reliability and value of the additional measurements. Methods and results The sample comprised 109 deciduous and 7 permanent teeth from 32 individuals of 19 families with Amelogenesis Imperfecta in Northern Sweden. A special holder for individual teeth was designed and the whole sample was examined using the extended EDI and an image analysis system. In addition to the extended EDI definitions, the calibrated images were measured for tooth surface area, defect area and percentage of surface affected using image analysis techniques. The extended EDI was assessed using weighted and unweighted Kappa statistics. The reliability of imaging and measurement was determined using Fleiss’ intra-class correlation coefficient (ICCC). Kappa values indicated good or excellent intra-operator repeatability and inter-operator reproducibility for the extended EDI. The Fleiss ICCC values indicated excellent repeatability for the image analysis measurements. Hypoplastic pits on the occlusal surfaces were the most frequent defect in this sample (82.6%). The occlusal surface displayed the most post-eruptive breakdown (39.13%) whilst the incisal portion of the buccal surfaces showed most diffuse opacities (53.4%). Image analysis methods demonstrated the largest mean hypoplastic pit areas were on the lingual surfaces. The largest mean post-eruptive breakdown areas were on the lingual surfaces of posterior teeth. The largest mean demarcated opacity areas were found on the labial surfaces. Conclusions The extended EDI and the standardised image acquisition and analysis system provided additional information to conventional measurement techniques. Additional phenotypic variables were described. PMID

  8. Whole-exome sequencing, without prior linkage, identifies a mutation in LAMB3 as a cause of dominant hypoplastic amelogenesis imperfecta.

    PubMed

    Poulter, James A; El-Sayed, Walid; Shore, Roger C; Kirkham, Jennifer; Inglehearn, Chris F; Mighell, Alan J

    2014-01-01

    The conventional approach to identifying the defective gene in a family with an inherited disease is to find the disease locus through family studies. However, the rapid development and decreasing cost of next generation sequencing facilitates a more direct approach. Here, we report the identification of a frameshift mutation in LAMB3 as a cause of dominant hypoplastic amelogenesis imperfecta (AI). Whole-exome sequencing of three affected family members and subsequent filtering of shared variants, without prior genetic linkage, sufficed to identify the pathogenic variant. Simultaneous analysis of multiple family members confirms segregation, enhancing the power to filter the genetic variation found and leading to rapid identification of the pathogenic variant. LAMB3 encodes a subunit of Laminin-5, one of a family of basement membrane proteins with essential functions in cell growth, movement and adhesion. Homozygous LAMB3 mutations cause junctional epidermolysis bullosa (JEB) and enamel defects are seen in JEB cases. However, to our knowledge, this is the first report of dominant AI due to a LAMB3 mutation in the absence of JEB.

  9. Limited phenotypic variation of hypocalcified amelogenesis imperfecta in a Danish five-generation family with a novel FAM83H nonsense mutation.

    PubMed

    Haubek, Dorte; Gjørup, Hans; Jensen, Lillian G; Juncker, Inger; Nyegaard, Mette; Børglum, Anders D; Poulsen, Sven; Hertz, Jens M

    2011-11-01

    BACKGROUND.  Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI) is a disease with severe dental manifestations. OBJECTIVES.  The aims were by means of a genome-wide linkage scan to search for the gene underlying the ADHCAI phenotype in a Danish five-generation family and to study the phenotypic variation of the enamel in affected family members. RESULTS.  Significant linkage was found to a locus at chromosome 8q24.3 comprising the gene FAM83H identified to be responsible for ADHCAI in other families. Subsequent sequencing of FAM83H in affected family members revealed a novel nonsense mutation, p.Y302X. Limited phenotypic variation was found among affected family members with loss of translucency and discoloration of the enamel. Extensive posteruptive loss of enamel was found in all teeth of affected subjects. The tip of the cusps on the premolars and molars and a zone along the gingival margin seemed resistant to posteruptive loss of enamel. We have screened FAM83H in another five unrelated Danish patients with a phenotype of ADHCAI similar to that in the five-generation family, and identified a de novo FAM83H nonsense mutation, p.Q452X in one of these patients. CONCLUSION.  We have identified a FAM83H mutation in two of six unrelated families with ADHCAI and found limited phenotypic variation of the enamel in these patients.

  10. Identification of the first multi-exonic WDR72 deletion in isolated amelogenesis imperfecta, and generation of a WDR72-specific copy number screening tool.

    PubMed

    Hentschel, Julia; Tatun, Dana; Parkhomchuk, Dmitri; Kurth, Ingo; Schimmel, Bettina; Heinrich-Weltzien, Roswitha; Bertzbach, Sabine; Peters, Hartmut; Beetz, Christian

    2016-09-15

    Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous disorder of tooth development which is due to aberrant deposition or composition of enamel. Both syndromic and isolated forms exist; they may be inherited in an X-linked, autosomal recessive, or autosomal dominant manner. WDR72 is one of ten currently known genes for recessive isolated AI; nine WDR72 mutations affecting single nucleotides have been described to date. Based on whole exome sequencing in a large consanguineous AI pedigree, we obtained evidence for presence of a multi-exonic WDR72 deletion. A home-made multiplex ligation-dependent probe amplification assay was used to confirm the aberration, to narrow its extent, and to identify heterozygous carriers. Our study extends the mutational spectrum for WDR72 to include large deletions, and supports a relevance of the previously proposed loss-of-function mechanism. It also introduces an easy-to-use and highly sensitive tool for detecting WDR72 copy number alterations.

  11. Improved protocol to purify untagged amelogenin – Application to murine amelogenin containing the equivalent P70→T point mutation observed in human amelogenesis imperfecta

    DOE PAGES

    Buchko, Garry W.; Shaw, Wendy J.

    2014-10-13

    Amelogenin is the predominant extracellular protein responsible for converting carbonated hydroxyapatite into dental enamel, the hardest and most heavily mineralized tissue in vertebrates. Despite much effort, the precise mechanism by which amelogenin regulates enamel formation is not fully understood. To assist efforts aimed at understanding the biochemical mechanism of enamel formation, more facile protocols to purify recombinantly expressed amelogenin, ideally without any tag to assist affinity purification, are advantageous. Here we describe an improved method to purify milligram quantities of amelogenin that exploits its high solubility in 2% glacial acetic acid under conditions of low ionic strength. The method involvesmore » heating the frozen cell pellet for two 15 min periods at ~70 ºC with two minutes of sonication in between, dialysis twice in 2% acetic acid (1:250 v/v), and reverse phase chromatography. A further improvement in yield is obtained by resuspending the frozen cell pellet in 6 M guanidine hydrochloride in the first step. The acetic acid heating method is illustrated with a murine amelogenin containing the corresponding P70→T point mutation observed in an human amelogenin associated with amelogenesis imperfecta (P71T), while the guanidine hydrochloride heating method is illustrated with wild type murine amelogenin (M180). The self-assembly properties of P71T were probed by NMR chemical shift perturbation studies as a function of protein (0.1 to 1.8 mM) and NaCl (0 to 367 mM) concentration. In conclusion, relative to similar studies with wild type murine amelogenin, P71T self-associates at lower protein or salt concentrations with the interactions initiated near the N-terminus.« less

  12. Improved protocol to purify untagged amelogenin – Application to murine amelogenin containing the equivalent P70→T point mutation observed in human amelogenesis imperfecta

    SciTech Connect

    Buchko, Garry W.; Shaw, Wendy J.

    2014-10-13

    Amelogenin is the predominant extracellular protein responsible for converting carbonated hydroxyapatite into dental enamel, the hardest and most heavily mineralized tissue in vertebrates. Despite much effort, the precise mechanism by which amelogenin regulates enamel formation is not fully understood. To assist efforts aimed at understanding the biochemical mechanism of enamel formation, more facile protocols to purify recombinantly expressed amelogenin, ideally without any tag to assist affinity purification, are advantageous. Here we describe an improved method to purify milligram quantities of amelogenin that exploits its high solubility in 2% glacial acetic acid under conditions of low ionic strength. The method involves heating the frozen cell pellet for two 15 min periods at ~70 ºC with two minutes of sonication in between, dialysis twice in 2% acetic acid (1:250 v/v), and reverse phase chromatography. A further improvement in yield is obtained by resuspending the frozen cell pellet in 6 M guanidine hydrochloride in the first step. The acetic acid heating method is illustrated with a murine amelogenin containing the corresponding P70→T point mutation observed in an human amelogenin associated with amelogenesis imperfecta (P71T), while the guanidine hydrochloride heating method is illustrated with wild type murine amelogenin (M180). The self-assembly properties of P71T were probed by NMR chemical shift perturbation studies as a function of protein (0.1 to 1.8 mM) and NaCl (0 to 367 mM) concentration. In conclusion, relative to similar studies with wild type murine amelogenin, P71T self-associates at lower protein or salt concentrations with the interactions initiated near the N-terminus.

  13. Improved protocol to purify untagged amelogenin - Application to murine amelogenin containing the equivalent P70→T point mutation observed in human amelogenesis imperfecta.

    PubMed

    Buchko, Garry W; Shaw, Wendy J

    2015-01-01

    Amelogenin is the predominant extracellular protein responsible for converting carbonated hydroxyapatite into dental enamel, the hardest and most heavily mineralized tissue in vertebrates. Despite much effort, the precise mechanism by which amelogenin regulates enamel formation is not fully understood. To assist efforts aimed at understanding the biochemical mechanism of enamel formation, more facile protocols to purify recombinantly expressed amelogenin, ideally without any tag to assist affinity purification, are advantageous. Here we describe an improved method to purify milligram quantities of amelogenin that exploits its high solubility in 2% glacial acetic acid under conditions of low ionic strength. The method involves heating the frozen cell pellet for two 15min periods at ∼70°C with 2min of sonication in between, dialysis twice in 2% acetic acid (1:250 v/v), and reverse phase chromatography. A further improvement in yield is obtained by resuspending the frozen cell pellet in 6M guanidine hydrochloride in the first step. The acetic acid heating method is illustrated with a murine amelogenin containing the corresponding P70→T point mutation observed in an human amelogenin associated with amelogenesis imperfecta (P71T), while the guanidine hydrochloride heating method is illustrated with wild type murine amelogenin (M180). The self-assembly properties of P71T were probed by NMR chemical shift perturbation studies as a function of protein (0.1-1.8mM) and NaCl (0-367mM) concentration. Relative to similar studies with wild type murine amelogenin, P71T self-associates at lower protein or salt concentrations with the interactions initiated near the N-terminus.

  14. Amelogenesis imperfecta with bilateral nephrocalcinosis.

    PubMed

    Poornima, P; Katkade, Shashikant; Mohamed, Roshan Noor; Mallikarjuna, Rachappa

    2013-05-24

    A 12-year-old patient presented with a severe delay of eruption in permanent maxillary and mandibular incisors. On examination, there was over-retained primary teeth and delayed eruption of permanent teeth. Retained primary teeth showed light yellow discolouration whereas permanent teeth were distinct yellow with thin or little enamel. Subsequent imaging revealed all the premolars except maxillary left first premolar showed signs of intra-alveolar coronal resorption, nephrocalcinosis with bilateral multiple calculi and small papillary tip calcifications, marked increase in alkaline phosphatase. Subsequent dental treatment for restoring the functional and aesthetic requirement followed by appropriate treatment for renal problem was undertaken.

  15. A Functional Study of Mutations in K+-dependent Na+-Ca2+ Exchangers Associated with Amelogenesis Imperfecta and Non-syndromic Oculocutaneous Albinism.

    PubMed

    Jalloul, Ali H; Rogasevskaia, Tatiana P; Szerencsei, Robert T; Schnetkamp, Paul P M

    2016-06-17

    K(+)-dependent Na(+)/Ca(2+) exchangers belong to the solute carrier 24 (SLC24A1-5) gene family of membrane transporters. Five different gene products (NCKX1-5) have been identified in humans, which play key roles in biological processes including vision, olfaction, and skin pigmentation. NCKXs are bi-directional membrane transporters that transport 1 Ca(2+)+K(+) ions in exchange for 4 Na(+) ions. Recent studies have linked mutations in the SLC24A4 (NCKX4) and SLC24A5 (NCKX5) genes to amylogenesis imperfecta (AI) and non-syndromic oculocutaneous albinism (OCA6), respectively. Here, we introduced mutations found in patients with AI and OCA6 into human SLC24A4 (NCKX4) cDNA leading to single residue substitutions in the mutant NCKX4 proteins. We measured NCKX-mediated Ca(2+) transport activity of WT and mutant NCKX4 proteins expressed in HEK293 cells. Three mutant NCKX4 cDNAs represent mutations found in the SCL24A4 gene and three represent mutations found in the SCL24A5 gene involving residues conserved between NCKX4 and NCKX5. Five mutant proteins had no observable NCKX activity, whereas one mutation resulted in a 78% reduction in transport activity. Total protein expression and trafficking to the plasma membrane (the latter with one exception) were not affected in the HEK293 cell expression system. We also analyzed two mutations in a Drosophila NCKX gene that have been reported to result in an increased susceptibility for seizures, and found that both resulted in mutant proteins with significantly reduced but observable NCKX activity. The data presented here support the genetic analyses that mutations in SLC24A4 and SLC24A5 are responsible for the phenotypic defects observed in human patients.

  16. U.S. Army Medical Department Journal, January-March 2006

    DTIC Science & Technology

    2006-03-01

    Caries Detection z MAJ Jerry Carbone, DC, USA, et al Prosthodontic Rehabilitation of a Patient with Amelogenesis Imperfecta : 41 A Clinical Report LTC...Prosthodontic Rehabilitation of a Patient with Amelogenesis Imperfecta : A Clinical Report LTC Minaxi I. Patel, DC, USA LTC David A. Mott, DC, USA COL...hypocalcification appears Type 1 hypoplastic amelogenesis imperfecta . The normal but poorly mineralized while hypomaturation patient presented with

  17. Osteogenesis Imperfecta

    MedlinePlus

    ... imperfecta (OI) is a genetic disorder in which bones break easily. Sometimes the bones break for no known reason. OI can also ... you make collagen, a protein that helps make bones strong. OI can range from mild to severe, ...

  18. Osteogenesis imperfecta

    MedlinePlus

    ... for couples considering pregnancy if there is a personal or family history of this condition. Alternative Names Brittle bone disease; Congenital disease; OI Images Pectus excavatum References Marini JC. Osteogenesis imperfecta In: ...

  19. Osteogenesis imperfecta.

    PubMed

    Forlino, Antonella; Marini, Joan C

    2016-04-16

    Osteogenesis imperfecta is a phenotypically and molecularly heterogeneous group of inherited connective tissue disorders that share similar skeletal abnormalities causing bone fragility and deformity. Previously, the disorder was thought to be an autosomal dominant bone dysplasia caused by defects in type I collagen, but in the past 10 years discoveries of novel (mainly recessive) causative genes have lent support to a predominantly collagen-related pathophysiology and have contributed to an improved understanding of normal bone development. Defects in proteins with very different functions, ranging from structural to enzymatic and from intracellular transport to chaperones, have been described in patients with osteogenesis imperfecta. Knowledge of the specific molecular basis of each form of the disorder will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches. In this Seminar, together with diagnosis, management, and treatment, we describe the defects causing osteogenesis imperfecta and their mechanism and interrelations, and classify them into five groups on the basis of the metabolic pathway compromised, specifically those related to collagen synthesis, structure, and processing; post-translational modification; folding and cross-linking; mineralisation; and osteoblast differentiation.

  20. Osteogenesis Imperfecta Issues: Constipation

    MedlinePlus

    ... called rectal prolapse. Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ... 2005, 2007, 2016 Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ...

  1. Transcriptional factor DLX3 promotes the gene expression of enamel matrix proteins during amelogenesis.

    PubMed

    Zhang, Zhichun; Tian, Hua; Lv, Ping; Wang, Weiping; Jia, Zhuqing; Wang, Sainan; Zhou, Chunyan; Gao, Xuejun

    2015-01-01

    Mutation of distal-less homeobox 3 (DLX3) is responsible for human tricho-dento-osseous syndrome (TDO) with amelogenesis imperfecta, indicating a crucial role of DLX3 in amelogenesis. However, the expression pattern of DLX3 and its specific function in amelogenesis remain largely unknown. The aim of this study was to investigate the effects of DLX3 on enamel matrix protein (EMP) genes. By immunohistochemistry assays of mouse tooth germs, stronger immunostaining of DLX3 protein was identified in ameloblasts in the secretory stage than in the pre-secretory and maturation stages, and the same pattern was found for Dlx3 mRNA using Realtime PCR. In a mouse ameloblast cell lineage, forced expression of DLX3 up-regulated the expression of the EMP genes Amelx, Enam, Klk4, and Odam, whereas knockdown of DLX3 down-regulated these four EMP genes. Further, bioinformatics, chromatin immunoprecipitation, and luciferase assays revealed that DLX3 transactivated Enam, Amelx, and Odam through direct binding to their enhancer regions. Particularly, over-expression of mutant-DLX3 (c.571_574delGGGG, responsible for TDO) inhibited the activation function of DLX3 on expression levels and promoter activities of the Enam, Amelx, and Odam genes. Together, our data show that DLX3 promotes the expression of the EMP genes Amelx, Enam, Klk4, and Odam in amelogenesis, while mutant-DLX3 disrupts this regulatory function, thus providing insights into the molecular mechanisms underlying the enamel defects of TDO disease.

  2. Congenital adrenal hyperplasia with localized aggressive periodontitis and amelogenesis imperfecta.

    PubMed

    Ajlan, Sumaiah Abdulbaqi

    2015-11-01

    Congenital adrenal hyperplasia (CAH) is an inherited medical condition that implies defects in steroid biosynthesis. The dental findings of a female patient with CAH are reported. The patient suffered from severe periodontal tissue destruction, obvious enamel defects, as well as some occlusal problems. The management approach is presented and the possibility of interrelation of her dental findings with her medical condition is discussed.

  3. Child Abuse or Osteogenesis Imperfecta?

    MedlinePlus

    ... less than normal. Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ... undiagnosed osteogenesis imperfecta. Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ...

  4. Osteogenesis imperfecta/lobstein syndrome associated with dentinogenesis imperfecta.

    PubMed

    Lingaraju, Naresh; Nagarathna, P J; Vijayalakshmi, R; Sheshadri, P

    2013-01-01

    Osteogenesis imperfecta is a collagen related disorder characterized by increased bone fragility and low bone mass. The important oral finding in osteogenesis imperfect is the presence of dentinogenesis imperfecta. This article presents a case of osteogenesis imperfecta (type IV B) with dentinogenesis imperfecta where a 7-year-old girl had opalacent primary teeth associated with severe bone deformity, scoliosis, barrel shaped rib cage, and short stature. The clinical, radiographic ad histologic features are reviewed along with management aspects.

  5. What Is Osteogenesis Imperfecta?

    MedlinePlus

    ... About Osteogenesis Imperfecta and Other Related Conditions: NIH Osteoporosis and Related Bone Diseases ~ National Resource Center 2 ... searchable catalog of FDA-approved drug products. NIH Osteoporosis and Related Bone Diseases ~ National Resource Center 2 ...

  6. Dentinogenesis imperfecta associated with osteogenesis imperfecta

    PubMed Central

    Biria, Mina; Abbas, Fatemeh Mashhadi; Mozaffar, Sedighe; Ahmadi, Rahil

    2012-01-01

    This paper presents a case with dentinogenesis imperfecta (DI) associated with osteogenesis imperfecta. Systemic and dental manifestations of OI and its medical and dental treatments are discussed in this paper. A 5-year-old child with the diagnosis of OI was referred to the Dental School of Shaid Beheshti University of Medical Sciences. On clinical examination yellow/brown discoloration of primary teeth with the attrition of the exposed dentin and class III malocclusion was observed. Enamel of first permanent molars was hypoplastic. Radiographic examinations confirmed the diagnosis of DI. A histological study was performed on one of the exfoliating teeth, which showed abnormal dentin. Primary teeth with DI were more severely affected compared to permanent teeth; enamel disintegration occurred in teeth with DI, demonstrating the need for restricts recalls for these patients. PMID:23162594

  7. Retinoic Acid Excess Impairs Amelogenesis Inducing Enamel Defects

    PubMed Central

    Morkmued, Supawich; Laugel-Haushalter, Virginie; Mathieu, Eric; Schuhbaur, Brigitte; Hemmerlé, Joseph; Dollé, Pascal; Bloch-Zupan, Agnès; Niederreither, Karen

    2017-01-01

    Abnormalities of enamel matrix proteins deposition, mineralization, or degradation during tooth development are responsible for a spectrum of either genetic diseases termed Amelogenesis imperfecta or acquired enamel defects. To assess if environmental/nutritional factors can exacerbate enamel defects, we investigated the role of the active form of vitamin A, retinoic acid (RA). Robust expression of RA-degrading enzymes Cyp26b1 and Cyp26c1 in developing murine teeth suggested RA excess would reduce tooth hard tissue mineralization, adversely affecting enamel. We employed a protocol where RA was supplied to pregnant mice as a food supplement, at a concentration estimated to result in moderate elevations in serum RA levels. This supplementation led to severe enamel defects in adult mice born from pregnant dams, with most severe alterations observed for treatments from embryonic day (E)12.5 to E16.5. We identified the enamel matrix proteins enamelin (Enam), ameloblastin (Ambn), and odontogenic ameloblast-associated protein (Odam) as target genes affected by excess RA, exhibiting mRNA reductions of over 20-fold in lower incisors at E16.5. RA treatments also affected bone formation, reducing mineralization. Accordingly, craniofacial ossification was drastically reduced after 2 days of treatment (E14.5). Massive RNA-sequencing (RNA-seq) was performed on E14.5 and E16.5 lower incisors. Reductions in Runx2 (a key transcriptional regulator of bone and enamel differentiation) and its targets were observed at E14.5 in RA-exposed embryos. RNA-seq analysis further indicated that bone growth factors, extracellular matrix, and calcium homeostasis were perturbed. Genes mutated in human AI (ENAM, AMBN, AMELX, AMTN, KLK4) were reduced in expression at E16.5. Our observations support a model in which elevated RA signaling at fetal stages affects dental cell lineages. Thereafter enamel protein production is impaired, leading to permanent enamel alterations. PMID:28111553

  8. Prosthodontic rehabilitation of dentinogenesis imperfecta

    PubMed Central

    Goud, Anil; Deshpande, Saee

    2011-01-01

    Dentinogenesis imperfecta and its prosthodontic management is a challenging task. Treatment protocol varies according to clinical case. Although various reports in the literature suggest general guidelines for treatment planning, the present case report describes a full mouth rehabilitation of a young patient with dentinogenesis imperfecta treated by maxillary fixed partial dentures and mandibular fiber reinforced overdenture with metal occlusal surfaces. PMID:21957394

  9. Genetics Home Reference: dentinogenesis imperfecta

    MedlinePlus

    ... Gu T, Jeffords L, MacDougall M. Dentin phosphoprotein compound mutation in dentin sialophosphoprotein causes dentinogenesis imperfecta type ... the human DSPP gene. Hum Mutat. 2008 Dec;29(12):1392-404. doi: 10.1002/humu.20783. ...

  10. Osteogenesis imperfecta: cesarean deliveries in identical twins.

    PubMed

    Dinges, E; Ortner, C; Bollag, L; Davies, J; Landau, R

    2015-02-01

    Osteogenesis imperfecta is a congenital disorder resulting in multiple fractures and extremely short stature, usually necessitating cesarean delivery. Identical twins with severe osteogenesis imperfecta each of whom underwent a cesarean delivery with different anesthetic modalities are presented. A review of the literature and anesthetic options for cesarean delivery and postoperative analgesia for women with osteogenesis imperfecta are discussed.

  11. MiR-153 Regulates Amelogenesis by Targeting Endocytotic and Endosomal/lysosomal Pathways–Novel Insight into the Origins of Enamel Pathologies

    PubMed Central

    Yin, Kaifeng; Lin, Wenting; Guo, Jing; Sugiyama, Toshihiro; Snead, Malcolm L.; Hacia, Joseph G.; Paine, Michael L.

    2017-01-01

    Amelogenesis imperfecta (AI) is group of inherited disorders resulting in enamel pathologies. The involvement of epigenetic regulation in the pathogenesis of AI is yet to be clarified due to a lack of knowledge about amelogenesis. Our previous genome-wide microRNA and mRNA transcriptome analyses suggest a key role for miR-153 in endosome/lysosome-related pathways during amelogenesis. Here we show that miR-153 is significantly downregulated in maturation ameloblasts compared with secretory ameloblasts. Within ameloblast-like cells, upregulation of miR-153 results in the downregulation of its predicted targets including Cltc, Lamp1, Clcn4 and Slc4a4, and a number of miRNAs implicated in endocytotic pathways. Luciferase reporter assays confirmed the predicted interactions between miR-153 and the 3′-UTRs of Cltc, Lamp1 (in a prior study), Clcn4 and Slc4a4. In an enamel protein intake assay, enamel cells transfected with miR-153 show a decreased ability to endocytose enamel proteins. Finally, microinjection of miR-153 in the region of mouse first mandibular molar at postnatal day 8 (PN8) induced AI-like pathologies when the enamel development reached maturity (PN12). In conclusion, miR-153 regulates maturation-stage amelogenesis by targeting key genes involved in the endocytotic and endosomal/lysosomal pathways, and disruption of miR-153 expression is a potential candidate etiologic factor contributing to the occurrence of AI. PMID:28287144

  12. Hereditary dentine disorders: dentinogenesis imperfecta and dentine dysplasia

    PubMed Central

    Barron, Martin J; McDonnell, Sinead T; MacKie, Iain; Dixon, Michael J

    2008-01-01

    The hereditary dentine disorders, dentinogenesis imperfecta (DGI) and dentine dysplasia (DD), comprise a group of autosomal dominant genetic conditions characterised by abnormal dentine structure affecting either the primary or both the primary and secondary dentitions. DGI is reported to have an incidence of 1 in 6,000 to 1 in 8,000, whereas that of DD type 1 is 1 in 100,000. Clinically, the teeth are discoloured and show structural defects such as bulbous crowns and small pulp chambers radiographically. The underlying defect of mineralisation often results in shearing of the overlying enamel leaving exposed weakened dentine which is prone to wear. Currently, three sub-types of DGI and two sub-types of DD are recognised but this categorisation may change when other causative mutations are found. DGI type I is inherited with osteogenesis imperfecta and recent genetic studies have shown that mutations in the genes encoding collagen type 1, COL1A1 and COL1A2, underlie this condition. All other forms of DGI and DD, except DD-1, appear to result from mutations in the gene encoding dentine sialophosphoprotein (DSPP), suggesting that these conditions are allelic. Diagnosis is based on family history, pedigree construction and detailed clinical examination, while genetic diagnosis may become useful in the future once sufficient disease-causing mutations have been discovered. Differential diagnoses include hypocalcified forms of amelogenesis imperfecta, congenital erythropoietic porphyria, conditions leading to early tooth loss (Kostmann's disease, cyclic neutropenia, Chediak-Hegashi syndrome, histiocytosis X, Papillon-Lefevre syndrome), permanent teeth discolouration due to tetracyclines, Vitamin D-dependent and vitamin D-resistant rickets. Treatment involves removal of sources of infection or pain, improvement of aesthetics and protection of the posterior teeth from wear. Beginning in infancy, treatment usually continues into adulthood with a number of options including

  13. Osteogenesis imperfecta: pathophysiology and treatment.

    PubMed

    Hoyer-Kuhn, Heike; Netzer, Christian; Semler, Oliver

    2015-07-01

    Osteogenesis imperfecta is a rare hereditary disease mostly caused by mutations impairing collagen synthesis and modification. Recently recessive forms have been described influencing differentiation and activity of osteoblasts and osteoclasts. Most prominent signs are fractures due to low traumata and deformities of long bones and vertebrae. Additional patients can be affected by dwarfism, scoliosis Dentinogenesis imperfecta, deafness and a blueish discoloration of the sclera. During childhood state of the art medical treatment are i.v. bisphosphonates to increase bone mass and to reduce fracture rate. Surgical interventions are needed to treat fractures, to correct deformities and should always be accompanied by physiotherapeutic and rehabilitative interventions.

  14. Epileptic encephalopathy and amelogenesis imperfecta: Kohlschütter-Tönz syndrome.

    PubMed

    Schossig, Anna; Wolf, Nicole I; Kapferer, Ines; Kohlschütter, Alfried; Zschocke, Johannes

    2012-05-01

    Kohlschütter-Tönz syndrome is a rare genetic disorder with epilepsy, psychomotor regression, and a severe enamel defect with yellow or brownish discoloration of the teeth. The first affected family was described in 1974, and 25 patients in 11 families have been reported until now. Inheritance is autosomal recessive. Epilepsy usually starts within the first or second year of life. All affected individuals show a psychomotor regression after onset of epilepsy or a developmental delay from birth on. Clinical course and disease severity are variable even within families. There are no known biochemical or other diagnostic markers of the condition. Very recently it has been shown that the condition is caused by mutations in the gene ROGDI but molecular data have only been reported for three families. It remains to be seen whether Kohlschütter-Tönz syndrome has the same molecular basis in all affected individuals.

  15. Bmp2 deletion causes an amelogenesis imperfecta phenotype via regulating enamel gene expression.

    PubMed

    Guo, Feng; Feng, Junsheng; Wang, Feng; Li, Wentong; Gao, Qingping; Chen, Zhuo; Shoff, Lisa; Donly, Kevin J; Gluhak-Heinrich, Jelica; Chun, Yong Hee Patricia; Harris, Stephen E; MacDougall, Mary; Chen, Shuo

    2015-08-01

    Although Bmp2 is essential for tooth formation, the role of Bmp2 during enamel formation remains unknown in vivo. In this study, the role of Bmp2 in regulation of enamel formation was investigated by the Bmp2 conditional knock out (Bmp2 cKO) mice. Teeth of Bmp2 cKO mice displayed severe and profound phenotypes with asymmetric and misshaped incisors as well as abrasion of incisors and molars. Scanning electron microscopy analysis showed that the enamel layer was hypoplastic and enamel lacked a typical prismatic pattern. Teeth from null mice were much more brittle as tested by shear and compressive moduli. Expression of enamel matrix protein genes, amelogenin, enamelin, and enamel-processing proteases, Mmp-20 and Klk4 was reduced in the Bmp2 cKO teeth as reflected in a reduced enamel formation. Exogenous Bmp2 up-regulated those gene expressions in mouse enamel organ epithelial cells. This result for the first time indicates Bmp2 signaling is essential for proper enamel development and mineralization in vivo.

  16. The Spine in Patients With Osteogenesis Imperfecta.

    PubMed

    Wallace, Maegen J; Kruse, Richard W; Shah, Suken A

    2017-02-01

    Osteogenesis imperfecta is a genetic disorder of type I collagen. Although multiple genotypes and phenotypes are associated with osteogenesis imperfecta, approximately 90% of the mutations are in the COL1A1 and COL1A2 genes. Osteogenesis imperfecta is characterized by bone fragility. Patients typically have multiple fractures or limb deformity; however, the spine can also be affected. Spinal manifestations include scoliosis, kyphosis, craniocervical junction abnormalities, and lumbosacral pathology. The incidence of lumbosacral spondylolysis and spondylolisthesis is higher in patients with osteogenesis imperfecta than in the general population. Use of diphosphonates has been found to decrease the rate of progression of scoliosis in patients with osteogenesis imperfecta. A lateral cervical radiograph is recommended in patients with this condition before age 6 years for surveillance of craniocervical junction abnormalities, such as basilar impression. Intraoperative and anesthetic considerations in patients with osteogenesis imperfecta include challenges related to fracture risk, airway management, pulmonary function, and blood loss.

  17. Hypercalcaemia in osteogenesis imperfecta treated with pamidronate

    PubMed Central

    Williams, C; Smith, R; Ball, R; Wilkinson, H

    1997-01-01

    Accepted 10 September 1996
 The response to the bisphophosphonate, pamidronate, is reported in a child with osteogenesis imperfecta who had recurrent symptomatic hypercalcaemia after immobilisation following fractures. Oral clodronate was effective in the prevention of immobilisation hypercalcaemia in the same child. The bisphosphonates may have other roles in osteogenesis imperfecta by decreasing bone turnover.

 PMID:9068314

  18. Surface integrity governs the proteome of hypomineralized enamel.

    PubMed

    Mangum, J E; Crombie, F A; Kilpatrick, N; Manton, D J; Hubbard, M J

    2010-10-01

    Growing interest in the treatment and prevention of Molar/Incisor Hypomineralization (MIH) warrants investigation into the protein composition of hypomineralized enamel. Hypothesizing abnormality akin to amelogenesis imperfecta, we profiled proteins in hypomineralized enamel from human permanent first molars using a biochemical approach. Hypomineralized enamel was found to have from 3- to 15-fold higher protein content than normal, but a near-normal level of residual amelogenins. This distinguished MIH from hypomaturation defects with high residual amelogenins (amelogenesis imperfecta, fluorosis) and so typified it as a hypocalcification defect. Second, hypomineralized enamel was found to have accumulated various proteins from oral fluid and blood, with differential incorporation depending on integrity of the enamel surface. Pathogenically, these results point to a pre-eruptive disturbance of mineralization involving albumin and, in cases with post-eruptive breakdown, subsequent protein adsorption on the exposed hydroxyapatite matrix. These insights into the pathogenesis and properties of hypomineralized enamel hold significance for prevention and treatment of MIH.

  19. Recent developments in osteogenesis imperfecta

    PubMed Central

    Shaker, Joseph L.; Albert, Carolyne; Fritz, Jessica; Harris, Gerald

    2015-01-01

    Osteogenesis imperfecta (OI) is an uncommon genetic bone disease associated with brittle bones and fractures in children and adults. Although OI is most commonly associated with mutations of the genes for type I collagen, many other genes (some associated with type I collagen processing) have now been identified. The genetics of OI and advances in our understanding of the biomechanical properties of OI bone are reviewed in this article. Treatment includes physiotherapy, fall prevention, and sometimes orthopedic procedures. In this brief review, we will also discuss current understanding of pharmacologic therapies for treatment of OI. PMID:26401268

  20. Intramedullary rodding in osteogenesis imperfecta.

    PubMed

    Mulpuri, K; Joseph, B

    2000-01-01

    The results of intramedullary rodding of long bones of 16 children with osteogenesis imperfecta, over a 10-year period, were analyzed. Sheffield elongating rods or non-elongating rods were used. The frequency of fractures was dramatically reduced after implantation of either type of rod, and the ambulatory status improved in all instances. The results were significantly better after Sheffield rodding with regard to the frequency of complications requiring reoperations and the longevity of the rods. Migration of the rods, encountered frequently, appears to be related to improper placement of the rods in the bone. It seems likely that if care is taken to ensure precise placement of a rod of appropriate size, several of these complications may be avoided.

  1. New Perspectives on Osteogenesis Imperfecta

    PubMed Central

    Forlino, Antonella; Cabral, Wayne A.; Barnes, Aileen M.; Marini, Joan C.

    2012-01-01

    A new paradigm has emerged for osteogenesis imperfecta (OI) as a collagen-related disorder. The more prevalent autosomal dominant forms of OI are caused by primary defects in type I collagen, while autosomal recessive forms are caused by deficiency of proteins which interact with type I procollagen for post-translational modification and/or folding. Factors contributing to the mechanism of dominant OI include intracellular stress, disruption of interactions between collagen and non-collagenous proteins, compromised matrix structure, abnormal cell-cell and cell-matrix interactions and tissue mineralization. Recessive OI is caused by deficiency of any of the three components of the collagen prolyl 3-hydroxylation complex; absence of 3-hydroxylation is associated with increased modification of the collagen helix, supporting delayed collagen folding. Other causes of recessive OI include deficiency of collagen chaperones, FKBP65 or HSP47. Murine models are crucial to uncovering the common pathways in dominant and recessive OI bone dysplasia. Clinical management of OI is multidiscipinary, encompassing substantial progress in physical rehabilitation and surgical procedures, managment of hearing, dental and pulmonary abnormalities, as well as drugs such as bisphosphonates and rGH. Novel treatments using cell therapy or new drug regimens hold promise for the future. PMID:21670757

  2. Suspect osteogenesis imperfecta in a male kitten.

    PubMed

    Evason, Michelle D; Taylor, Susan M; Bebchuk, Trevor N

    2007-03-01

    A 4.5-month-old, male domestic shorthair was presented with bilateral femoral fractures after falling from a low height. Radiographs revealed reduced radio-opacity and thin cortices of all long bones. A presumptive diagnosis of osteodystrophy, secondary to osteogenesis imperfecta, was made on postmortem examination.

  3. Bone Material Properties in Osteogenesis Imperfecta.

    PubMed

    Bishop, Nick

    2016-04-01

    Osteogenesis imperfecta entrains changes at every level in bone tissue, from the disorganization of the collagen molecules and mineral platelets within and between collagen fibrils to the macroarchitecture of the whole skeleton. Investigations using an array of sophisticated instruments at multiple scale levels have now determined many aspects of the effect of the disease on the material properties of bone tissue. The brittle nature of bone in osteogenesis imperfecta reflects both increased bone mineralization density-the quantity of mineral in relation to the quantity of matrix within a specific bone volume-and altered matrix-matrix and matrix mineral interactions. Contributions to fracture resistance at multiple scale lengths are discussed, comparing normal and brittle bone. Integrating the available information provides both a better understanding of the effect of current approaches to treatment-largely improved architecture and possibly some macroscale toughening-and indicates potential opportunities for alternative strategies that can influence fracture resistance at longer-length scales.

  4. Structure of initial crystals formed during human amelogenesis

    NASA Astrophysics Data System (ADS)

    Cuisinier, F. J. G.; Voegel, J. C.; Yacaman, J.; Frank, R. M.

    1992-02-01

    X-ray diffraction analysis revealed only the existence of carbonated hydroxyapatite (c.HA) during amelogenesis, whereas conventional transmission electron microscopy investigations showed that developing enamel crystals have a ribbon-like habit. The described compositional changes could be an indication for the presence of minerals different from c.HA. However, the absence of identification of such a mineral shows the need of studies by high resolution electron microscopy (HREM) of initial formed human enamel crystals. We demonstrate the existence of two crystal families involved in the early stages of biomineralization: (a) nanometer-size particles which appeared as a precursor phase; (b) ribbon-like crystals, with a structure closely related to c.HA, which by a progressive thickening process tend to attain the mature enamel crystal habit.

  5. A rare combination of amniotic constriction band with osteogenesis imperfecta.

    PubMed

    Shah, Krupa Hitesh; Shah, Hitesh

    2015-11-11

    Amniotic constriction bands and osteogenesis imperfecta are disorders arising from a collagen defect. We report a rare association of amniotic bands with osteogenesis imperfecta in a child. The child was born with multiple amniotic bands involving the right leg, both hands and both feet. Multiple fractures of long bones of lower limbs occurred in childhood due to trivial trauma. Deformities of the femur and tibia due to malunion with osteopenia and blue sclerae were present. The patient was treated with z plasty of constriction band of the right tibia and bisphosphonate for osteogenesis imperfecta. This rare association of both collagen diseases may provide further insight for the pathogenesis of these diseases.

  6. Osteogenesis Imperfecta, Pseudoachalasia, and Gastric Cancer

    PubMed Central

    Mizrak, Dilsa; Alkan, Ali; Erdogdu, Batuhan; Utkan, Gungor

    2015-01-01

    Osteogenesis imperfecta (OI) is a rare, inherited skeletal disorder characterized by abnormalities of type 1 collagen. Malignancy is rarely reported in patients with OI and it was suggested that this disease can protect against cancer. Here, we report a 41-year-old woman with symptoms of achalasia where repeated treatment of pneumatic dilation and stent replacement was unsuccessful; therefore, surgery was performed. Pathology showed gastric adenocarcinoma unexpectedly. Chemotherapy was given after assessing dihydropyrimidine dehydrogenase (DPD) enzyme activity, which can be deficient in OI patients. This is the first report of gastric cancer mimicking achalasia in a patient with OI. PMID:25874139

  7. Basilar impression in osteogenesis imperfecta tarda. Case report.

    PubMed

    Kurimoto, M; Ohara, S; Takaku, A

    1991-01-01

    A case is presented of basilar impression secondary to osteogenesis imperfecta tarda, associated with hemifacial spasm and brain-stem compression syndrome. The symptoms improved with posterior fossa decompression and posterior fusion.

  8. How Do Health Care Providers Diagnose Osteogenesis Imperfecta?

    MedlinePlus

    ... Information Clinical Trials Resources and Publications How do health care providers diagnose osteogenesis imperfecta (OI)? Skip sharing on ... Page Content If OI is moderate or severe, health care providers usually diagnose it during prenatal ultrasound at ...

  9. Anesthesia for maxillary and mandibular osteotomies in osteogenesis imperfecta.

    PubMed Central

    Rodrigo, C.

    1995-01-01

    A 21-yr-old female suffering from osteogenesis imperfecta was anesthetized for correction of maxillary and mandibular deformities that had restricted her chewing. Preoperative assessment revealed a difficult intubation, restrictive lung disease secondary to bony deformities, and multiple repairs of fractures. Management of anesthesia for this operation--which is very rarely carried out in this disorder--is described along with a review of the problems of anesthesia associated with osteogenesis imperfecta. PMID:8934957

  10. The Specific Role of FAM20C in Amelogenesis

    PubMed Central

    Wang, X.; Jung, J.; Liu, Y.; Yuan, B.; Lu, Y.; Feng, J.Q.; Qin, C.

    2013-01-01

    Previously, we showed that Sox2-Cre;Fam20Cfl/fl mice in which Fam20C was ubiquitously inactivated had severe defects in dentin, enamel, and bone, along with hypophosphatemia. It remains to be determined if the enamel defects in the mice with universal inactivation of Family with sequence similarity 20-C (FAM20C) were associated with the dentin defects and whether hypophosphatemia in the knockout mice contributed to the enamel defects. In this study, we crossed Fam20Cfl/fl mice with keratin 14-Cre (K14-Cre) transgenic mice to specifically inactivate Fam20C in the epithelial cells, including the dental epithelial cells that are responsible for forming tooth enamel. X-ray, backscattered scanning electron microscopic, and histological analyses showed that the K14-Cre;Fam20Cfl/fl mice had severe enamel and ameloblast defects, while their dentin and alveolar bone were not significantly affected. Accordingly, serum biochemistry of the K14-Cre;Fam20Cfl/fl mice showed normal phosphate and FGF23 levels in the circulation. Analysis of these data indicates that, while FAM20C is a molecule essential to amelogenesis, its inactivation in the dental epithelium does not significantly affect dentinogenesis. Hypophosphatemia makes no significant contribution to the enamel defects in the mice with the ubiquitous deletion of Fam20C. PMID:24026952

  11. Single Molecule Effects of Osteogenesis Imperfecta Mutations in Tropocollagen Protein Domains

    DTIC Science & Technology

    2008-12-02

    associated symptoms, including short stature, loose joints, blue sclearae, dentinogenesis imperfecta , hearing loss , and neurological and pulmo- nary...Single molecule effects of osteogenesis imperfecta mutations in tropocollagen protein domains Alfonso Gautieri,1,2 Simone Vesentini,2 Alberto...2008 proteinscience.org Abstract: Osteogenesis imperfecta (OI) is a genetic disease characterized by fragile bones, skeletal deformities and, in severe

  12. [Orthotic management for patients with osteogenesis imperfecta].

    PubMed

    Alguacil Diego, I M; Molina Rueda, F; Gómez Conches, M

    2011-02-01

    Osteogenesis imperfecta (OI) is a disease caused by a genetic defect in the qualitative and quantitative synthesis of type I collagen. There is a wide variation in its clinical signs, characterized by bone fragility, resulting in a bone vulnerable to external and internal forces, determining the occurrence of frequent fractures with minimal or no trauma. The therapeutic objective is directed to improve the functional capacity of the child or adult concerned, adopting those compensatory strategies to optimise their independence. In this sense, the use of different orthoses and assistive technology are important for achieving these objectives. We reviewed the main contributions to this orthotic disease and the evolution of the different devices used in different databases over the last 25 years.

  13. Valvular and aortic diseases in osteogenesis imperfecta.

    PubMed

    Lamanna, Arvin; Fayers, Trevor; Clarke, Sophie; Parsonage, William

    2013-10-01

    Osteogenesis imperfecta (OI) is an inheritable connective tissue disorder caused by defective collagen synthesis with the principal manifestations of bone fragility. OI has been associated with left sided valvular regurgitation and aortic dilation. Valve and aortic surgery are technically feasible in patients with OI but are inherently high risk due to the underlying connective tissue defect. This report reviews the valvular and aortic pathology associated with OI and their management. We describe two cases of patients with OI who have significant aortic and mitral valve regurgitation, one of whom has been managed conservatively and the other who has undergone successful mitral valve repair and aortic valve replacement. The latter case represents the fifth case of mitral valve repair in a patient with OI reported in the medical literature.

  14. IFITM5 mutations and osteogenesis imperfecta.

    PubMed

    Hanagata, Nobutaka

    2016-03-01

    Interferon-induced transmembrane protein 5 (IFITM5) is an osteoblast-specific membrane protein that has been shown to be a positive regulatory factor for mineralization in vitro. However, Ifitm5 knockout mice do not exhibit serious bone abnormalities, and thus the function of IFITM5 in vivo remains unclear. Recently, a single point mutation (c.-14C>T) in the 5' untranslated region of IFITM5 was identified in patients with osteogenesis imperfecta type V (OI-V). Furthermore, a single point mutation (c.119C>T) in the coding region of IFITM5 was identified in OI patients with more severe symptoms than patients with OI-V. Although IFITM5 is not directly involved in the formation of bone in vivo, the reason why IFITM5 mutations cause OI remains a major mystery. In this review, the current state of knowledge of OI pathological mechanisms due to IFITM5 mutations will be reviewed.

  15. [Osteogenesis imperfecta: quality of life in children].

    PubMed

    Fano, Virginia; del Pino, Mariana; Rodríguez Celin, Mercedes; Buceta, Susana; Obregón, M Gabriela

    2013-01-01

    The impact produced by osteogenesis imperfecta in childrens' quality of life almost has not been reported; 65 children, 38 males, were evaluated according to the questionnaire PedsQL 4.0 Argentinean Spanish version. Median age was 7.76 years; 35 children with OI type I were compared with 30 type III-IV (according to Sillence Classification) finding significant difference in the physical domain in both visions, children and parents, and only in parents' vision in the social area. Multivariate analysis showed an association between better PedQL scores and treatment compliance (coef. β= 19.41 p= 0.03) in children's vision. In parental report on the other hand, the association was found with greater pamidronate doses (coef. β 1.44 p=0.037), lower height compromise (coef. β= 3.8; p= 0.039) and less number of fractures (coef. β= 0.69; p= 0.003).

  16. [Limb lengthening in children with osteogenesis imperfecta].

    PubMed

    Sułko, Jerzy; Radło, Wojciech

    2005-01-01

    The authors operated on 7 children (5 girls, 2 boys) suffering from osteogenesis imperfecta (oi) type I according to Sillence classification, with lower limbs discrepancy. We elongated 10 segments (7 femurs and 3 tibias). Mean age at operation time was 14.7 years (13-17 years). The mean leg length discrepancy was 9.3 cm (4-18 cm), and shortening of one bone was 6.5 cm (4-9 cm). We used Ilizarov technique twice in tibial lengthening. We used Wagner technique in one tibial elongation and in 7 femur elongation. Except for one tibia, in the remaining cases there was Rush rod inserted intramedullary in the bone being elongated. During tibial elongation we fixed lateral malleous by screw. The osteotomy was performed in proximal metaphysis of the 5 femurs and 3 tibias, and in distal femurs in two cases. The elongation was 1 mm for day, with frequency 4 x 1/4 mm. The mean bone lengthening achieved was 5.5 cm (2-9 cm); the mean lengthening of the limb was 7.9 cm (2-18 cm). The mean time of elongation was 2.8 months (2-5 months). Elongation index was 26 days for 1 cm of lengthening. The mean time of fixator removal was 9.2 months (4-13 months). Healing index was 58 day/1 cm (overall number of days for 1 cm lengthening). The complications occurred in all the patients. Although the risk of numerous complication is high, lower limbs lengthening in children with type I osteogeneis imperfecta is possible to perform and allows equalizing discrepant limbs or, at least reducing the difference.

  17. Basilar impression and platybasia in osteogenesis imperfecta tarda.

    PubMed

    Frank, E; Berger, T; Tew, J M

    1982-02-01

    Osteogenesis imperfecta, a rare, genetically transmitted disorder of bone, is known to be associated with the development of basilar impression and platybasia. These deformities of the base of the skull may cause neurosurgical abnormalities secondary to compression of the brainstem and hydrocephalus. The case is presented of a young boy with a family history of osteogenesis imperfecta tarda who suffered respiratory arrest during hospitalization. Cranial nerves and pyramidal tract signs were demonstrated. Roentgenograms showed severe basilar impression and hydrocephalus. Decompression of the brainstem and shunting were performed with improvement in the patient's neurological status. This case represents a rare by significant central nervous system complication of osteogenesis imperfecta. Early recognition and implementation of aggressive treatment are important if irreversible neurological deficits are to be avoided.

  18. Osteogenesis imperfecta: a case with hand deformities.

    PubMed

    Oz, Bengi; Olmez, Nese; Memis, Asuman

    2005-09-01

    In a 51-year-old woman with a history of fractures and dislocations after low intensity trauma in childhood, intensive blue sclera, short stature, and hearing loss, the diagnosis of osteogenesis imperfecta (OI) was suspected. She was referred to our clinic with hand deformities and left knee pain and stiffness. She had difficulty in walking and reported a history of immobilization for 6 months because of knee pain. She had bilateral flexion contracture of the elbows which occurred following dislocations of the elbows in childhood. She had Z deformity of the first phalanges, reducible swan-neck deformity of the third finger of the left and the second finger of the right hand, flexion contracture of the proximal interphalangeal joint of the fifth finger of the left hand, and syndactyly of the third and fourth fingers of the right hand. Flexion contractures of both knees were observed. Pes planus and short toes were the deformities of the feet. Acute phase reactants of the patient were normal. She had no history of arthritis or morning stiffness. Bone mineral density evaluated by dual-energy X-ray absorptiometry (DEXA) showed severe osteoporosis of the femur and lumbar vertebrae. She had radiographic evidence of healed fractures of the left fibula, the third metacarpal, and the fourth and fifth middle phalanges of the right hand. OI, affecting the type I collagen tissue of the sclera, skin, ligaments, and skeleton, presenting with ligament laxity resulting in subluxations and hand deformities may be misdiagnosed as hand deformities of rheumatoid arthritis.

  19. Skeletal muscle weakness in osteogeneis imperfecta mice

    PubMed Central

    Gentry, Bettina A; Ferreira, J. Andries; McCambridge, Amanda J.; Brown, Marybeth; Phillips, Charlotte L.

    2010-01-01

    Exercise intolerance, muscle fatigue and weakness are often-reported, little-investigated concerns of patients with osteogenesis imperfecta (OI). OI is a heritable connective tissue disorder hallmarked by bone fragility resulting primarily from dominant mutations in the proα1(I) or proα2(I) collagen genes and the recently discovered recessive mutations in post-translational modifying proteins of type I collagen. In this study we examined the soleus (S), plantaris (P), gastrocnemius (G), tibialis anterior (TA) and quadriceps (Q) muscles of mice expressing mild (+/oim) and moderately severe (oim/oim) OI for evidence of inherent muscle pathology. In particular, muscle weight, fiber cross-sectional area (CSA), fiber type, fiber histomorphology, fibrillar collagen content, absolute, relative and specific peak tetanic force (Po, Po/mg and Po/CSA respectively) of individual muscles were evaluated. Oim/oim mouse muscles were generally smaller, contained less fibrillar collagen, had decreased Po and an inability to sustain Po for the 300 ms testing duration for specific muscles; +/oim mice had a similar but milder skeletal muscle phenotype. +/oim mice had mild weakness of specific muscles but were less affected than their oim/oim counterparts which demonstrated readily apparent skeletal muscle pathology. Therefore muscle weakness in oim mice reflects inherent skeletal muscle pathology. PMID:20619344

  20. Dentinogenesis imperfecta: an early treatment strategy.

    PubMed

    Sapir, S; Shapira, J

    2001-01-01

    Dentinogenesis imperfecta (DI) type 2 is a disease inherited in a simple autosomal dominant mode. As soon as the teeth erupt the parents may notice the problem and look for a pediatric dentist's advice and treatment. Early diagnosis and treatment of DI is recommended, as it may prevent or intercept deterioration of the teeth and occlusion and improve esthetics. The purpose of this article is to present the objectives, treatment options, and problems encountered in the treatment of DI in the early primary dentition. A two-stage treatment of a toddler under general anesthesia is described and discussed. This paper recommends for severe cases of DI two treatment stages performed under general anesthesia. Stage 1 is early (around age 18-20 months) and is directed to covering the incisors with composite restorations and the first primary molars with preformed crowns. Stage 2 (around age 28-30 months) seeks to protect the second primary molars with preformed crowns and cover the canines with composite restorations.

  1. Intravenous pamidronate in osteogenesis imperfecta type VII.

    PubMed

    Cheung, Moira S; Glorieux, Francis H; Rauch, Frank

    2009-03-01

    Cyclical intravenous treatment with pamidronate is widely used to treat osteogenesis imperfecta (OI) types I, III, and IV, which are due to dominant mutations affecting collagen type I alpha chains. There is no information about the effects of pamidronate in children with OI type VII, an autosomal-recessive form of OI caused by a mutation in the cartilage-associated protein gene. In this retrospective single-center study, we compared the effects of pamidronate in four girls with OI type VII (age range 3.9-12.7 years) to those in eight girls with OI types caused by collagen type I mutations who were matched for age and disease severity. During 3 years of pamidronate therapy, lumbar spine areal bone mineral density increased and lumbar vertebral bodies improved in shape in patients with OI type VII. Other outcomes such as fracture rates and mobility scores did not show statistically significant changes in this small study cohort. There were no significant side effects noted during the time of follow-up. Thus, intravenous treatment with pamidronate seems to be safe and of some benefit in patients with OI type VII.

  2. Novel WDR72 Mutation and Cytoplasmic Localization

    PubMed Central

    Lee, S.-K.; Seymen, F.; Lee, K.-E.; Kang, H.-Y.; Yildirim, M.; Bahar Tuna, E.; Gencay, K.; Hwang, Y.-H.; Nam, K.H.; De La Garza, R.J.; Hu, J.C.-C.; Simmer, J.P.; Kim, J.-W.

    2010-01-01

    The proven candidate genes for amelogenesis imperfecta (AI) are AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72. We performed mutation analyses on seven families with hypomaturation AI. A novel WDR72 dinucleotide deletion mutation (g.57,426_57,427delAT; c.1467_ 1468delAT; p.V491fsX497) was identified in both alleles of probands from Mexico and Turkey. Haplotype analyses showed that the mutations arose independently in the two families. The disease perfectly segregated with the genotype. Only persons with both copies of the mutant allele were affected. Their hypomineralized enamel suffered attrition and orange-brown staining following eruption. Expression of WDR72 fused to green fluorescent protein showed a cytoplasmic localization exclusively and was absent from the nucleus. We conclude that WDR72 is a cytoplasmic protein that is critical for dental enamel formation. PMID:20938048

  3. Musculoskeletal manifestations of mild osteogenesis imperfecta in the adult.

    PubMed

    McKiernan, Fergus E

    2005-12-01

    The musculoskeletal manifestations of mild forms of osteogenesis imperfecta are not well defined in the adult. The aim of this study was to characterize the musculoskeletal manifestations and resulting impairments reported by adults with mild osteogenesis imperfecta. For this task a survey of musculoskeletal symptoms and impairments was hosted on the Osteogenesis Imperfecta Foundation web site for 6 weeks. Survey responses are reported herein. There were 111 unduplicated, adult respondents (78 female). Mean age was 40.8 years. More than one-quarter of 3,410 lifetime fractures occurred in adulthood. Nearly half of respondents reported an established diagnosis of "arthritis" (usually osteoarthritis), and the majority of these reported some degree of impairment attributable to arthritis. Articular pain, stiffness and instability were dominant in the large, weight-bearing joints of the lower extremities. Back pain and scoliosis were common. Of the respondents, 15% required assistance with light physical tasks and personal care. Two-thirds reported joint hyper-mobility, and one-third reported a previous tendon rupture. Complex regional pain syndrome was rare. Respondents reported frequent use of medications known to have potential adverse skeletal effects. In spite of these concerns the majority rated their overall physical health as good or excellent. Adults with mild osteogenesis imperfecta continue to sustain fractures into adulthood, and the majority reports some functional impairment due to musculoskeletal issues. Significant impairment is not rare.

  4. A type IV osteogenesis imperfecta family and pregnancy: a case report and literature review.

    PubMed

    Feng, Zhao-yi; Chen, Qian; Shi, Chun-yan; Wen, Hong-wu; Ma, Ke; Yang, Hui-xia

    2012-04-01

    Osteogenesis imperfecta is a group of inherited connective-tissue disorders in which synthesis or structure of type I collagen is defective and causes osseous fragility. Type IV osteogenesis imperfecta is dominant inheritance. Here, we report a case of type IV osteogenesis imperfecta family and their female member's pregnancy. Abnormal sonographic findings (marked bowing and shortening of long bones) and family history made the diagnosis of fetus with osteogenesis imperfecta. The parents decided to give up rescuing the infant and a caesarean section at 27 weeks of gestation was implemented. In conclusion, it is possible to make a prenatal diagnosis of osteogenesis imperfecta by ultrasound. For the pregnant women with osteogenesis imperfecta, management decision should be made on an individual basis.

  5. A Guide to Education for Children with Osteogenesis Imperfecta. What Is OIF? Care of an Osteogenesis Imperfecta Baby and Child.

    ERIC Educational Resources Information Center

    Ostegenesis Imperfecta Foundation, Inc., Manchester, NH.

    Three pamphlets provide basic information on the care and education of children with osteogenesis imperfecta (OI) a lifelong liability to fractures due to imperfectly formed "brittle bones." The first brochure, a guide to education for children with OI, addresses the importance of attitudes, the value of early education, public school…

  6. Children with Osteogenesis Imperfecta and Their Life Situation. Report and Documentation.

    ERIC Educational Resources Information Center

    Brodin, Jane

    Children with osteogenesis imperfecta form a small and relatively unknown group, with 5 to 10 children diagnosed in Sweden each year and a total of around 200 people under the age of 17 having the condition. A questionnaire was completed by families of 24 Swedish children with osteogenesis imperfecta, and three families were interviewed. The…

  7. Intravenous pamidronate treatment of infants with severe osteogenesis imperfecta

    PubMed Central

    Åström, Eva; Jorulf, Håkan; Söderhäll, Stefan

    2007-01-01

    Objective Children with the severe forms of osteogenesis imperfecta have in several studies been treated with intravenous pamidronate, but there are only few reports of the effect of early treatment. Aim To evaluate the effect of treatment started in infancy. Methods In a prospective observational study, with a historic control group, intravenous disodium pamidronate (APD) was given as monthly infusions to 11 children with osteogenesis imperfecta aged 3–13 (median 3.6) months, who had severe osteogenesis imperfecta with congenital bowing of the femora and vertebral compression fractures. Results During treatment of children aged between 3 and 6 (median 4.5) years, dual‐energy x ray absorptiometry measurements of the lumbar spine showed a gradual increase in bone density. Bone metabolism parameters in serum (alkaline phosphatase, osteocalcin, procollagen 1 carboxy‐terminal peptide, collagen 1 teleopeptide) and in urine (deoxypyridinoline) indicated a decrease in bone turnover. An improvement of mobility was seen and at the latest recording, at the age of 3.3–6.5 (median 4.8) years, the children could all walk. Vertebral remodelling was seen, with increased vertebral height, and no child developed scoliosis, kyphosis or basilar impression. All children required femoral intramedullar rods for fractures, and five needed tibial rodding for extreme curvatures that prevented functional standing and walking. No adverse effects were seen on growth, fracture healing or blood chemistry. Conclusions APD is an efficient symptomatic treatment for infants with severe osteogenesis imperfecta, but additional orthopaedic surgery is often needed. Early treatment may prevent scoliosis and basilar impression. Long‐term follow‐up is important. PMID:17114205

  8. Osteogenesis imperfecta type I with unusual dental abnormalities.

    PubMed

    Levin, L S; Young, R J; Pyeritz, R E

    1988-12-01

    A large kindred with dominantly inherited osteogenesis imperfecta was evaluated. Affected individuals had bone fractures, blue sclerae, and hearing loss. In addition, all had dental abnormalities distinct from those previously described in other families with this syndrome. Deciduous teeth were normal in color or blue-grey. On radiographs of an early developing deciduous dentition, pulps were larger than normal. In patients with mixed dentitions, pulp chambers of deciduous teeth were partially obliterated. Increased constriction at the junctions of the crowns and roots was found in some deciduous teeth. One patient had large pulp stones in the pulp chambers of all maxillary deciduous molars. Permanent teeth were normal in color but had oval pulp chambers with apical extensions into the coronal portions of the roots, large coronal pulp stones, narrow root canals, and thin roots. Individuals in this family who did not have osteogenesis imperfecta had normal teeth. In addition, a well circumscribed radiolucency without a sclerotic periphery, involving the apices of all permanent mandibular incisors, was found in the anterior mandible in one patient. These findings support the hypothesis that this family has yet another type I osteogenesis imperfecta "syndrome".

  9. Basilar impression in osteogenesis imperfecta. A report of three cases in one family.

    PubMed

    Pozo, J L; Crockard, H A; Ransford, A O

    1984-03-01

    Basilar impression is a well-recognised though rare complication of osteogenesis imperfecta. Three patients, all members of the same family, with advanced basilar impression complicating osteogenesis imperfecta tarda, are described. The clinical features in these cases illustrate the natural history of this condition: from asymptomatic ventricular dilatation, through the foramen magnum compression syndrome, to death from brain-stem compression. The radiological criteria on which the diagnosis is based, are defined. Review of the literature reveals only seven previously documented cases, all in patients with mild forms of osteogenesis imperfecta. The unusually low incidence of basilar impression in osteogenesis imperfecta and its apparent restriction to patients with mild forms of the disease is discussed. The examination of close relatives of patients with basilar impression and osteogenesis imperfecta is emphasised in order to anticipate the onset of severe neurological complications.

  10. Expression of Steroid Receptors in Ameloblasts during Amelogenesis in Rat Incisors

    PubMed Central

    Houari, Sophia; Loiodice, Sophia; Jedeon, Katia; Berdal, Ariane; Babajko, Sylvie

    2016-01-01

    Endocrine disrupting chemicals (EDCs) play a part in the modern burst of diseases and interfere with the steroid hormone axis. Bisphenol A (BPA), one of the most active and widely used EDCs, affects ameloblast functions, leading to an enamel hypomineralization pattern similar to that of Molar Incisor Hypomineralization (MIH). In order to explore the molecular pathways stimulated by BPA during amelogenesis, we thoroughly investigated the receptors known to directly or indirectly mediate the effects of BPA. The expression patterns of high affinity BPA receptors (ERRγ, GPR30), of ketosteroid receptors (ERs, AR, PGR, GR, MR), of the retinoid receptor RXRα, and PPARγ were established using RT-qPCR analysis of RNAs extracted from microdissected enamel organ of adult rats. Their expression was dependent on the stage of ameloblast differentiation, except that of ERβ and PPARγ which remained undetectable. An additional large scale microarray analysis revealed three main groups of receptors according to their level of expression in maturation-stage ameloblasts. The expression level of RXRα was the highest, similar to the vitamin D receptor (VDR), whereas the others were 13 to 612-fold lower, with AR and GR being intermediate. Immunofluorescent analysis of VDR, ERα and AR confirmed their presence mainly in maturation- stage ameloblasts. These data provide further evidence that ameloblasts express a specific combination of hormonal receptors depending on their developmental stage. This study represents the first step toward understanding dental endocrinology as well as some of the effects of EDCs on the pathophysiology of amelogenesis. PMID:27853434

  11. Osteogenesis imperfecta due to compound heterozygosity for the LEPRE1 gene.

    PubMed

    Moul, Adrienne; Alladin, Amanda; Navarrete, Cristina; Abdenour, George; Rodriguez, Maria M

    2013-10-01

    Osteogenesis imperfecta is a rare connective tissue disorder characterized by bone fragility and low bone density. Most cases are caused by an autosomal dominant mutation in either COL1A1 or COL1A2 gene encoding type I collagen. However, autosomal recessive forms have been identified. We present a patient with severe respiratory distress due to osteogenesis imperfecta simulating type II, born to a non-consanguineous couple with mixed African-American and African-Hispanic ethnicity. Cultured skin fibroblasts demonstrated compound heterozygosity for mutations in the LEPRE1 gene encoding prolyl 3-hydroxylase 1 confirming the diagnosis of autosomal recessive osteogenesis imperfecta type VIII, perinatal lethal type.

  12. Basilar impression complicating osteogenesis imperfecta type IV: the clinical and neuroradiological findings in four cases

    PubMed Central

    Hayes, M; Parker, G; Ell, J; Sillence, D

    1999-01-01

    OBJECTIVES—To describe the clinical and neuroradiological features of basilar impression in patients with osteogenesis imperfecta type IV.
METHODS—Four patients with basilar impression were ascertained in a population study of osteogenesis imperfecta. All four had detailed clinical and neuroradiological examination with both CT and MRI of the craniocervical junction andposterior fossa structures.
RESULTS—All four showed significant compression of the posterior fossa structures and surgical decompression was performed with relief of symptoms.
CONCLUSION—Symptoms of cough headache and trigeminal neuralgia occurring in patients with osteogenesis imperfecta are indications for detailed clinical and neuroradiological investigation to document basilar impression.

 PMID:10084535

  13. Osteogenesis Imperfecta: A Case Report and Review of Literature

    PubMed Central

    Edelu, BO; Ndu, IK; Asinobi, IN; Obu, HA; Adimora, GN

    2014-01-01

    Osteogenesis imperfecta (OI) is a group of rare inherited disorders of connective tissue with the common feature of excessive fragility of bones caused by mutations in collagen. Diagnosis is mainly based on the clinical features of the disorder. We report, the case of a male neonate delivered to a 33-year-old para 2 female at University of Nigeria Teaching Hospital, Enugu with no family history suggestive of OI. He had clinical features of a type II OI and severe birth asphyxia. Multidisciplinary management was instituted, but he died on the 7th day of life. PMID:25031897

  14. Genotype-Phenotype Correlations in Autosomal Dominant Osteogenesis Imperfecta

    PubMed Central

    Ben Amor, I. Mouna; Glorieux, Francis H.; Rauch, Frank

    2011-01-01

    Osteogenesis imperfecta, discussed in Baldridge et al. 2008 is an inherited bone fragility disorder with a wide range of clinical severity that in the majority of cases is caused by mutations in COL1A1 or COL1A2, the genes that encode the two collagen type I alpha chains. Here we describe genotype-phenotype correlations in OI patients who have mutations affecting collagen type I. This paper is based on findings in a large single-centre OI population and a review of the literature. PMID:21912751

  15. The operative management of basilar impression in osteogenesis imperfecta.

    PubMed

    Harkey, H L; Crockard, H A; Stevens, J M; Smith, R; Ransford, A O

    1990-11-01

    Four patients with osteogenesis imperfecta and neurologically significant basilar impression have been treated over the past 8 years. The experience has resulted in changes in our therapeutic strategy for this particularly difficult problem. These cases are discussed with respect to the disease process, neurological involvement, radiological findings, and modes of surgical therapy. The errors in management as well as the success resulting from our learning experience are described. Currently, we recommend the extensive removal of the anterior bony compression by a transoral approach. This should be followed by a posterior rigid fixation that transfers the weight of the head to the thoracic spine, in an effort to prevent further basilar invagination.

  16. Adhesive Restorations as An Esthetic Solution in Dentinogenesis Imperfecta.

    PubMed

    Ubaldini, Adriana Lemos Mori; Giorgi, Maria Cecília Caldas; Carvalho, Ariany Borges; Pascon, Fernanda Miori; Lima, Débora Alves Nunes Leite; Baron, Gisele Maria Marchi; Paulillo, Luís Alexandre Maffei Sartini; Aguiar, Flávio Henrique Baggio

    2015-01-01

    Loss of tooth structure is the main sequela of dentinogenesis imperfecta (DI). Due to severe enamel attrition, patients with DI often present with esthetic, occlusal, endodontic, and speech complications. Therefore, an interdisciplinary approach, divided into separate clinical steps, should be developed to provide comprehensive dental rehabilitation. The purpose of this case report is to discuss the use of composite resin restorations as a transitional treatment step for the anterior teeth of an eight-year-old boy with DI until his bone and dental development permit orthodontic and orthognatic surgery.

  17. Perinatal lethal type II osteogenesis imperfecta: a case report.

    PubMed

    Ayadi, Imene Dahmane; Hamida, Emira Ben; Rebeh, Rania Ben; Chaouachi, Sihem; Marrakchi, Zahra

    2015-01-01

    We report a new case of osteogenesis imperfecta (OI) type II which is a perinatal lethal form. First trimester ultrasound didn't identified abnormalities. Second trimester ultrasound showed incurved limbs, narrow chest, with hypomineralization and multiple fractures of ribs and long bones. Parents refused pregnancy termination; they felt that the diagnosis was late. At birth, the newborn presented immediate respiratory distress. Postnatal examination and bone radiography confirmed the diagnosis of OI type IIA. Death occurred on day 25 of life related to respiratory failure.

  18. Clinical perspectives on osteogenesis imperfecta versus non-accidental injury.

    PubMed

    Pereira, Elaine Maria

    2015-12-01

    Although non-accidental injuries (NAI) are more common in cases of unexplained fractures than rare disorders such as osteogenesis imperfecta (OI), ruling out OI and other medical causes of fracture is always indicated. The majority of OI patients can be diagnosed with the help of family history, physical examination, and radiographic findings. In particular, there are a few radiological findings which are seen more commonly in NAI than in OI which may help guide clinician considerations regarding the probability of either of these diagnoses. At the same time, molecular testing still merits careful consideration in cases with unexplained fractures without obvious additional signs of abuse.

  19. Update on the evaluation and treatment of osteogenesis imperfecta.

    PubMed

    Harrington, Jennifer; Sochett, Etienne; Howard, Andrew

    2014-12-01

    Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that presents with a wide clinical phenotype spectrum: from perinatal lethality and severe deformities to very mild forms without fractures. Most cases of OI are due to autosomal dominant mutations of the type I collagen genes. A multidisciplinary approach with rehabilitation, orthopedic surgery, and consideration of medical therapy with bisphosphonates underpins current management. Greater understanding of the pathogenesis of OI may lead to novel, therapeutic approaches to help improve clinical symptoms of children with OI in the future.

  20. [PREPARATIONS OF PAMIDRONOVIC ACID IN COMPLEX TREATMENT ON OSTEOGENESIS IMPERFECTA].

    PubMed

    Zyma, A M; Guk, Yu M; Magomedov, O M; Gayko, O G; Kincha-Polishchuk, T A

    2015-07-01

    Modern view of drug therapy in the complex treatment of orthopedic manifestations of osteogenesis imperfecta (OI) was submitted. Developed and tested system of drug correction of structural and functional state of bone tissue (BT) using drugs pamidronovic acid, depending on osteoporosis severity and type of disease. Such therapy is appropriate to apply both independently and in conjunction with surgery to correct deformations of long bones of the lower extremities. Effectiveness and feasibility of the proposed methods of drug therapy was proved, most patients resume features walking and support.

  1. Basilar impression and osteogenesis imperfecta in a three-year-old girl: CT and MRI.

    PubMed

    Rush, P J; Berbrayer, D; Reilly, B J

    1989-01-01

    A 3-year-old girl with osteogenesis imperfecta developed symptomatic basilar impression. Her neurological symptoms were treated by foramen magnum decompression and laminectomy. This is an unusually young patient to have this condition.

  2. Osteogenesis imperfecta types I-XI: implications for the neonatal nurse.

    PubMed

    Womack, Jody

    2014-10-01

    Osteogenesis imperfecta (OI), also called "brittle bone disease," is a rare heterozygous connective tissue disorder that is caused by mutations of genes that affect collagen. Osteogenesis imperfecta is characterized by decreased bone mass, bone fragility, and skin hyperlaxity. The phenotype present is determined according to the mutation on the affected gene as well as the type and location of the mutation. Osteogenesis imperfecta is neither preventable nor treatable. Osteogenesis imperfecta is classified into 11 types to date, on the basis of their clinical symptoms and genetic components. This article discusses the definition of the disease, the classifications on the basis of its clinical features, incidence, etiology, and pathogenesis. In addition, phenotype, natural history, diagnosis and management of this disease, recurrence risk, and, most importantly, the implications for the neonatal nurse and management for the family are discussed.

  3. Hearing Loss in Osteogenesis Imperfecta: Characteristics and Treatment Considerations

    PubMed Central

    Pillion, Joseph P.; Vernick, David; Shapiro, Jay

    2011-01-01

    Osteogenesis imperfecta (OI) is the most common heritable disorder of connective tissue. It is associated with fractures following relatively minor injury, blue sclerae, dentinogenesis imperfecta, increased joint mobility, short stature, and hearing loss. Structures in the otic capsule and inner ear share in the histologic features common to other skeletal tissues. OI is due to mutations involving several genes, the most commonly involved are the COL1A1 or COL1A2 genes which are responsible for the synthesis of the proalpha-1 and proalpha-2 polypeptide chains that form the type I collagen triple helix. A genotype/phenotype relationship to hearing loss has not been established in OI. Hearing loss is commonly found in OI with prevalence rates ranging from 50 to 92% in some studies. Hearing loss in OI may be conductive, mixed, or sensorineural and is more common by the second or third decade. Treatment options such as hearing aids, stapes surgery, and cochlear implants are discussed. PMID:22567374

  4. Advances in the Classification and Treatment of Osteogenesis Imperfecta.

    PubMed

    Thomas, Inas H; DiMeglio, Linda A

    2016-02-01

    Osteogenesis imperfecta (OI) is a rare disorder of type 1 collagen with 13 currently identified types attributable to inherited abnormalities in type 1 collagen amount, structure, or processing. The disease is characterized by an increased susceptibility to bony fracture. In addition to the skeletal phenotype, common additional extraskeletal manifestations include blue sclerae, dentinogenesis imperfecta, vascular fragility, and hearing loss. Medical management is focused on minimizing the morbidity of fractures, pain, and bone deformities by maximizing bone health. Along with optimizing Vitamin D status and calcium intake and physical/occupational therapy, individualized surgical treatment may be indicated. Pharmacological therapy with bisphosphonate medications is now routinely utilized for moderate to severe forms and appears to have a good safety profile and bone health benefits. New therapies with other anti-resorptives as well as anabolic agents and transforming growth factor (TGF)β antibodies are in development. Other potential treatment modalities could include gene therapy or mesenchymal cell transplant. In the future, treatment choices will be further individualized in order to reduce disease morbidity and mortality.

  5. Orthopaedic Considerations for the Adult With Osteogenesis Imperfecta.

    PubMed

    Roberts, Timothy T; Cepela, Daniel J; Uhl, Richard L; Lozman, Jeffery

    2016-05-01

    Osteogenesis imperfecta is a heritable group of collagen-related disorders that affects up to 50,000 people in the United States. Although the disease is most symptomatic in childhood, adults with osteogenesis imperfecta also are affected by the sequelae of the disease. Orthopaedic manifestations include posttraumatic and accelerated degenerative joint disease, kyphoscoliosis, and spondylolisthesis. Other manifestations of abnormal collagen include brittle dentition, hearing loss, cardiac valve abnormalities, and basilar invagination. In general, nonsurgical treatment is preferred for management of acute fractures. High rates of malunion, nonunion, and subsequent deformity have been reported with both closed and open treatment. When surgery is necessary, surgeons should opt for load-sharing intramedullary devices that span the entire length of the bone; locking plates and excessively rigid fixation generally should be avoided. Arthroplasty may be considered for active patients, but the procedure frequently is associated with complications in this patient population. Underlying deformities, such as malunion, bowing, rotational malalignment, coxa vara, and acetabular protrusio, pose specific surgical challenges and underscore the importance of preoperative planning.

  6. Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V

    PubMed Central

    Brizola, Evelise; Mattos, Eduardo P.; Ferrari, Jessica; Freire, Patricia O.A.; Germer, Raquel; Llerena Jr, Juan C.; Félix, Têmis M.

    2015-01-01

    Osteogenesis imperfecta type V (OI-V) has a wide clinical variability, with distinct clinical/radiological features, such as calcification of the interosseous membrane (CIM) between the radius-ulna and/or tibia-fibula, hyperplastic callus (HPC) formation, dislocation of the radial head (DRH), and absence of dentinogenesis imperfecta (DI). Recently, a single heterozygous mutation (c.-14C>T) in the 5′UTR of the IFITM5 gene was identified to be causative for OI-V. Here, we describe 7 individuals from 5 unrelated families that carry the c.-14C>T IFITM5 mutation. The clinical findings in these cases are: absence of DI in all patients, presence of blue sclera in 2 cases, and 4 patients with DRH. Radiographic findings revealed HPC in 3 cases. All patients presented CIM between the radius and ulna, while 4 patients presented additional CIM between the tibia and fibula. Spinal fractures by vertebral compression were observed in all individuals. The proportion of cases identified with this mutation represents 4% of OI cases at our institution. The clinical identification of OI-V is crucial, as this mutation has an autosomal dominant inheritance with variable expressivity. PMID:26648832

  7. Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V.

    PubMed

    Brizola, Evelise; Mattos, Eduardo P; Ferrari, Jessica; Freire, Patricia O A; Germer, Raquel; Llerena, Juan C; Félix, Têmis M

    2015-10-01

    Osteogenesis imperfecta type V (OI-V) has a wide clinical variability, with distinct clinical/radiological features, such as calcification of the interosseous membrane (CIM) between the radius-ulna and/or tibia-fibula, hyperplastic callus (HPC) formation, dislocation of the radial head (DRH), and absence of dentinogenesis imperfecta (DI). Recently, a single heterozygous mutation (c.-14C>T) in the 5'UTR of the IFITM5 gene was identified to be causative for OI-V. Here, we describe 7 individuals from 5 unrelated families that carry the c.-14C>T IFITM5 mutation. The clinical findings in these cases are: absence of DI in all patients, presence of blue sclera in 2 cases, and 4 patients with DRH. Radiographic findings revealed HPC in 3 cases. All patients presented CIM between the radius and ulna, while 4 patients presented additional CIM between the tibia and fibula. Spinal fractures by vertebral compression were observed in all individuals. The proportion of cases identified with this mutation represents 4% of OI cases at our institution. The clinical identification of OI-V is crucial, as this mutation has an autosomal dominant inheritance with variable expressivity.

  8. End-stage posttraumatic osteoarthritis treated with THA in osteogenesis imperfecta.

    PubMed

    Chaus, George W; Heare, Travis

    2012-06-01

    Osteogenesis imperfecta is an incurable genetic disorder manifested with altered bone quality that predisposes patients to a multitude of fractures throughout their lives, including acetabular fractures. The management of acetabular fractures in patients with osteogenesis imperfecta remains a challenging clinical problem, with a paucity of literature supporting treatments and their outcomes. Limited reports in the literature validate the use of total hip arthroplasty (THA) in patients with osteogenesis imperfecta, and they describe the adult population only.This article describes a case of delayed diagnosis of a transverse acetabular fracture and femoral head impaction fracture that led to posttraumatic end-stage hip osteoarthritis in a 16-year-old boy with osteogenesis imperfecta (Sillence Type I) that was sustained after minimal trauma. Clinical examination 3 months postinjury revealed a significant pelvic obliquity, severe pain with hip range of motion, and limited hip range of motion. Imaging studies revealed a complete loss of articular cartilage and significant joint effusion.The patient underwent THA. No postoperative complications occurred. Two-year follow-up showed an excellent clinical result. The patient's hip was pain free, and he was able to walk with no limp.The authors are unaware of any reported cases of children with osteogenesis imperfecta undergoing THA. Based on the reported literature and the authors' experience, THA can be a reliable surgical option for patients with osteogenesis imperfecta.

  9. Androgen Receptor Involvement in Rat Amelogenesis: An Additional Way for Endocrine-Disrupting Chemicals to Affect Enamel Synthesis.

    PubMed

    Jedeon, Katia; Loiodice, Sophia; Salhi, Khaled; Le Normand, Manon; Houari, Sophia; Chaloyard, Jessica; Berdal, Ariane; Babajko, Sylvie

    2016-11-01

    Endocrine-disrupting chemicals (EDCs) that interfere with the steroid axis can affect amelogenesis, leading to enamel hypomineralization similar to that of molar incisor hypomineralization, a recently described enamel disease. We investigated the sex steroid receptors that may mediate the effects of EDCs during rat amelogenesis. The expression of androgen receptor (AR), estrogen receptor (ER)-α, and progesterone receptor was dependent on the stage of ameloblast differentiation, whereas ERβ remained undetectable. AR was the only receptor selectively expressed in ameloblasts involved in final enamel mineralization. AR nuclear translocation and induction of androgen-responsive element-containing promoter activity upon T treatment, demonstrated ameloblast responsiveness to androgens. T regulated the expression of genes involved in enamel mineralization such as KLK4, amelotin, SLC26A4, and SLC5A8 but not the expression of genes encoding matrix proteins, which determine enamel thickness. Vinclozolin and to a lesser extent bisphenol A, two antiandrogenic EDCs that cause enamel defects, counteracted the actions of T. In conclusion, we show, for the first time, the following: 1) ameloblasts express AR; 2) the androgen signaling pathway is involved in the enamel mineralization process; and 3) EDCs with antiandrogenic effects inhibit AR activity and preferentially affect amelogenesis in male rats. Their action, through the AR pathway, may specifically and irreversibly affect enamel, potentially leading to the use of dental defects as a biomarker of exposure to environmental pollutants. These results are consistent with the steroid hormones affecting ameloblasts, raising the issue of the hormonal influence on amelogenesis and possible sexual dimorphism in enamel quality.

  10. The Small Alternatively Spliced Amelogenin LRAP Modulates Early Stage Ameloblast Differentiation

    DTIC Science & Technology

    2014-01-30

    matrix (Gibson et al., 2001). This phenotype is similar to some tooth phenotypes found in humans from families with X-linked amelogenesis imperfecta ...deficient mice display an amelogenesis imperfecta phenotype. J Biol Chem 276, 31871-31875. Gibson, C.W., Yuan, Z.A., Li, Y., Daly, B., Suggs, C., Aragon...Y.H., Al Hazzazzi, T., and Simmer, J.P. (2007). Enamel formation and amelogenesis imperfecta . Cells Tissues Organs 186, 78-85. 42 Huang, Y

  11. Prenatal transplantation of mesenchymal stem cells to treat osteogenesis imperfecta

    PubMed Central

    Chan, Jerry K. Y.; Götherström, Cecilia

    2014-01-01

    Osteogenesis imperfecta (OI) can be a severe disorder that can be diagnosed before birth. Transplantation of mesenchymal stem cells (MSC) has the potential to improve the bone structure, growth, and fracture healing. In this review, we give an introduction to OI and MSC, and the basis for pre- and postnatal transplantation in OI. We also summarize the two patients with OI who have received pre- and postnatal transplantation of MSC. The findings suggest that prenatal transplantation of allogeneic MSC in OI is safe. The cell therapy is of likely clinical benefit with improved linear growth, mobility, and reduced fracture incidence. Unfortunately, the effect is transient. For this reason, postnatal booster infusions using same-donor MSC have been performed with clinical benefit, and without any adverse events. So far there is limited experience in this specific field and proper studies are required to accurately conclude on clinical benefits of MSC transplantation to treat OI. PMID:25346689

  12. Fatal intraoperative hemorrhage during spinal fusion surgery for osteogenesis imperfecta.

    PubMed

    Sperry, K

    1989-03-01

    Osteogenesis imperfecta (OI) is an uncommon inherited systemic disorder of the connective tissues characterized primarily by varying degrees of bony fragility. Consequently, individuals affected by this condition frequently suffer severe skeletal injuries from otherwise innocuous traumatic events. This syndrome has other associated abnormalities, including hydrocephalus and brain stem compression on the basis of cranial developmental defects (platybasia), cardiac and vascular problems, respiratory disease from spinal deformities, vascular fragility, a bleeding disorder caused by an apparent platelet function abnormality, and anesthesia-related hyperpyrexia. A case is presented here of a young girl with advanced OI in whom intraoperative death occurred as a consequence of inadvertent rib fractures, with subsequent uncontrollable hemorrhage. OI may also potentially be mistaken for child abuse by an inexperienced examiner.

  13. Impact of three genetic musculoskeletal diseases: a comparative synthesis of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta.

    PubMed

    Dogba, Maman Joyce; Rauch, Frank; Douglas, Erin; Bedos, Christophe

    2014-10-25

    Achondroplasia, Duchenne muscular dystrophy, and osteogenesis imperfecta are among the most frequent rare genetic disorders affecting the musculoskeletal system in children. Rare genetic disorders are severely disabling and can have substantial impacts on families, children, and on healthcare systems. This literature review aims to classify, summarize and compare these non-medical impacts of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta.

  14. Respiratory failure during infusion of pamidronate in a 3 year-old male with osteogenesis imperfecta: a case report.

    PubMed

    Olson, Jennifer Ann

    2014-01-01

    Bisphosphonates are being used more frequently as part of the multi-disciplinary management of moderate to severe Osteogenesis Imperfecta (OI). This report details the development of respiratory failure during the second infusion of pamidronate in a 3.5 year-old male with osteogenesis imperfecta type 1 and no prior history of respiratory disease.

  15. [Postoperative radiation therapy for a patient with osteogenesis imperfecta: case report].

    PubMed

    Ducournau, A; Lagarde, P; Henriques de Figueiredo, B; Antoine, M; Breton-Callu, C; Petit, A; Dallaudière, B; Sargos, P

    2014-03-01

    Osteogenesis imperfecta is an unusual disease also called Lobstein disease. Characterized by abnormalities of collagen biosynthesis, a possible mutation on 17th chromosome is described. On the other hand, 29% of breast cancers present a mutation on the same chromosome. Nevertheless, the association of osteogenesis imperfecta and breast cancer is at the moment unknown. Therapeutic management is very difficult because of a loss in dihydropyrimidine dehydrogenase for patients having osteogenesis imperfecta, generating some toxicity by default in catabolism of 5-fluorouracil. We report the case of a 49-year-old woman with a breast cancer in the context of osteogenesis imperfecta. Dosimetric considerations permitting to reduce chess dose level have been performed for this patient. With a follow-up of 6 months, no imaging fracture has been revealed after radiotherapy. No evident conclusion about radiation injury from a case report could be described in case of osteogenesis imperfecta. To our knowledge, this is the first case which take into account potential radiation induced toxicities.

  16. Anatomic and dynamic aspects of stomatognathic structures in osteogenesis imperfecta: a case report.

    PubMed

    Ortega, Adriana de Oliveira L; Rosa, Vera L M; Zwir, Liete M L Figueiredo; Ciamponi, Ana L; Guimarães, Antonio S; Alonso, Luis G

    2007-04-01

    The osteogenesis imperfecta congenita (OMIM 166210) type II phenotype can be caused by mutation in either the COL1A1 gene or the COL1A2 gene that encode the chains of type I procollagen, the major protein in bones. Patients can therefore present a combination of features, including multiple long bone fractures and deformities, growth deficiency, joint laxity, hearing loss, blue sclera, and dentinogenesis imperfecta. The purpose of this study is to describe a clinical case of this syndrome, focusing on the anatomy of the temporomandibular joint (TMJ) that was assessed using computed tomography (CT) method. Clinical examination included evaluation of mandibular dynamics and investigation of temporomandibular dysfunction (TMD).

  17. Osteogenesis imperfecta associated with basilar impression and cerebral atrophy: a case report.

    PubMed

    Brooks, M L; Gall, C; Wang, A M; Schick, R; Rumbaugh, C L

    1989-01-01

    Osteogenesis imperfecta is a disease of bone formation subdivided into two types, congenita and tarda. It is associated with bony fragility, blue sclerae and abnormality of tooth dentin. Rarely the tarda form is associated with basilar invagination or infolding of the foramen magnum and upper cervical segments into the posterior fossa. This results in hydrocephalus and a spectrum of neurologic dysfunction known as the foramen magnum compression syndrome. Many radiologic methods have been used to evaluate basilar invagination including plain film and CT. We describe a patient with osteogenesis imperfecta tarda examined with CT, with a unique finding of diffuse cerebral atrophy associated with basilar invagination.

  18. Successful operative rib fixation of traumatic flail chest in a patient with osteogenesis imperfecta.

    PubMed

    Kulaylat, Afif N; Chesnut, Charles H; Santos, Ariel P; Armen, Scott B

    2014-09-01

    Increasing attention has been directed towards operative rib fixation of traumatic flail chest; reported benefits include more rapid weaning from the ventilator, decreased intensive care unit stays, decreased complications and improved functional results. The outcomes of this surgical intervention in patients with osteogenesis imperfecta, a rare condition characterized by low bone density and bone fragility, are unknown. This case demonstrates that, in the management of traumatic flail chest in a patient with osteogenesis imperfecta, surgical fixation can be successful and should be considered early.

  19. Current and emerging treatments for the management of osteogenesis imperfecta

    PubMed Central

    Monti, Elena; Mottes, Monica; Fraschini, Paolo; Brunelli, PierCarlo; Forlino, Antonella; Venturi, Giacomo; Doro, Francesco; Perlini, Silvia; Cavarzere, Paolo; Antoniazzi, Franco

    2010-01-01

    Osteogenesis imperfecta (OI) is the most common bone genetic disorder and it is characterized by bone brittleness and various degrees of growth disorder. Clinical severity varies widely; nowadays eight types are distinguished and two new forms have been recently described although not yet classified. The approach to such a variable and heterogeneous disease should be global and therefore multidisciplinary. For simplicity, the objectives of treatment can be reduced to three typical situations: the lethal perinatal form (type II), in which the problem is survival at birth; the severe and moderate forms (types III–IX), in which the objective is ‘autonomy’; and the mild form (type I), in which the aim is to reach ‘normal life’. Three types of treatment are available: non-surgical management (physical therapy, rehabilitation, bracing and splinting), surgical management (intramedullary rod positioning, spinal and basilar impression surgery) and medical-pharmacological management (drugs to increase the strength of bone and decrease the number of fractures as bisphosphonates or growth hormone, depending on the type of OI). Suggestions and guidelines for a therapeutic approach are indicated and updated with the most recent findings in OI diagnosis and treatment. PMID:20856683

  20. An unusual presentation of osteogenesis imperfecta type I

    PubMed Central

    Rebelo, Marta; Lima, Jandira; Vieira, José Diniz; Costa, José Nascimento

    2011-01-01

    Osteogenesis imperfecta (OI) is a rare inherited disorder with a broad spectrum of clinical and genetic variability. The genetic diversity involves, in the majority of the cases, mutations in one of the genes that encodes the type 1 collagen protein (COL1 A1 and COL1 A2), but it is not a requirement for the diagnosis. The most benign form is OI type I. The authors present a case report of a 25-year-old woman who had severe low back pain associated with incapacity to walk and breast-feed post-partum. Symptoms developed 2 weeks after delivery. The radiological examination revealed severe osteoporosis with no abnormalities in the laboratory findings. The clinical signs and a positive personal and family history of multiple fractures in childhood suggested OI type I, although other diagnosis, such as pregnancy-associated osteoporosis, was also considered. The atypical presentation of this rare disorder in adulthood calls attention to the need for early diagnosis for prompt treatment. Treatment of OI is never curative, but it improves the quality of the patient’s life. PMID:23754901

  1. Roentgenographic Evaluation of the Spine in Patients With Osteogenesis Imperfecta.

    PubMed

    de Lima, Marcos Vaz; de Lima, Fabiana Vaz; Akkari, Miguel; Resende, Vanessa Ribeiro de; Santili, Claudio

    2015-11-01

    Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder that leads to bone weakness and deformities, especially in the spine, which can lead to poor outcomes.The aim of this study was to find patterns and risk factors in spinal deformities in patients with OI.In a retrospective study, 70 patients with OI were selected. Radiographs of the spine were evaluated. We observed the presence or absence of the following changes: biconcave vertebrae, chest and vertebral deformities, unilateral rib, and thoracolumbar kyphosis. The greater curve was considered the primary one, and the secondary curve considered compensatory.In the study sample, we observed that the patients' ages ranged between 7 and 50 years, with a mean equal to 13 years, and 76% had scoliosis. In 68% of cases the main curve in the thoracic region was observed with the convexity to the right.The following was found in patients with OI: scoliosis, biconcave vertebrae, vertebral and chest deformity, unilateral rib, and thoracolumbar kyphosis. The thoracolumbar kyphosis is highly associated with thoracic hypokyphosis in patients with OI.

  2. Physical activity in youth with osteogenesis imperfecta type I

    PubMed Central

    Pouliot-Laforte, A.; Veilleux, L-N.; Rauch, F.; Lemay, M.

    2015-01-01

    Introduction: Individuals with Osteogenesis Imperfecta (OI) type I often show muscular weakness. However, it is unclear whether muscular weakness is a consequence of physical inactivity or a result of the disease itself. The aim was to assess muscle function in youth with OI type I and evaluate physical activity (PA). Methods: Fourteen children with OI type I (mean age [SD]: 12.75 [4.62] years) were compared to 14 age- and gender-matched controls (mean age [SD]: 12.75 [4.59] years). Muscle force and power were determined through mechanography. PA and daily energy expenditure were measured with an accelerometer and a questionnaire. Results: Compared to controls, children with OI type I had lower muscle force and power. OI type I children were as active as their healthy counterparts. Conclusions: Children and adolescents with OI type I and their healthy counterparts did not reached daily recommendations of PA. Given their muscle function deficit, youth with OI type I would benefit to reach these recommendations to prevent precocious effect of aging on muscles. PMID:26032209

  3. Osteogenesis Imperfecta Type VI in Individuals from Northern Canada.

    PubMed

    Ward, Leanne; Bardai, Ghalib; Moffatt, Pierre; Al-Jallad, Hadil; Trejo, Pamela; Glorieux, Francis H; Rauch, Frank

    2016-06-01

    Osteogenesis imperfecta (OI) type VI is a recessively inherited form of OI that is caused by mutations in SERPINF1, the gene coding for pigment-epithelium derived factor (PEDF). Here, we report on two apparently unrelated children with OI type VI who had the same unusual homozygous variant in intron 6 of SERPINF1 (c.787-10C>G). This variant created a novel splice site that led to the in-frame addition of three amino acids to PEDF (p.Lys262_Ile263insLeuSerGln). Western blotting showed that skin fibroblasts with this mutation produced PEDF but failed to secrete it. Both children were treated with intravenous bisphosphonates, but the treatment of Individual 1 was switched to subcutaneous injections of denosumab (dose 1 mg per kg body weight, repeated every 3 months). An iliac bone sample obtained after 5 denosumab injections (and 3 months after the last injection) showed no change in the increased osteoid parameters that are typical of OI type VI, but the number of osteoclasts in trabecular bone was markedly increased. This suggests that the effect of denosumab on osteoclast suppression is of shorter duration in children with OI type VI than what has previously been reported on adults with osteoporosis.

  4. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment.

    PubMed

    Van Dijk, F S; Sillence, D O

    2014-06-01

    Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

  5. Mutations in SERPINF1 cause osteogenesis imperfecta type VI.

    PubMed

    Homan, Erica P; Rauch, Frank; Grafe, Ingo; Lietman, Caressa; Doll, Jennifer A; Dawson, Brian; Bertin, Terry; Napierala, Dobrawa; Morello, Roy; Gibbs, Richard; White, Lisa; Miki, Rika; Cohn, Daniel H; Crawford, Susan; Travers, Rose; Glorieux, Francis H; Lee, Brendan

    2011-12-01

    Osteogenesis imperfecta (OI) is a spectrum of genetic disorders characterized by bone fragility. It is caused by dominant mutations affecting the synthesis and/or structure of type I procollagen or by recessively inherited mutations in genes responsible for the posttranslational processing/trafficking of type I procollagen. Recessive OI type VI is unique among OI types in that it is characterized by an increased amount of unmineralized osteoid, thereby suggesting a distinct disease mechanism. In a large consanguineous family with OI type VI, we performed homozygosity mapping and next-generation sequencing of the candidate gene region to isolate and identify the causative gene. We describe loss of function mutations in serpin peptidase inhibitor, clade F, member 1 (SERPINF1) in two affected members of this family and in an additional unrelated patient with OI type VI. SERPINF1 encodes pigment epithelium-derived factor. Hence, loss of pigment epithelium-derived factor function constitutes a novel mechanism for OI and shows its involvement in bone mineralization.

  6. Anesthetic management in a patient with osteogenesis imperfecta for rush nail removal in femur

    PubMed Central

    Gupta, Divanshu; Purohit, Alaka

    2016-01-01

    Osteogenesis imperfecta (OI) is a rare genetically inherited syndrome involving connective tissues, resulting in anatomic and physiologic abnormalities, which results in any form of anesthesia, a challenging task. We hereby report a case of OI type I presented with distinctively blue sclera, hearing loss, kyphoscoliosis, and mild pulmonary restrictive disease who underwent rush nail removal in the femur. PMID:27746572

  7. Fracture of mandible during yawning in a patient with osteogenesis imperfecta.

    PubMed

    Ram, Hari; Shadab, Mohammad; Vardaan, Ajay; Aga, Pallavi

    2014-08-07

    Osteogenesis imperfecta is a genetic disorder characterised by fragility and multiple fractures of bones. Clinical signs and symptoms vary depending on the type of disease. Fractures of facial bones are rare compared with load-bearing long bones. We report a case of fracture of the mandible during yawning which was managed by open reduction and internal fixation.

  8. Three Preschool Children with Osteogenesis Imperfecta--Interviews with Parents. Handicap Research Group Report No. 5.

    ERIC Educational Resources Information Center

    Brodin, Jane; Millde, Kristina

    The report describes three preschool Swedish children with osteogenesis imperfecta (brittle bones) and the psychosocial support families require from society. Introductory sections explain the condition, review international research on brittle bones, consider the life situation of children with brittle bones, and examine societal support for…

  9. Children with Osteogenesis Imperfecta and Their Daily Living. Handicap Research Group Report No. 4.

    ERIC Educational Resources Information Center

    Brodin, Jane

    The study examined aspects of daily living of Swedish children with osteogenesis imperfecta, a mineral deficiency in the skeleton which results in stunted growth and frequent fractures. A questionnaire was administered to 24 families with children under the age of 18 and 3 families were interviewed. The study found the families in great need of…

  10. Unilateral spinal anaesthesia in a patient with Osteogenesis Imperfecta with a lower leg fracture: a case report.

    PubMed

    Baranovic, Senka; Lubina, Ivan Zvonimir; Vlahovic, Tomislav; Bakota, Bore; Maldini, Branka

    2013-09-01

    Osteogenesis Imperfecta is a rare, genetically determined disease with several possible complications in anaesthesia. Anaesthesiologists therefore pay special attention to the treatment of patients suffering from Osteogenesis Imperfecta since they commonly suffer from a difficult airway and intraoperative positioning difficulties. We report here the case of unilateral spinal anaesthesia in a patient suffering from Osteogenesis Imperfecta type I. A 28-year-old patient diagnosed with Osteogenesis Imperfecta type I was admitted to the hospital due to lower leg fracture requiring surgical treatment. The patient had blue sclerae, triangular-shaped face, macroglossia, scoliosis of thoracic and lumbar parts of the spine, pectus carinatum and thrombocytopenia. Upon the correction of thrombocytopenia, unilateral spinal anaesthesia with hyperbaric levobupivacain was chosen in order to avoid possible complications typical for general anaesthesia. Consequently, unilateral spinal anaesthesia with a customized local anesthetic could be consdered as a safe anesthetic method for such patients.

  11. Serum microRNA is a promising biomarker for osteogenesis imperfecta.

    PubMed

    Wang, Ziqiang; Lu, Yanqin; Zhang, Xiumei; Ren, Xiuzhi; Wang, Yanzhou; Li, Zhiliang; Xu, Chao; Han, Jinxiang

    2012-05-01

    The purpose of our study was to screen preliminary differential expression bone-related microRNAs (miRNAs) in serum of patients with osteogenesis imperfacta and to clarify whether serum microRNA is a promising biomarker for osteogenesis imperfecta. geNorm and several other programes were performed to select suitable reference genes for quantitative detection of serum miRNAs from 6 candidate control genes. With geometric averaging of selected reference genes as a normalization factor, fluorescence-based quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to detect expression levels of more than 100 bone-related miRNAs obtained by means of miRanda, Targetscan and Pictar software calculations and reading the literature. Through analysis of expression stability and pairwise variations, all 6 candidate reference genes had a stable expression level in serum of 8 healthy controls and 8 patients with different characrteristics, and the optimal number of reference genes for normalization was 4 (snRNAU6, miR-92a, miR-16, and Let-7a). For further validation, the expression stability of 4 reference genes remained steady in serum of another 8 healthy controls and 16 patients with osteogenesis imperfecta (M < 1.5). When normalized using multiple control genes, 11 bone-related miRNAs showed differential expression in serum of 8 osteogenesis imperfecta patients compared with 8 healthy controls. In conclusion, we identified snRNAU6, miR-92a, miR-16, and Let-7a as an internal reference gene group for qRT-PCR normalization and screening results revealed that there existed many differential expression bone-related miRNAs in serum of patients with osteogenesis imperfecta compared with healthy controls, and that these miRNAs had potential to be biomarkers for serologic tests and diagnosis of osteogenesis imperfecta with analysis of bioinformation.

  12. Fractures at Diagnosis in Infants and Children with Osteogenesis Imperfecta

    PubMed Central

    Greeley, Christopher Spencer; Donaruma-Kwoh, Marcella; Vettimattam, Melanie; Lobo, Christine; Williard, Coco; Mazur, Lynnette

    2012-01-01

    Background In infants and children with fractures from an unclear cause, Osteogenesis Imperfecta (OI) is often included as a potential etiology. In infants and children with OI there exists a gap in the published literature regarding the fracture pattern seen at the time of diagnosis. As an additional aid to the diagnosis of OI, we sought to characterize the fracture patterns in infants and children at the time of their diagnosis. Methods We performed a retrospective chart review of a series of infants and children under 18 years of age who have the diagnosis of OI (any type) from a single institution. Results We identified 68 infants and children with OI: 23 (34%) type 1, 1(2%) type 2, 17(25%) type 3, 24(35%) type 4 and 3(4%) unknown type. A family history of OI is present in 46% of children. Forty-nine (72.0%) patients were diagnosed solely on clinical characteristics, without genetic or fibroblast confirmation. Rib fractures were noted in 21% of the subjects with none being identified during infancy. The number of fractures identified at diagnosis ranged from 1 to >37 with 7 (10%) having more than 2 fractures. All subjects with more than 2 fractures were diagnosed prenatally or in the immediate newborn period. Seventeen (25%) infants were diagnosed after 1 week of age but prior to 12 months of age. None of these infants had either rib fractures or more than 1 fracture at the time of diagnosis. Conclusion The majority of children diagnosed with OI are diagnosed by clinical features alone. The fracture pattern at the time of diagnosis in OI is variable with 10% having more than 2 fractures. The diagnosis of OI was made in utero or at delivery in 43% of children. Multiple rib fractures in an infant would be an unexpected finding in OI. Level Of Evidence Level III PMID:23232376

  13. Large osteoclasts in pediatric osteogenesis imperfecta patients receiving intravenous pamidronate.

    PubMed

    Cheung, Moira S; Glorieux, Francis H; Rauch, Frank

    2009-04-01

    Intravenous pamidronate is widely used to treat children with moderate to severe osteogenesis imperfecta (OI). Changes in the appearance of osteoclasts have previously been noted in children receiving pamidronate and have been interpreted as signs of toxicity. In this study, we analyzed osteoclast parameters in paired iliac bone specimens before and after 2-4 yr of cyclical intravenous pamidronate therapy in 44 pediatric OI patients (age range: 1.4-17.5 yr; 21 girls). During pamidronate treatment, average osteoclast diameter and the mean number of nuclei present per osteoclast increased by 18% (p = 0.02) and 43% (p < 0.001), respectively. The number of samples containing large osteoclasts (LOcs, diameter > 50 mum) increased from 6 (14%) before treatment to 23 (52%) after pamidronate therapy (p < 0.001 by chi(2) test). Post-treatment samples containing LOcs had a greater core width (p = 0.04) and a higher cancellous bone volume per tissue volume (p < 0.001), because cancellous bone volume had increased more during pamidronate treatment (p < 0.001). Osteoclast number and surface were higher in samples with LOcs, but there was no difference in cancellous bone formation parameters. The presence of LOcs was independent of OI type, type of collagen type I mutation, lumbar spine BMD, and other clinical or biochemical measures. In conclusion, this study did not show any indication that LOcs during pamidronate treatment are indicative of toxicity. It seems more likely that the observed abnormalities in osteoclast morphology are part of the mechanism of action of this drug.

  14. Pamidronate affects the mandibular cortex of children with osteogenesis imperfecta.

    PubMed

    Apolinário, A C; Figueiredo, P T; Guimarães, A T; Acevedo, A C; Castro, L C; Paula, A P; Paula, L M; Melo, N S; Leite, A F

    2015-03-01

    We hypothesized that mandibular cortical width (MCW) is smaller in children with osteogenesis imperfecta (OI) than in healthy children and that pamidronate can improve the cortical mandibular thickness. The aim of this study was to assess changes in the MCW on dental panoramic radiographs (DPRs) of children with normal bone mineral density (BMD) and with OI. We also compared the MCW of children with different types of OI regarding the number of pamidronate cycles and age at the beginning of treatment. MCW measurements were retrospectively obtained from 197 DPRs of 66 children with OI types I, III, and IV who were in treatment with a comparable dosage of cyclical intravenous pamidronate between 2007 and 2013. The control group had 92 DPRs from normal BMD children. Factorial analysis of variance was used to compare MCW measurements among different age groups and between sexes and also to compare MCW measurements of children with different types of OI among different pamidronate cycles and age at the beginning of treatment. No significant differences in results were found between male and female subjects in both OI and healthy children, so they were evaluated altogether (P > 0.05). There was an increase of MCW values related to aging in all normal BMD and OI children but on a smaller scale in children with OI types I and III. Children with OI presented lower mean MCW values than did children with normal BMD at the beginning of treatment (P < 0.05). A linear model estimated the number of pamidronate cycles necessary to achieve mean MCW values equivalent to those of healthy children. The thinning of the mandibular cortex depended on the number of pamidronate cycles, the type of OI, and the age at the beginning of treatment. DPRs could thus provide a way to identify cyclic pamidronate treatment outcomes in patients with OI.

  15. Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: a new target for osteogenesis imperfecta pharmacological therapy.

    PubMed

    Gioia, Roberta; Panaroni, Cristina; Besio, Roberta; Palladini, Giovanni; Merlini, Giampaolo; Giansanti, Vincenzo; Scovassi, Ivana A; Villani, Simona; Villa, Isabella; Villa, Anna; Vezzoni, Paolo; Tenni, Ruggero; Rossi, Antonio; Marini, Joan C; Forlino, Antonella

    2012-07-01

    The molecular basis underlying the clinical phenotype in bone diseases is customarily associated with abnormal extracellular matrix structure and/or properties. More recently, cellular malfunction has been identified as a concomitant causative factor and increased attention has focused on stem cells differentiation. Classic osteogenesis imperfecta (OI) is a prototype for heritable bone dysplasias: it has dominant genetic transmission and is caused by mutations in the genes coding for collagen I, the most abundant protein in bone. Using the Brtl mouse, a well-characterized knockin model for moderately severe dominant OI, we demonstrated an impairment in the differentiation of bone marrow progenitor cells toward osteoblasts. In mutant mesenchymal stem cells (MSCs), the expression of early (Runx2 and Sp7) and late (Col1a1 and Ibsp) osteoblastic markers was significantly reduced with respect to wild type (WT). Conversely, mutant MSCs generated more colony-forming unit-adipocytes compared to WT, with more adipocytes per colony, and increased number and size of triglyceride drops per cell. Autophagy upregulation was also demonstrated in mutant adult MSCs differentiating toward osteogenic lineage as consequence of endoplasmic reticulum stress due to mutant collagen retention. Treatment of the Brtl mice with the proteasome inhibitor Bortezomib ameliorated both osteoblast differentiation in vitro and bone properties in vivo as demonstrated by colony-forming unit-osteoblasts assay and peripheral quantitative computed tomography analysis on long bones, respectively. This is the first report of impaired MSC differentiation to osteoblasts in OI, and it identifies a new potential target for the pharmacological treatment of the disorder.

  16. Cranial base abnormalities in osteogenesis imperfecta: phenotypic and genotypic determinants.

    PubMed

    Cheung, Moira S; Arponen, Heidi; Roughley, Peter; Azouz, Michel E; Glorieux, Francis H; Waltimo-Sirén, Janna; Rauch, Frank

    2011-02-01

    Cranial base abnormalities are an important complication of osteogenesis imperfecta (OI), a hereditary bone fragility disorder that in most patients is caused by mutations affecting collagen type I. To elucidate which clinical characteristics are associated with the occurrence of cranial base abnormalities in OI, we compared cephalometric results of 187 OI patients (median age 12.0 years, range 3.4 to 47 years; 96 female) with those of 191 healthy subjects and related findings to clinical descriptors of the disease. Overall, 41 patients (22%) had at least one unambiguously abnormal skull base measure. Multivariate logistic regression analysis in patients with OI types I, III, and IV (n = 169) revealed that height Z-score [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.43-0.66, p < .001]--but not age, gender, scleral hue, lumbar spine areal bone mineral density, or a history of bisphosphonate treatment--was a significant independent determinant of skull base abnormalities. Among patients with a height Z-score below -3, 48% had a skull base abnormality regardless of whether they had received bisphosphonate treatment in the first year of life or not. Genotype-phenotype correlations were evaluated in patients with detectable mutations in COL1A1 or COL1A2, the genes coding for collagen type I (n = 140). Skull base abnormalities were present in 6% of patients with haploinsufficiency (frameshift or nonsense) mutations, in 43% of patients with helical glycine substitutions caused by COL1A1 mutations, in 32% of patients with helical glycine substitutions owing to COL1A2 mutations, and in 17% of patients with splice-site mutations affecting either COL1A1 or COL1A2. However, multivariate logistic regression analysis showed that height Z-score but not the type of collagen type I mutation was independently associated with the prevalence of skull base abnormalities. In conclusion, this study shows that clinical severity of OI, as expressed by the height Z-score, was

  17. Osteogenesis imperfecta and clubfoot—a rare combination

    PubMed Central

    Persiani, Pietro; Ranaldi, Filippo Maria; Martini, Lorena; Zambrano, Anna; Celli, Mauro; D’Eufemia, Patrizia; Villani, Ciro

    2016-01-01

    Abstract Background: Osteogenesis imperfecta (OI) is a rare congenital genetic osteodystrophy, which has a prevalence of 1:20,000. OI is caused by the mutation of the COL1A1/COL1A2 genes, leading to a deficit of quality and/or quantity in the synthesis of procollagen-α type 1. Seven different forms of diverse clinical entity have been classified by Sillence and Glorieux, although, recently, up to 11 forms characterized by different genetic mutations have been recognized. Patients with OI suffer from extreme bone fragility and osteoporosis, which often predisposes them to frequent fractures. This paper presents the case of a child with OI type IV who, at birth, was also diagnosed with a severe clubfoot (congenital talipes equinovarus) grade III. Patient's mother also suffers from OI type IV. Methods: The treatment was started by placing femoro-podalic corrective casts, according to the Ponseti method, but some unexpected problems occurred during this treatment. When the patient was 3 months of age, we decided to correct the clubfoot before the time limit planned, performing a bilateral posteromedial surgical release. Results: Three weeks after surgery the casts were removed and replaced with bilateral Spica cast-like braces. On the 6th postoperative week, the patient began wearing Bebax corrective shoes, after 1 year ambidextrous orthopedic shoes. Now, he is 2 years old and has started to walk properly without any orthesis. Conclusion: In the presence of an orthopedic pathology associated with OI, it is recommended to manage the patient according to the underlying pathology, always considering the bone fragility associated with OI. The final surgical treatment to correct the clubfoot can be done earlier, if necessary. In our opinion, this uncommon association between OI and clubfoot is non-syndromic. This means that the two congenital diseases are not necessarily included in a singular uncommon genetic syndrome, but the clubfoot was caused by multifactorial causes

  18. Chronic ventilator use in osteogenesis imperfecta congenita with basilar impression: a case report.

    PubMed

    Wang, T G; Yang, G F; Alba, A

    1994-06-01

    Osteogenesis imperfecta, a rare connective tissue disorder, is known to be associated sometimes with the invagination of the basilar skull. This deformity may disturb respiratory function secondary to brain stem compression and hydrocephalus. In addition, the deformed thoracic cage and fragile ribs make pulmonary care more complicated. A case of 24-year-old man is presented with brain stem compression syndrome secondary to osteogenesis imperfecta congenita with basilar impression. He developed respiratory failure and became tracheostomy positive-pressure ventilator dependent at the age of 21 years. He also suffered multiple skeletal abnormalities and mental retardation, and following the brain stem compression, severe quadriparesis. The patient's condition is stable since he has been using the ventilator and he is currently living in the community.

  19. Dentinogenesis imperfecta type I: A case report with literature review on nomenclature system

    PubMed Central

    Devaraju, D; Devi, BK Yashoda; Vasudevan, Vijeev; Manjunath, V

    2014-01-01

    Dentinogenesis imperfecta (DI) is an inherited disorder affecting dentin. Defective dentin formation results in discolored teeth that are prone to attrition and fracture. Mutation in dentin sialophosphoprotein (DSPP) has been found to cause the dentin disorders DI - I and II (shields II and III). Early diagnosis and treatment of DI is recommended as it may prevent or intercept deterioration of the teeth and occlusion and improve esthetics. Here, we report a case with characteristic clinical, radiological and histological features of DI-I. The etiology and classification followed in literature is confusing since dentinoenamel junction (DEJ) in DI seems to be structurally and functionally normal and DI is clearly a disorder distinct from osteogenesis imperfecta (OI), but we still relate etiology of DI to DEJ and follow Shields classification. Therefore, we have briefly reviewed etiology and nomenclature system of DI. PMID:25364163

  20. Osteogenesis imperfecta and hearing loss--description of three case reports.

    PubMed

    Pereira da Silva, Ana; Feliciano, Telma; Figueirinhas, Rosário; Almeida E Sousa, Cecília

    2013-01-01

    Osteogenesis imperfecta is the commonest connective tissue hereditary disease. Its clinical presentation has a wide spectrum of characteristics, which includes skeletal deformities and hearing loss. We describe three case reports of individuals carriers of this disease presenting with different patterns of hearing loss. Hearing loss prevalence and patterns are variable and have no clear relation with genotype. Its assessment at initial evaluation and posterior monitoring is essential to provide the best therapeutic alternatives.

  1. A rare presentation of a child with osteogenesis imperfecta and congenital laryngomalacia for herniotomy

    PubMed Central

    Chandran, Roshith; Dave, Nandini; Padvi, Amit; Garasia, Madhu

    2011-01-01

    Sometimes anaesthesiologists come across rare congenital anomalies in their practice. The inherent complications associated with the disorder necessitate tailor-made approaches for providing anaesthesia to even seemingly simple surgical interventions. Here, we share our experience of anaesthesia management of an infant with congenital laryngomalacia and recently diagnosed osteogenesis imperfecta type 1 who had presented to us with an acute abdomen for a semi-emergency herniotomy. PMID:22174477

  2. Dentinogenesis imperfecta: a case report of comprehensive treatment for a teenager.

    PubMed

    Biethman, Rick; Capati, Laura Richards; Eldger, Nicole

    2014-01-01

    Improving a smile can change a person's self-image. This case report describes treatment for an adolescent boy with dentinogenesis imperfecta. Soon to begin high school, the 14-year-old patient was severely obese and disliked his stained teeth. A combination of surgical periodontal treatment, endodontic treatment, and veneers improved both his smile and self-perception-which may have played a role in achieving his weight loss goal of 125 lb at 12 months post-treatment.

  3. A cephalometric method to diagnosis the craniovertebral junction abnormalities in osteogenesis imperfecta patients

    PubMed Central

    Ríos-Rodenas, Mercedes; Gutiérrez-Díez, María-Pilar; Feijóo, Gonzalo; Mourelle, Maria-Rosa; Garcilazo, Mario; Ortega-Aranegui, Ricardo

    2015-01-01

    Osteogenesis imperfecta (OI) is a hereditary bone fragility disorder that in most patients is caused by mutations affecting collagen type I. Their typical oral and craneofacial characteristics (Dentinogenesis imperfecta type I and class III malocclusion), involve the dentist in the multidisciplinary team that treat these patients. It is usual to perform lateral skull radiographs for the orthodontic diagnosis. In addition, this radiograph is useful to analyse the junctional area between skull base and spine, that could be damaged in OI. Pathology in the craneovertebral junction (CVJ) is a serious complication of OI with a prevalence ranging from rare to 37%. To diagnosis early skull base anomalies in these patients, previously the neurological symptoms have been appear, we make a simple cephalometric analysis of the CVJ. This method has four measurements and one angle. Once we calculate the values of the OI patient, we compare the result with the mean and the standard deviations of an age-appropriate average in healthy controls. If the patient has a result more than 2,5 SDs above the age-appropriate average in healthy controls, we should to refer the patient to his/her pediatrician or neurologist. These doctors have to consider acquiring another diagnostic images to be used to determine cranial base measurements with more reliability. Thereby, dentists who treat these patients, must be aware of the normal radiological anatomy of the cervical spine on the lateral cephalogram. Key words:Osteogenesis imperfecta, craniovertebral junction, cephalometric. PMID:25810828

  4. Identification of a Frameshift Mutation in Osterix in a Patient with Recessive Osteogenesis Imperfecta

    PubMed Central

    Lapunzina, Pablo; Aglan, Mona; Temtamy, Samia; Caparrós-Martín, José A.; Valencia, Maria; Letón, Rocío; Martínez-Glez, Victor; Elhossini, Rasha; Amr, Khalda; Vilaboa, Nuria; Ruiz-Perez, Victor L.

    2010-01-01

    Osteogenesis imperfecta, or “brittle bone disease,” is a type I collagen-related condition associated with osteoporosis and increased risk of bone fractures. Using a combination of homozygosity mapping and candidate gene approach, we have identified a homozygous single base pair deletion (c.1052delA) in SP7/Osterix (OSX) in an Egyptian child with recessive osteogenesis imperfecta. The clinical findings from this patient include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing, and white sclera. OSX encodes a transcription factor containing three Cys2-His2 zinc-finger DNA-binding domains at its C terminus, which, in mice, has been shown to be essential for bone formation. The frameshift caused by the c.1052delA deletion removes the last 81 amino acids of the protein, including the third zinc-finger motif. This finding adds another locus to the spectrum of genes associated with osteogenesis imperfecta and reveals that SP7/OSX also plays a key role in human bone development. PMID:20579626

  5. A cephalometric method to diagnosis the craniovertebral junction abnormalities in osteogenesis imperfecta patients.

    PubMed

    Ríos-Rodenas, Mercedes; de Nova, Joaquín; Gutiérrez-Díez, María-Pilar; Feijóo, Gonzalo; Mourelle, Maria-Rosa; Garcilazo, Mario; Ortega-Aranegui, Ricardo

    2015-02-01

    Osteogenesis imperfecta (OI) is a hereditary bone fragility disorder that in most patients is caused by mutations affecting collagen type I. Their typical oral and craneofacial characteristics (Dentinogenesis imperfecta type I and class III malocclusion), involve the dentist in the multidisciplinary team that treat these patients. It is usual to perform lateral skull radiographs for the orthodontic diagnosis. In addition, this radiograph is useful to analyse the junctional area between skull base and spine, that could be damaged in OI. Pathology in the craneovertebral junction (CVJ) is a serious complication of OI with a prevalence ranging from rare to 37%. To diagnosis early skull base anomalies in these patients, previously the neurological symptoms have been appear, we make a simple cephalometric analysis of the CVJ. This method has four measurements and one angle. Once we calculate the values of the OI patient, we compare the result with the mean and the standard deviations of an age-appropriate average in healthy controls. If the patient has a result more than 2,5 SDs above the age-appropriate average in healthy controls, we should to refer the patient to his/her pediatrician or neurologist. These doctors have to consider acquiring another diagnostic images to be used to determine cranial base measurements with more reliability. Thereby, dentists who treat these patients, must be aware of the normal radiological anatomy of the cervical spine on the lateral cephalogram. Key words:Osteogenesis imperfecta, craniovertebral junction, cephalometric.

  6. Osteonectin, bone proteoglycan, and phosphophoryn defects in a form of bovine osteogenesis imperfecta.

    PubMed Central

    Termine, J D; Robey, P G; Fisher, L W; Shimokawa, H; Drum, M A; Conn, K M; Hawkins, G R; Cruz, J B; Thompson, K G

    1984-01-01

    Bovine osteogenesis imperfecta is a congenital disease in Holstein cattle having several characteristics in common with human osteogenesis imperfecta syndromes. In particular, affected calves have multiple bone fractures and friable teeth. Bone collagen isolated from the affected animals (Texas variant) showed slightly decreased alpha 1(I) and alpha 2(I) chain electrophoretic mobility and increased hydroxylysine content. Overall collagen was present in the affected bones at 80-90% of normal values. However, osteonectin, a 32,000 Mr bone-specific protein found previously to promote collagen mineralization in vitro and present in abundance (approximately equal to 3% of total protein) in normal calf bone, was severely depleted (less than 2% of normal levels) in the osteogenesis imperfecta bone and dentin. The bone proteoglycan was similarly depleted. In contrast, the bone sialoprotein was not as severely affected. Further, the diseased teeth lacked (less than 10% of normal values) phosphophoryn, a dentin-specific protein normally present as 4-5% of the total calf dentin matrix. The data suggest multiple hard tissue matrix protein deletions, perhaps due to impaired cell development. Images PMID:6585794

  7. Phase angle and World Health Organization criteria for the assessment of nutritional status in children with osteogenesis imperfecta

    PubMed Central

    Pileggi, Vicky Nogueira; Scalize, Antonio Rodolpho Hakime; Camelo, José Simon

    2016-01-01

    Abstract Objective: To compare the phase angle of patients with osteogenesis imperfecta treated at a tertiary university hospital with patients in a control group of healthy children, and to assess the nutritional status of these patients through the body mass index proposed by the World Health Organization. Methods: Cross-sectional study carried out in a university hospital that included seven patients with osteogenesis imperfecta and a control group of 17 healthy children of the same gender and age. Weight and height were measured and bioelectrical impedance was performed. Subsequently, the phase angle was calculated based on resistance and reactance values. Results: The phase angle of the group of children with osteogenesis imperfecta was significantly lower than that of the control group (p<0.05). The body mass index criterion for age of the World Health Organization showed no difference between groups. Conclusions: Children with osteogenesis imperfecta have a nutritional risk detected by the phase angle, which is a useful tool for nutritional screening. The calculation result could help in the diet therapy of patients with osteogenesis imperfecta. PMID:27102998

  8. Systematic Review on the Incidence of Bisphosphonate Related Osteonecrosis of the Jaw in Children Diagnosed with Osteogenesis Imperfecta

    PubMed Central

    Jayasinghe, Jap; Khajeh, Janette; Macfarlane, Tatiana V.

    2013-01-01

    ABSTRACT Objectives To conduct a systematic review of epidemiological literature to determine the incidence of bisphosphonate related osteonecrosis of the jaw occurring either spontaneously or after dental surgery, in children and adolescents diagnosed with osteogenesis imperfecta. Material and Methods MEDLINE, HMIC and EMBASE were used to search for English-language articles published from 1946 - 2013. Inclusion criteria consisted of population based studies of children and adolescents (24 years and younger) diagnosed with osteogenesis imperfecta, only studies which included a dental examination, and patients treated with intravenous bisphosphonates were included. Articles were excluded if patients had any other co-morbidity which could affect osteonecrosis of the jaw, and those which treated patients with oral bisphosphonates only. Results Five studies consisting of four retrospective cohort studies and one case series were identified. Study populations ranged from 15 to 278 patients and number of subjects with osteogenesis imperfecta ranged from 15 to 221. Mean duration of intravenous bisphosphonate use ranged from 4.5 to 6.8 years. All patients were clinically examined and no patients were found to have osteonecrosis of the jaw. Conclusions There is no evidence to support hypothesis of causal relationship between bisphosphonates and osteonecrosis of the jaw in children and adolescents with osteogenesis imperfecta. More prospective studies on bisphosphonate use in osteogenesis imperfecta needs to be carried out. PMID:24478911

  9. Surgical treatment in Osteogenesis Imperfecta – 10 years experience

    PubMed Central

    Georgescu, I; Vlad, C; Gavriliu, TȘ; Dan, S; Pârvan, AA

    2013-01-01

    Introduction. Osteogenesis imperfecta (OI) is a very rare disease compared to other afflictions, running the risk of social isolation for children and their parents, due to the problems specific to the disease. All the social, psychological and physical disadvantages must be removed or at least mitigated, all within the society’s limited resources. In Romania, this situation has led in the last couple of years to the selection of a number of extremely severe cases, which could not be solved by orthopedic and classic surgical treatment methods. These patients exhibit gracile long bones, which are distorted, often with cystic degeneration at the level of the extremities, pseudarthroses, limb length discrepancies, most of them being unable to walk, being condemned to sitting in a wheelchair. Aim. This paper deals with the experience of the Orthopedics Department of "Maria Sklodowska Curie" Clinical Emergency Hospital for Children, in Bucharest, in the field of surgical treatment for moderate and severe forms of OI, within the time frame of May 2002-May 2012. For the first time in Romania, on May 20, 2002, the team led by Professor Gh. Burnei, MD, has implanted telescopic rods in the femur and tibia of a patient with OI. One of the most important themes, of great interest in the orthopedic surgery, is the osteoarticular regularization and reconstruction in severe forms of OI, which should allow the patients to stand and walk. These cases are a challenge for the surgeon, who is in the position of applying new, complex procedures, or perfecting, modifying and adapting techniques that have already been established. The aim of the surgical treatment is the increase of the quality of life of these children and adolescents and of their social integration. Methods and results. In the above-mentioned period, from the OI patients who are in the evidence of our clinic, 32 were operated on, totaling 81 surgeries. Out of these, 28 patients, aged 2-27 years, have benefited from

  10. Evolution of Klk4 and enamel maturation in eutherians

    PubMed Central

    Kawasaki, Kazuhiko; Hu, Jan C.-C; Simmer, James P.

    2014-01-01

    Kallikrein-related peptidase 4 (KLK4) is a secreted serine protease that degrades residual enamel proteins to facilitate their removal by ameloblasts, which increases mineralization and hardens the enamel. Mutations in human KLK4 cause hypomaturation amelogenesis imperfecta. Enamel formed by Klk4 null mice is normal in thickness and prism structure, but the enamel layer retains proteins, is hypomineralized, and undergoes rapid attrition following tooth eruption. We searched multiple databases, retrieved Klk4 and Klk5 from various mammalian genomes, and identified Klk4 in 47 boreoeutherian genomes. In non-Boreoeutheria, Klk4 was detected in only one afrotherian genome (as a pseudogene), and not in the other six afrotherian, two xenarthran, or three marsupial genomes. In contrast, Klk5 was detected in both marsupial and eutherian mammals. Our phylogenetic and mutation rate analyses support the hypothesis that Klk4 arose from Klk5 by gene duplication near the divergence of Afrotheria, Xenarthra and Boreoeutheria, and that functionally- differentiated Klk4 survived only in Boreoeutheria. Afrotherian mammals share the feature of delayed dental eruption relative to boreoeutherian mammals. KLK4 shortens the time required for enamel maturation and could have alleviated negative selection following mutations that resulted in thicker enamel or earlier tooth eruption, without reducing enamel hardness or causing dental attrition. PMID:25153384

  11. DLX3 mutation in a new family and its phenotypic variations.

    PubMed

    Lee, S-K; Lee, Z H; Lee, S-J; Ahn, B-D; Kim, Y-J; Lee, S-H; Kim, J-W

    2008-04-01

    Tricho-dento-osseous syndrome (TDO) is an autosomal-dominant disease characterized by curly hair at birth, enamel hypoplasia, taurodontism, and a thick cortical bone. A common DLX3 gene mutation (c.571_574delGGGG) has been identified in multiple families with variable clinical phenotypes. Recently, another DLX3 gene mutation (c.561_562delCT) was reported to cause amelogenesis imperfecta with taurodontism (AIHHT). We identified a Korean family with overlapping phenotypes of TDO and AIHHT. We performed mutational analysis to discover its genetic etiology. The identified mutation was c.561_562delCT mutation in the DLX3 gene. The enamel was hypomature and hypoplastic. The characteristic taurodontic features were not identified. Increased bone density or thickness could not be revealed by cephalometric, hand-wrist, and panoramic radiographs. Affected individuals reported that their nails were brittle, and they had curly hair at birth. This study clearly showed that the c.561_562delCT mutation had not only enamel defects, but also other clinical phenotypes resembling those of TDO syndrome.

  12. Shear bond strength of dentin and deproteinized enamel of AI mouse incisors

    PubMed Central

    Pugach, M.K.; Ozer, F.; Mulmadgi, R.; Li, Y.; Suggs, C.; Wright, J.T.; Bartlett, J.D.; Gibson, C.W.; Lindemeyer, R.G.

    2014-01-01

    Purpose To investigate the adhesion through shear bond strength (SBS) testing of a resin composite bonded with a self-etching bonding system (SEB) to amelogenesis imperfecta (AI)-affected deproteinized mouse enamel or dentin; and to compare wild-type (WT), amelogenin null (AmelxKO) and matrix metalloproteinase-20 null (Mmp20KO) enamel and dentin phenotypes using microCT and nanoindentation. Methods Enamel incisor surfaces of WT, AmelxKO and Mmp20KO mice were treated with SEB with and without NaOCl and tested for SBS. Incisor dentin was also treated with SEB and tested for SBS. These surfaces were further examined by SEM. MicroCT and nanoindentation analyses were performed on mouse dentin and enamel. Data were analyzed for significance by ANOVA. Results Deproteinization did not improve SBS of SEB to these AI-affected enamel surfaces. SBS of AmelxKO teeth was similar in dentin and enamel; however, it was higher in Mmp20KO dentin. The nanohardness of knockout enamel was significantly lower than WT, while knockout dentin nanohardness was not different from WT. Conclusions Using animal AI models, it was demonstrated that enamel NaOCl deproteinization of hypoplastic and hypoplastic-hypomaturation enamel did not increase shear bond strength while removal of the defective enamel allowed optimal dentin bonding. PMID:25303500

  13. Dentinogenesis imperfecta associated with short stature, hearing loss and mental retardation: a new syndrome with autosomal recessive inheritance?

    PubMed

    Cauwels, R G E C; De Coster, P J; Mortier, G R; Marks, L A M; Martens, L C

    2005-08-01

    The follow-up history and oral findings in two brothers from consanguineous parents suggest that the association of dentinogenesis imperfecta (DI), delayed tooth eruption, mild mental retardation, proportionate short stature, sensorineural hearing loss and dysmorphic facies may represent a new syndrome with autosomal recessive inheritance. Histological examination of the dentin matrix of a permanent molar from one of the siblings reveals morphological similarities with defective dentinogenesis as presenting in patients affected with Osteogenesis Imperfecta (OI), a condition caused by deficiency of type I collagen. A number of radiographic and histological characteristics, however, are inconsistent with classical features of DI. These findings suggest that DI may imply greater genetical heterogeneity than currently assumed.

  14. Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation

    PubMed Central

    Wang, Shih-Kai; Hu, Yuanyuan; Yang, Jie; Smith, Charles E; Nunez, Stephanie M; Richardson, Amelia S; Pal, Soumya; Samann, Andrew C; Hu, Jan C-C; Simmer, James P

    2015-01-01

    Defects in WDR72 (WD repeat-containing protein 72) cause autosomal recessive hypomaturation amelogenesis imperfecta. We generated and characterized Wdr72-knockout/lacZ-knockin mice to investigate the role of WDR72 in enamel formation. In all analyses, enamel formed by Wdr72 heterozygous mice was indistinguishable from wild-type enamel. Without WDR72, enamel mineral density increased early during the maturation stage but soon arrested. The null enamel layer was only a tenth as hard as wild-type enamel and underwent rapid attrition following eruption. Despite the failure to further mineralize enamel deposited during the secretory stage, ectopic mineral formed on the enamel surface and penetrated into the overlying soft tissue. While the proteins in the enamel matrix were successfully degraded, the digestion products remained inside the enamel. Interactome analysis of WDR72 protein revealed potential interactions with clathrin-associated proteins and involvement in ameloblastic endocytosis. The maturation stage mandibular incisor enamel did not stain with methyl red, indicating that the enamel did not acidify beneath ruffle-ended ameloblasts. Attachment of maturation ameloblasts to the enamel layer was weakened, and SLC24A4, a critical ameloblast calcium transporter, did not localize appropriately along the ameloblast distal membrane. Fewer blood vessels were observed in the papillary layer supporting ameloblasts. Specific WDR72 expression by maturation stage ameloblasts explained the observation that enamel thickness and rod decussation (established during the secretory stage) are normal in the Wdr72 null mice. We conclude that WDR72 serves critical functions specifically during the maturation stage of amelogenesis and is required for both protein removal and enamel mineralization. PMID:26247047

  15. Endoscopic transnasal decompression for management of basilar invagination in osteogenesis imperfecta.

    PubMed

    Hansen, Mitchell A; da Cruz, Melville J; Owler, Brian K

    2008-10-01

    Osteogenesis imperfecta (OI) is a disorder of bone development caused by a genetic dysfunction of collagen synthesis. Basilar invagination (BI) is an uncommon but serious complication of OI. Brainstem decompression in OI is undertaken in certain circumstances. Transoral-transpalatopharyngeal ventral decompression with posterior occipitocervical fusion has become the treatment of choice when required. This technical note outlines a novel endoscopic transnasal approach for ventral decompression. The literature is reviewed and a strategy for the management of BI in patients with OI is outlined.

  16. Surgical technique of double valve replacement in a patient with osteogenesis imperfecta.

    PubMed

    Sumi, Mizuki; Ariyoshi, Tsuneo; Matsukuma, Seiji; Nakaji, Shun; Hashizume, Koji; Kinoshita, Naoe; Eishi, Kiyoyuki

    2016-04-01

    Osteogenesis imperfecta (OI) is an inherited connective tissue disorder. Left ventricle dilation and valve insufficiency are complications in patients with OI and such patients are at high risk of mortality and complications related to bleeding and tissue friability during cardiac surgery. Valve dehiscence due to extreme friability of the annulus is a major complication of cardiac valve replacement with OI. We describe OI in a male patient who underwent double valve replacement with mechanical valves using a tissue protective method to prevent valve dehiscence.

  17. Effect of osteogenesis imperfecta mutations in tropocollagen molecule on strength of biomimetic tropocollagen-hydroxyapatite nanocomposites

    NASA Astrophysics Data System (ADS)

    Dubey, Devendra K.; Tomar, Vikas

    2010-01-01

    Osteogenesis Imperfecta (OI) is a genetic disorder that affects cellular synthesis of Type-I collagen fibrils and causes extreme bone fragility. This study reports the effects of OI mutations in Tropocollagen (TC) molecules on strength of model Tropocollagen-Hydroxyapatite biomaterials with two different mineral [hydroxyapatite (HAP)] distributions using three dimensional atomistic simulations. Results show that the effect of TC mutations on the strength of TC-HAP biomaterials is insignificant. Instead, change in mineral distribution showed significant impact on the overall strength of TC-HAP biomaterials. Study suggests that TC mutations manifest themselves by changing the mineral distribution during hydroxyapatite growth and nucleation period.

  18. Dental Management of a Child with Dentinogenesis Imperfecta: A Case Report

    PubMed Central

    Akhlaghi, Najmeh; Eshghi, Ali-Reza; Mohamadpour, Mehrnaz

    2016-01-01

    Dentinogenesis imperfecta (DI) is a hereditary dentin defect caused by an autosomal dominant mutation in dentin sialophosphoprotein gene. Defective dentin development results in discolored teeth that are prone to wear and fracture. Early diagnosis and proper treatment are necessary to achieve better functional and esthetic results and minimize nutritional deficiencies and psychosocial distress. In order to prevent excessive loss of tooth structure, placement of stainless steel crowns (SSCs) on deciduous and young permanent posterior teeth is recommended as soon as such teeth erupt. This clinical report presents the clinical manifestations and management of a 3.5-year-old child diagnosed with DI type II. PMID:27928242

  19. Investigation of the Human Disease Osteogenesis Imperfecta: A Research-Based Introduction to Concepts and Skills in Biomolecular Analysis

    ERIC Educational Resources Information Center

    Mate, Karen; Sim, Alistair; Weidenhofer, Judith; Milward, Liz; Scott, Judith

    2013-01-01

    A blended approach encompassing problem-based learning (PBL) and structured inquiry was used in this laboratory exercise based on the congenital disease Osteogenesis imperfecta (OI), to introduce commonly used techniques in biomolecular analysis within a clinical context. During a series of PBL sessions students were presented with several…

  20. How tough is Brittle Bone? Investigating Osteogenesis Imperfecta in Mouse Bone††

    PubMed Central

    Carriero, A.; Zimmermann, E. A.; Paluszny, A.; Tang, S. Y.; Bale, H.; Busse, B.; Alliston, T.; Kazakia, G.

    2015-01-01

    The multiscale hierarchical structure of bone is naturally optimized to resist fractures. In osteogenesis imperfecta, or brittle bone disease, genetic mutations affect the quality and/or quantity of collagen, dramatically increasing bone fracture risk. Here we reveal how the collagen defect results in bone fragility in a mouse model of osteogenesis imperfecta (oim), which has homotrimeric α1(I) collagen. At the molecular level we attribute the loss in toughness to a decrease in the stabilizing enzymatic crosslinks and an increase in non-enzymatic crosslinks, which may break prematurely inhibiting plasticity. At the tissue level, high vascular canal density reduces the stable crack growth, and extensive woven bone limits the crack-deflection toughening during crack growth. This demonstrates how modifications at the bone molecular level have ramifications at larger length scales affecting the overall mechanical integrity of the bone; thus, treatment strategies have to address multiscale properties in order to regain bone toughness. In this regard, findings from the heterozygous oim bone, where defective as well as normal collagen are present, suggest that increasing the quantity of healthy collagen in these bones helps to recover toughness at the multiple length scales. PMID:24420672

  1. Combined Treatment with Laser Sintering and Zirconium: A Case Report of Dentinogenesis Imperfecta

    PubMed Central

    Sahin, Cem; Akgün, Özlem Marti; Basak, Feridun

    2013-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous disorder of connective tissue that manifests mainly as skeletal deformity and bone fragility. Dentinogenesis imperfecta (DI) is sometimes an accompanying symptom of OI. The treatment protocol of these patients varies according to the clinical appearance. The case report here describes complete mouth rehabilitation of an 18-year-old male patient with OI and DI using direct metal laser sintering (DMLS) technique of metal-ceramic restorations and zirconium all-ceramic crowns. DMLS is an additive metal fabrication technology that is simpler, more precise, and healthier than conventional manufacturing and can be remarkably cost effective. Moreover, the technique affords highly accurate production of fixed partial dentures with ideal marginal fit and excellent mechanical properties. The patient was treated using a multidisciplinary strategy that focused on controlling caries, protecting teeth from further wear, obtaining an appropriate vertical dimension, and providing soft tissue support to return the facial profile to a normal appearance using new technology in the field of prosthetics. PMID:23533828

  2. What every clinical geneticist should know about testing for osteogenesis imperfecta in suspected child abuse cases.

    PubMed

    Pepin, Melanie G; Byers, Peter H

    2015-12-01

    Non-accidental injury (NAI) is a major medical concern in the United States. One of the challenges in evaluation of children with unexplained fractures is that genetic forms of bone fragility are one of the differential diagnoses. Infants who present with fractures with mild forms of osteogenesis imperfecta (OI) (OI type I or OI type IV), the most common genetic form of bone disease leading to fractures might be missed if clinical evaluation alone is used to make the diagnosis. Diagnostic clinical features (blue sclera, dentinogenesis imperfecta, Wormian bones on X-rays or positive family history) may not be present or apparent at the age of evaluation. The evaluating clinician faces the decision about whether genetic testing is necessary in certain NAI cases. In this review, we outline clinical presentations of mild OI and review the history of genetic testing for OI in the NAI versus OI setting. We summarize our data of molecular testing in the Collagen Diagnostic Laboratory (CDL) from 2008 to 2014 where NAI was noted on the request for DNA sequencing of COL1A1 and COL1A2. We provide recommendations for molecular testing in the NAI versus OI setting. First, DNA sequencing of COL1A1, COL1A2, and IFITM5 simultaneously and duplication/deletion testing is recommended. If a causative variant is not identified, in the absence of a pathologic clinical phenotype, no additional gene testing is indicated. If a VUS is found, parental segregation studies are recommended.

  3. Osteogenesis imperfecta type V: clinical and radiographic manifestations in mutation confirmed patients.

    PubMed

    Kim, Ok-Hwa; Jin, Dong-Kyu; Kosaki, Keisuke; Kim, Jung-Wook; Cho, Sung Yoon; Yoo, Won Joon; Choi, In Ho; Nishimura, Gen; Ikegawa, Shiro; Cho, Tae-Joon

    2013-08-01

    Osteogenesis imperfecta (OI) type V is a specific OI phenotype with interosseous membrane calcification of the forearm and hyperplastic callus formation as typical features. The causative gene mutation for OI type V has been recently discovered. The purpose of this report is to review the clinical and radiographic characteristics of mutation confirmed OI type V in detail. Sixteen (nine familial and seven sporadic) patients were enrolled in the study. Blue sclera and dentinogenesis imperfecta were not evident in any patient. However, hypodontia in the permanent teeth, ectopic eruption, and short roots in molars were additionally observed in 11 patients. Of the radiographic abnormalities, cortical thickening and bony excrescence of interosseous margin of the ulna was the most common finding, followed by overgrowth of the olecranon and/or coronoid process of the ulna. Slender ribs and sloping of the posterior ribs with or without fractures were also a consistent finding. Hyperplastic callus was detected in 75% of patients and was commonly encountered at the femur. Heterotopic ossification in the muscles and tendon insertion sites were noted in four patients, which resulted in bony ankylosis or contracture of joints. The current study confirms common clinical and radiographic findings of OI type V and reports additional phenotypic information. These observations provide clues to recognize OI type V more promptly and guide to direct targeted molecular study. © 2013 Wiley Periodicals, Inc.

  4. Developmental charts for children with osteogenesis imperfecta, type I (body height, body weight and BMI).

    PubMed

    Graff, Krzysztof; Syczewska, Malgorzata

    2017-03-01

    Osteogenesis imperfecta (OI) is a rare genetic disorder of type I collagen. Type I is the most common, which is called a non-deforming type of OI, as in this condition, there are no major bone deformities. This type is characterised by blue sclera and vertebral fractures, leading to mild scoliosis. The body height of these patients is regarded as normal, or only slightly reduced, but there are no data proving this in the literature. The aim of this study is the preparation of the developmental charts of children with OI type I. The anthropometric data of 117 patients with osteogenesis imperfecta were used in this study (61 boys and 56 girls). All measurements were pooled together into one database (823 measurements in total). To overcome the problem of the limited number of data being available in certain age classes and gender groups, the method called reverse transformation was used. The body height of the youngest children, aged 2 and 3 years, is less than that of their healthy peers. Children between 4 and 7 years old catch up slightly, but at later ages, development slows down, and in adults, the median body height shows an SDS of -2.7.

  5. Deficient expression of the small proteoglycan decorin in a case of severe/lethal osteogenesis imperfecta

    SciTech Connect

    Dyne, K.M.; Valli, M.; Forlino, A.; Cetta, G.; Mottes, M.; Kresse, H.

    1996-05-03

    In osteogenesis imperfecta (OI) the effects of mutations in type I collagen genes generally reflect their nature and localization. Unrelated individuals sharing identical mutations present, in general, similar clinical phenotypes. However, in some such cases the clinical phenotype differs. This variable clinical expression could be the result of abnormalities in other connective tissue proteins. Since decorin is a component of connective tissue, binds to type I collagen fibrils and plays a role in matrix assembly, we studied decorin production in skin fibroblasts from OI patients. Cultured fibroblasts from one patient with extremely severe osteogenesis imperfecta (classified as type II/III) who has an {alpha}1(I)gly415ser mutation were found to secrete barely detectable amounts of decorin into culture medium. Western blotting using antibodies raised against decorin confirmed the reduction of the decorin core protein and Northern blot analysis showed decorin mRNA levels below the limit of detection. Cells from a patient, with a less severe phenotype, bearing a mutation in the same position of the triple helix ({alpha}1(1)gly415) expressed decorin normally. The different clinical phenotypes could be due to the differing genetic backgrounds of the patients, so it is tempting to conclude that in our most severely affected patient, the absence of decorin aggravates the clinical phenotype. 34 refs., 4 figs., 1 tab.

  6. Next-generation sequencing of common osteogenesis imperfecta-related genes in clinical practice

    PubMed Central

    Árvai, Kristóf; Horváth, Péter; Balla, Bernadett; Tobiás, Bálint; Kató, Karina; Kirschner, Gyöngyi; Klujber, Valéria; Lakatos, Péter; Kósa, János P.

    2016-01-01

    Next generation sequencing (NGS) is a rapidly developing area in genetics. Utilizing this technology in the management of disorders with complex genetic background and not recurrent mutation hot spots can be extremely useful. In this study, we applied NGS, namely semiconductor sequencing to determine the most significant osteogenesis imperfecta-related genetic variants in the clinical practice. We selected genes coding collagen type I alpha-1 and-2 (COL1A1, COL1A2) which are responsible for more than 90% of all cases. CRTAP and LEPRE1/P3H1 genes involved in the background of the recessive forms with relatively high frequency (type VII and VIII) represent less than 10% of the disease. In our six patients (1–41 years), we identified 23 different variants. We found a total of 14 single nucleotide variants (SNV) in COL1A1 and COL1A2, 5 in CRTAP and 4 in LEPRE1. Two novel and two already well-established pathogenic SNVs have been identified. Among the newly recognized mutations, one results in an amino acid change and one of them is a stop codon. We have shown that a new full-scale cost-effective NGS method can be developed and utilized to supplement diagnostic process of osteogenesis imperfecta with molecular genetic data in clinical practice. PMID:27335225

  7. Osteogenesis imperfecta presenting as aneurysmal subarachnoid haemorrhage in a 53-year-old man

    PubMed Central

    Kaliaperumal, Chandrasekaran; Walsh, Tom; Balasubramanian, Chandramouli; Wyse, Gerry; Fanning, Noel; Kaar, George

    2011-01-01

    The authors describe a case of aneurysmal subarachnoid haemorrhage in a 53-year-old man with background of osteogenesis imperfecta (OI). CT brain revealed diffuse subarachnoid haemorrhage (SAH) and cerebral angiogram subsequently confirmed vertebral artery aneurysm rupture leading to SAH. To the authors knowledge this is the first case of vertebral artery aneurysmal SAH described in OI. A previously undiagnosed OI was confirmed by genetic analysis (COL1A1 gene mutation). This aneurysm was successfully treated by endovascular route. Post interventional treatment patient developed stroke secondary to vasospasm. Communicating hydrocephalus, which developed in the process of management, was successfully treated with ventriculo-peritoneal shunt. The aetio-pathogenesis and management of this condition is described. The authors have reviewed the literature and genetic basis of this disease. PMID:22674700

  8. Phenotype Characterization and DSPP Mutational Analysis of Three Brazilian Dentinogenesis Imperfecta Type II Families

    PubMed Central

    Acevedo, A.C.; Santos, L.J.S.; Paula, L.M.; Dong, J.; MacDougall, M.

    2008-01-01

    The aim of this study was to perform phenotype analysis and dentin sialophosphoprotein (DSPP) mutational analysis on 3 Brazilian families diagnosed with dentinogenesis imperfecta type II (DGI-II) attending the Dental Anomalies Clinic in Brasilia, Brazil. Physical and oral examinations, as well as radiographic and histopathological analyses, were performed on 28 affected and unaffected individuals. Clinical, radiographic and histopathological analyses confirmed the diagnosis of DGI-II in 19 individuals. Pulp stones were observed in ground sections of several teeth in 2 families, suggesting that obliteration of pulp chambers and root canals results from the growth of these nodular structures. Mutational DSPP gene analysis of representative affected family members revealed 7 various non-disease-causing alterations in exons 1–4 within the dentin sialoprotein domain. Further longitudinal studies are necessary to elucidate the progression of pulpal obliteration in the DGI-II patients studied as well as the molecular basis of their disease. PMID:18797159

  9. Aortic valve replacement in a patient with ostegenesis imperfecta A case report.

    PubMed

    Concistrè, Giovanni; Casali, Giovanni; Della Monica, Paola Lilla; Montalto, Andrea; Ranocchi, Federeico; Fiorani, Brenno; Musumeci, Francesco

    2014-01-01

    L’Osteogenesi Imperfecta (OI) è un’alterazione ereditaria del tessuto connettivo in cui l’estrema fragilità ossea causa fratture. La dilatazione aneurismatica della radice aortica, l’insufficienza valvolare aortica ed il prolasso mitralico sono rare manifestazioni cardiovascolari di OI. L’intervento cardiochirurgico in questi pazienti può presentare importanti complicanze legate alla incrementata fragilità tissutale e capillare. Noi riportiamo un caso di chirurgia a cuore aperto in una donna con insufficienza valvolare aortica isolata secondaria ad OI. Il decorso postoperatorio è stato privo di complicanze maggiori e la paziente è stata dimessa presso propria abitazione in ottava giornata postoperatoria. È stata seguita con controlli frequenti per un anno. Nonostante la fragilità tissutale non abbia avuto impatto sul decorso postoperatorio, bisogna sempre tenere in considerazione la possibilità di eventi avversi nei pazienti con tale disordine connettivale. È necessario pertanto una meticolosa tecnica chirurgica che possa anticipare possibili complicanze postoperatorie.

  10. Osteogenesis imperfecta lethal in infancy: case report and scanning electron microscopic studies of the deciduous teeth.

    PubMed

    Levin, L S; Rosenbaum, K N; Brady, J M; Dorst, J P

    1982-12-01

    Radiologic evaluation of the skeleton and scanning electron microscopic studies of the teeth were performed on an infant boy with a lethal osteogenesis imperfecta (OI) syndrome who died at 10 mo of pneumonia. The skeletal findings included ribs that were focally expanded by fracture calluses, flat vertebral bodies, and wide limb bones. On fractured tooth surfaces, the enamel and dentin were normal as was the dentin calcification front. Although microscopic abnormalities have been noted in teeth from previously reported infants with lethal OI, a few studies also report infants with normal teeth. These differences in dental findings may indicate heterogeneity in OI lethal in infancy. Results of our study indicate that, until the primary biochemical defects in the OI syndromes are elucidated, examination of teeth from other infants with lethal OI and detailed evaluation of other clinical and skeletal features will aid in delineating heterogeneity and variation in expression in lethal OI.

  11. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

    PubMed Central

    Lindert, Uschi; Cabral, Wayne A.; Ausavarat, Surasawadee; Tongkobpetch, Siraprapa; Ludin, Katja; Barnes, Aileen M.; Yeetong, Patra; Weis, Maryann; Krabichler, Birgit; Srichomthong, Chalurmpon; Makareeva, Elena N.; Janecke, Andreas R.; Leikin, Sergey; Röthlisberger, Benno; Rohrbach, Marianne; Kennerknecht, Ingo; Eyre, David R.; Suphapeetiporn, Kanya; Giunta, Cecilia; Marini, Joan C.; Shotelersuk, Vorasuk

    2016-01-01

    Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development. PMID:27380894

  12. Basilar impression in osteogenesis imperfecta: can it be treated with halo traction and posterior fusion?

    PubMed

    Noske, D P; van Royen, B J; Bron, J L; Vandertop, W P

    2006-12-01

    Basilar impression (BI) and hydrocephalus complicating osteogenesis imperfecta (OI) is usually treated by anterior transoral decompression and posterior fixation. Nevertheless, it may be questioned if posterior fusion following axial halo traction is adequate in patients with symptomatic BI complicating OI. We report on a case with progressive symptomatic hydrocephalus and BI complicating OI that was successfully treated by halo traction followed by posterior occipitocervical fusion. However, after a symptom free interval of 2 years the patient suffered from recurrence of symptomatic hydrocephalus needing additional ventriculoperitoneal (VP) shunt placement. In conclusion, posterior fusion without additional VP shunt placement may not be effective in the long term for ameliorating symptoms and signs and halting progressive hydrocephalus in BI complicating OI.

  13. In utero stem cell transplantation for radical treatment of osteogenesis imperfecta: perspectives and controversies.

    PubMed

    Amin, Mariam Taher Mohamed; Shazly, Sherif Abd-Elkarim Mohammed

    2014-11-01

    Osteogenesis imperfecta (OI) is a lethal hereditary connective tissue disease that affects the synthesis of type I collagen. Current treatment options including surgical, physical, and medical treatment help to reduce pain, deformities, and rate of bone fracture. However, these choices are insufficient and are associated with many adverse effects. The development of stem cell therapy allows scientists to consider this option for radical treatment of many genetic diseases including OI. In utero stem cell transplantation provides a better opportunity for early prenatal intervention while the fetus is preimmune and before any permanent damage occurs. Few animal and human trials for treatment of OI have been published, and the results were promising but still controversial. Our objective is to review the available evidence and discuss the points of controversy including the parameters of treatment success and postnatal predictors of long-term treatment outcome.

  14. Beneficial effect of long term intravenous bisphosphonate treatment of osteogenesis imperfecta

    PubMed Central

    Astrom, E; Soderhall, S

    2002-01-01

    Aim: To find an effective symptomatic treatment for osteogenesis imperfecta (OI). Methods: In a prospective observational study disodium pamidronate (APD) was given as monthly intravenous infusions to 28 children and adolescents (aged 0.6–18 years) with severe OI or a milder form of the disease, but with spinal compression fractures. Results: During treatment for 2–9 years, dual energy x ray absorptiometry measurements of the total body and of the lumbar spine showed a gradual increase in bone density. All bone metabolism variables in serum (alkaline phosphatase, osteocalcin, procollagen 1 C-terminal peptide, collagen 1 teleopeptide) and urine (deoxypyridinoline) indicated that there was a decrease in bone turnover. All patients experienced beneficial effects and the younger patients reported a major improvement in wellbeing, pain, and mobility without significant side effects. Vertebral remodelling was also seen. Conclusions: APD seems to be an efficient symptomatic treatment for children and adolescents with OI. PMID:11970931

  15. Bone tissue ultrastructural defects in a mouse model for osteogenesis imperfecta: a Raman spectroscopy study

    NASA Astrophysics Data System (ADS)

    Chen, Tsoching; Kozloff, Kenneth M.; Goldstein, Steven A.; Morris, Michael D.

    2004-07-01

    Osteogenesis imperfecta (OI) is genetic defect in which the genes that code for the α1(I) or α2(I) chains of type I collagen are defective. The defects often result in substitution of a bulky amino acid for glycine, causing formation of collagen that can not form the normal triple helix. Depending on the details of the defects, the outcomes range from controllable to lethal. This study focuses on OI type IV, a more common and moderately severe form of the disease. People with the disease have a substantial increase in the risk and rate of fracture. We examine the spectroscopic consequences of these defects, using a mouse model (BRTL) that mimics OI type IV. We compare Raman images from tibial cortical tissue of wild-type mice and BRTL mice with single copy of mutation and show that both mineral to matrix ratios and collagen inter-fibril cross-links are different in wild-type and mutant mice.

  16. Identification and in vivo functional characterization of novel compound heterozygous BMP1 variants in osteogenesis imperfecta.

    PubMed

    Cho, Sung Yoon; Asharani, P V; Kim, Ok-Hwa; Iida, Aritoshi; Miyake, Noriko; Matsumoto, Naomichi; Nishimura, Gen; Ki, Chang-Seok; Hong, Geehay; Kim, Su Jin; Sohn, Young Bae; Park, Sung Won; Lee, Jieun; Kwun, Younghee; Carney, Thomas J; Huh, Rimm; Ikegawa, Shiro; Jin, Dong-Kyu

    2015-02-01

    Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal-dominant inheritance, but many autosomal-recessive genes have been reported. We applied whole-exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypofunctional nature of the two variants was demonstrated in a zebrafish assay.

  17. Mutations in FKBP10 Cause Recessive Osteogenesis Imperfecta and Bruck Syndrome

    PubMed Central

    Kelley, Brian P; Malfait, Fransiska; Bonafe, Luisa; Baldridge, Dustin; Homan, Erica; Symoens, Sofie; Willaert, Andy; Elcioglu, Nursel; Van Maldergem, Lionel; Verellen-Dumoulin, Christine; Gillerot, Yves; Napierala, Dobrawa; Krakow, Deborah; Beighton, Peter; Superti-Furga, Andrea; De Paepe, Anne; Lee, Brendan

    2011-01-01

    Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by bone fragility and alteration in synthesis and posttranslational modification of type I collagen. Autosomal dominant OI is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Bruck syndrome is a recessive disorder featuring congenital contractures in addition to bone fragility; Bruck syndrome type 2 is caused by mutations in PLOD2 encoding collagen lysyl hydroxylase, whereas Bruck syndrome type 1 has been mapped to chromosome 17, with evidence suggesting region 17p12, but the gene has remained elusive so far. Recently, the molecular spectrum of OI has been expanded with the description of the basis of a unique posttranslational modification of type I procollagen, that is, 3-prolyl-hydroxylation. Three proteins, cartilage-associated protein (CRTAP), prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene), and the prolyl cis-trans isomerase cyclophilin-B (PPIB), form a complex that is required for fibrillar collagen 3-prolyl-hydroxylation, and mutations in each gene have been shown to cause recessive forms of OI. Since then, an additional putative collagen chaperone complex, composed of FKBP10 (also known as FKBP65) and SERPINH1 (also known as HSP47), also has been shown to be mutated in recessive OI. Here we describe five families with OI-like bone fragility in association with congenital contractures who all had FKBP10 mutations. Therefore, we conclude that FKBP10 mutations are a cause of recessive osteogenesis imperfecta and Bruck syndrome, possibly Bruck syndrome Type 1 since the location on chromosome 17 has not been definitely localized. © 2011 American Society for Bone and Mineral Research. PMID:20839288

  18. Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

    PubMed Central

    Lindahl, Katarina; Åström, Eva; Rubin, Carl-Johan; Grigelioniene, Giedre; Malmgren, Barbro; Ljunggren, Östen; Kindmark, Andreas

    2015-01-01

    Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype–phenotype studies on >100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the α1- and α2-chains were associated with the absence of dentinogenesis imperfecta (P<0.0001 vs 0.0049), while only those in the α1-chain were associated with blue sclera (P=0.0110). Comparing glycine with serine substitutions, α1-alterations were associated with more severe phenotype (P=0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P<0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent >95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in >95% of an entire OI population. PMID:25944380

  19. Quantitative second harmonic generation imaging of the diseased state osteogenesis imperfecta: experiment and simulation.

    PubMed

    Lacomb, Ronald; Nadiarnykh, Oleg; Campagnola, Paul J

    2008-06-01

    We report the integrated use of 3D second harmonic generation (SHG) imaging microscopy and Monte Carlo simulation as a combined metric to quantifiably differentiate normal and diseased tissues based on the physical properties of the respective extracellular matrix. To achieve this, we have identified a set of parameters comprised of the SHG creation attributes and the bulk optical parameters, which are used collectively via comparative analysis. Monte Carlo simulations of the SHG axial directional and attenuation responses allow their decomposition into the underlying factors that are not readily obtainable through experimental techniques. Specifically, this approach allows for estimation of the SHG creation attributes (directionality and relative conversion efficiency) and separation of primary and secondary filter effects, collectively that form the observed SHG contrast. The quantitative metric is shown for the connective tissue disorder Osteogenesis Imperfecta (characterized by abnormal assembly of type I collagen) using a murine model that expresses the disease in the dermis layer of skin. Structural dissimilarities between the osteogenesis imperfecta mouse and wild-type tissues lead to significant differences in the SHG depth-dependent directionality and signal attenuation. The Monte Carlo simulations of these responses using measured bulk optical parameters reproduce the experimental data trends, and the extracted emission directionality and conversion efficiencies are consistent with independent determinations. The simulations also illustrate the dominance of primary filter affects on overall SHG generation and attenuation. Thus, the combined method of 3D SHG imaging and modeling forms an essential foundation for parametric description of the matrix properties that are not distinguishable by sole consideration of either bulk optical parameters or SHG alone. Moreover, due to the quasi-coherence of the SHG process in tissues, we submit that this approach

  20. Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta.

    PubMed

    Lindahl, Katarina; Åström, Eva; Rubin, Carl-Johan; Grigelioniene, Giedre; Malmgren, Barbro; Ljunggren, Östen; Kindmark, Andreas

    2015-08-01

    Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype-phenotype studies on >100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the α1- and α2-chains were associated with the absence of dentinogenesis imperfecta (P<0.0001 vs 0.0049), while only those in the α1-chain were associated with blue sclera (P=0.0110). Comparing glycine with serine substitutions, α1-alterations were associated with more severe phenotype (P=0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P<0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent >95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in >95% of an entire OI population.

  1. Increased intra-cortical porosity reduces bone stiffness and strength in pediatric patients with osteogenesis imperfecta.

    PubMed

    Vardakastani, V; Saletti, D; Skalli, W; Marry, P; Allain, J M; Adam, C

    2014-12-01

    Osteogenesis imperfecta (OI) is a heritable disease occurring in one out of every 20,000 births. Although it is known that Type I collagen mutation in OI leads to increased bone fragility, the mechanism of this increased susceptibility to fracture is not clear. The aim of this study was to assess the microstructure of cortical bone fragments from patients with osteogenesis imperfecta (OI) using polarized light microscopy, and to correlate microstructural observations with the results of previously performed mechanical compression tests on bone from the same source. Specimens of cortical bone were harvested from the lower limbs of three (3) OI patients at the time of surgery, and were divided into two groups. Group 1 had been subjected to previous micro-mechanical compression testing, while Group 2 had not been subjected to any prior testing. Polarized light microscopy revealed disorganized bone collagen architecture as has been previously observed, as well as a large increase in the areal porosity of the bone compared to typical values for healthy cortical bone, with large (several hundred micron sized), asymmetrical pores. Importantly, the areal porosity of the OI bone samples in Group 1 appears to correlate strongly with their previously measured apparent Young's modulus and compressive strength. Taken together with prior nanoindentation studies on OI bone tissue, the results of this study suggest that increased intra-cortical porosity is responsible for the reduction in macroscopic mechanical properties of OI cortical bone, and therefore that in vivo imaging modalities with resolutions of ~100 μm or less could potentially be used to non-invasively assess bone strength in OI patients. Although the number of subjects in this study is small, these results highlight the importance of further studies in OI bone by groups with access to human OI tissue in order to clarify the relationship between increased porosity and reduced macroscopic mechanical integrity.

  2. Genotype–phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I

    PubMed Central

    Rauch, Frank; Lalic, Liljana; Roughley, Peter; Glorieux, Francis H

    2010-01-01

    Osteogenesis imperfecta (OI) is a heritable disorder with bone fragility that is often associated with short stature, tooth abnormalities (dentinogenesis imperfecta), and blue sclera. The most common mutations associated with OI result from the substitution for glycine by another amino acid in the triple helical domain of either the α1 or the α2 chain of collagen type I. In this study, we compared the results of genotype analysis and clinical examination in 161 OI patients (median age: 13 years) who had glycine mutations in the triple helical domain of α1(I) (n=67) or α2(I) (n=94). Serine substitutions were the most frequently encountered type of mutation in both chains. Compared with patients with serine substitutions in α2(I) (n=40), patients with serine substitutions in α1(I) (n=42) on average were shorter (median height z-score −6.0 vs −3.4; P=0.005), indicating that α1(I) mutations cause a more severe phenotype. Height correlated with the location of the mutation in the α2(I) chain but not in the α1(I) chain. Patients with mutations affecting the first 120 amino acids at the amino-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta. Among patients from different families sharing the same mutation, about 90 and 75% were concordant for dentinogenesis imperfecta and blue sclera, respectively. These data should be useful to predict disease phenotype in newly diagnosed OI patients. PMID:20087402

  3. Reduced diaphyseal strength associated with high intracortical vascular porosity within long bones of children with osteogenesis imperfecta.

    PubMed

    Albert, Carolyne; Jameson, John; Smith, Peter; Harris, Gerald

    2014-09-01

    Osteogenesis imperfecta is a genetic disorder resulting in bone fragility. The mechanisms behind this fragility are not well understood. In addition to characteristic bone mass deficiencies, research suggests that bone material properties are compromised in individuals with this disorder. However, little data exists regarding bone properties beyond the microstructural scale in individuals with this disorder. Specimens were obtained from long bone diaphyses of nine children with osteogenesis imperfecta during routine osteotomy procedures. Small rectangular beams, oriented longitudinally and transversely to the diaphyseal axis, were machined from these specimens and elastic modulus, yield strength, and maximum strength were measured in three-point bending. Intracortical vascular porosity, bone volume fraction, osteocyte lacuna density, and volumetric tissue mineral density were determined by synchrotron micro-computed tomography, and relationships among these mechanical properties and structural parameters were explored. Modulus and strength were on average 64-68% lower in the transverse vs. longitudinal beams (P<0.001, linear mixed model). Vascular porosity ranged between 3 and 42% of total bone volume. Longitudinal properties were associated negatively with porosity (P≤0.006, linear regressions). Mechanical properties, however, were not associated with osteocyte lacuna density or volumetric tissue mineral density (P≥0.167). Bone properties and structural parameters were not associated significantly with donor age (P≥0.225, linear mixed models). This study presents novel data regarding bone material strength in children with osteogenesis imperfecta. Results confirm that these properties are anisotropic. Elevated vascular porosity was observed in most specimens, and this parameter was associated with reduced bone material strength. These results offer insight toward understanding bone fragility and the role of intracortical porosity on the strength of bone

  4. Reduced diaphyseal strength associated with high intracortical vascular porosity within long bones of children with Osteogenesis Imperfecta

    PubMed Central

    Jameson, John; Smith, Peter; Harris, Gerald

    2015-01-01

    Osteogenesis Imperfecta is a genetic disorder resulting in bone fragility. The mechanisms behind this fragility are not well understood. In addition to characteristic bone mass deficiencies, research suggests that bone material properties are compromised in individuals with this disorder. However, little data exists regarding bone properties beyond the microstructural scale in individuals with this disorder. Specimens were obtained from long bone diaphyses of nine children with osteogenesis imperfecta during routine osteotomy procedures. Small rectangular beams, oriented longitudinally and transversely to the diaphyseal axis, were machined from these specimens and elastic modulus, yield strength, and maximum strength were measured in three-point bending. Intracortical vascular porosity, bone volume fraction, osteocyte lacuna density, and volumetric tissue mineral density were determined by synchrotron micro-computed tomography, and relationships among these mechanical properties and structural parameters were explored. Modulus and strength were on average 64–68% lower in the transverse vs. longitudinal beams (P<0.001, linear mixed model). Vascular porosity ranged between 3–42% of total bone volume. Longitudinal properties were associated negatively with porosity (P≤0.006, linear regressions). Mechanical properties, however, were not associated with osteocyte lacuna density or volumetric tissue mineral density (P≥0.167). Bone properties and structural parameters were not associated significantly with donor age (p≥0.225, linear mixed models). This study presents novel data regarding bone material strength in children with osteogenesis imperfecta. Results confirm that these properties are anisotropic. Elevated vascular porosity was observed in most specimens, and this parameter was associated with reduced bone material strength. These results offer insight towards understanding bone fragility and the role of intracortical porosity on the strength of bone

  5. Bisphosphonates for the prevention of fractures in osteogenesis imperfecta: meta-analysis of placebo-controlled trials.

    PubMed

    Hald, Jannie D; Evangelou, Evangelos; Langdahl, Bente L; Ralston, Stuart H

    2015-05-01

    Bisphosphonates are widely used off-label in the treatment of patients with osteogenesis imperfecta (OI) with the intention of reducing the risk of fracture. Although there is strong evidence that bisphosphonates increase bone mineral density in osteogenesis imperfecta, the effects on fracture occurrence have been inconsistent. The aim of this study was to gain a better insight into the effects of bisphosphonate therapy on fracture risk in patients with osteogenesis imperfecta by conducting a meta-analysis of randomized controlled trials in which fractures were a reported endpoint. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials in which the effects of bisphosphonates on fracture risk in osteogenesis imperfecta were compared with placebo and conducted a meta-analysis of these studies using standard methods. Heterogeneity was assessed using the I2 statistic. Six eligible studies were identified involving 424 subjects with 751 patient-years of follow-up. The proportion of patients who experienced a fracture was not significantly reduced by bisphosphonate therapy (Relative Risk [RR] = 0.83 [95% confidence interval 0.69-1.01], p = 0.06) with no heterogeneity between studies (I2  = 0). The fracture rate was reduced by bisphosphonate treatment when all studies were considered (RR = 0.71 [0.52-0.96], p = 0.02), but with considerable heterogeneity (I2  = 36%) explained by one study where a small number of patients in the placebo group experienced a large number of fractures. When this study was excluded, the effects of bisphosphonates on fracture rate was not significant (RR = 0.79 [0.61-1.02], p = 0.07, I2  = 0%). We conclude that the effects of bisphosphonates on fracture prevention in osteogenesis imperfecta are inconclusive. Adequately powered trials with a fracture endpoint are needed to further investigate the risks and benefits of bisphosphonates in this condition.

  6. Safety enhancement of a specialized power assisted tricycle for a child with osteogenesis imperfecta type III.

    PubMed

    Geu, Matthew J; Tuffner, Francis F; Madsen, Robert O; Harman, William M; Barrett, Steven F

    2005-01-01

    A child in the community of Laramie, Wyoming was born with Osteogenesis Imperfecta which is a genetic disorder that limits the physical abilities, size, and strength of the child. A customized power assisted tricycle was developed, which offered a unique opportunity to serve multiple purposes in his childhood development. This tricycle will ultimately provide him with the opportunity to gain muscle mass, strength, coordination, and confidence. The tricycle was completed as a senior design project in 2002, funded by the National Science Foundation, Biomedical Engineering Program and research to Aid Persons with Disabilities Program and University of Wyoming, College of Engineering Undergraduate Design Project to Aid Wyoming Persons with Disabilities. Unfortunately, the tricycle did not provide the necessary features to allow him to ride the tricycle safely. For this reason the tricycle was redesigned to include many different redundant safety systems which allows the tricycle to be safe for the child's use. Being funded by the same grant, new systems were added to the tricycle. A panic kill switch, automatic brakes, numerous redundant velocity sensors, tip over prevention circuitry, a redesigned operating system, a battery recharge port, and other systems were added, allowing for the tricycle to provide a high level of safety. A great deal of testing and sound design practices have been taken into consideration throughout the addition of these systems. Without these improvements, the child would not have the opportunity to use the tricycle to help with his development.

  7. Muscle force sensitivity of a finite element fracture risk assessment model in osteogenesis imperfecta - biomed 2009.

    PubMed

    Fritz, Jessica M; Guan, Yabo; Wang, Mei; Smith, Peter A; Harris, Geald F

    2009-01-01

    Osteogenesis imperfecta (OI) is a heritable bone fragility disorder characterized by skeletal deformities and increased bone fragility. There is currently no established clinical method for quantifying fracture risk in OI patients. A method for developing a finite element model of the femur to assist in fracture risk assessment of a selected patient with OI type I was created. The material properties were based on nanoindentation testing of OI bone specimens collected during routine surgery. Dynamic data from clinical gait analysis was used to prescribe joint reaction forces and moments in a quasi-static model. Muscle forces were prescribed according to current literature. Von Mises stresses were analyzed across all seven phases of the gait cycle and analyzed for sensitivity to changes in muscle forces. The model showed that the patient with OI was not at current risk for fracture during normal gait. The highest stress levels occurred during mid stance and loading response. Maximum von Mises stresses were most sensitive to the gluteal muscles. Insight provided by the model may be useful for similar clinical applications, more refined model development and an improved ability for fracture prediction.

  8. A fracture risk assessment model of the femur in children with osteogenesis imperfecta (OI) during gait.

    PubMed

    Fritz, Jessica M; Guan, Yabo; Wang, Mei; Smith, Peter A; Harris, Gerald F

    2009-11-01

    Osteogenesis imperfecta (OI) is a heritable bone fragility disorder characterized by skeletal deformities and increased bone fragility. There is currently no established clinical method for quantifying fracture risk in OI patients. This study begins the development of a patient-specific model for femur fracture risk assessment and prediction based on individuals' gait analysis data, bone geometry from imaging and material properties from nanoindentation (Young's modulus=19 GPa, Poisson's ratio=0.3). Finite element models of the femur were developed to assess fracture risk of the femur in a pediatric patient with OI type I. Kinetic data from clinical gait analysis was used to prescribe loading conditions on the femoral head and condyles along with muscle forces on the bone's surface. von Mises stresses were analyzed against a fracture strength of 115 MPa. The patient with OI whose femur was modeled showed no risk of femoral fracture during normal gait. The highest stress levels occurred during the mid-stance and loading responses phases of gait. The location of high stress migrated throughout the femoral diaphysis across the gait cycle. Maximum femoral stress levels occurred during the gait cycle phases associated with the highest loading. The fracture risk (fracture strength/von Mises stress), however, was low. This study provides a relevant method for combining functional activity, material property and analytical methods to improve patient monitoring.

  9. Childhood Osteoporosis and Presentation of Two Cases with Osteogenesis Imperfecta Type V

    PubMed Central

    BRATANIC, Nina; DZODAN, Bojana; TREBUSAK PODKRAJSEK, Katarina; BERTOK, Sara; OSTANEK, Barbara; MARC, Janja; BATTELINO, Tadej; AVBELJ STEFANIJA, Magdalena

    2015-01-01

    Introduction Osteogenesis imperfecta (OI) is etiologically heterogeneous disorder characterized by childhood osteoporosis. A subtype OI type V is caused by the same c.-14C>T mutation in the IFITM5 gene. Nevertheless, there is a marked interindividual phenotypic variability in clinical presentation; however, response to bisphosphonates is reported to be good. Methods Two individuals with OI type V had multiple recurrent fractures with hypertrophic calluses, scoliosis and ossifications of the forearm interosseous membranes. Sequencing of IFITM5, genotyping of variants rs2297480 in farnesyl diphosphate synthase gene (FDPS), and rs3840452 in geranylgeranyl diphosphate synthase 1 gene (GGPS1), both involved in bisphosphonate metabolism, was performed. Results In patient 1 BMD reached normal values during bisphosphonate treatment and remained normal four years after the treatment discontinuation. In patient 2 no increase in BMD after five years of bisphosphonate treatment was observed and callus formation continued. The c.-14C>T IFITM5 mutation in heterozygous state was detected in both individuals. Additionally, both patients carried FDPS variant rs2297480 in homozygous state, and were heterozygous for GGPS 1 variant rs3840452. Conclusions The paper presents a short overview of childhood osteoporosis with a special emphasis on OI type V by presenting two cases. Both OI type V patients had identical disease-causing mutation, but marked interindividual phenotypic variability. The striking failure in response to bisphosphonate treatment in one of the patients could not be explained by the variants in genes involved in bisphosphonate metabolism. PMID:27646918

  10. Testing for osteogenesis imperfecta in cases of suspected non-accidental injury

    PubMed Central

    Marlowe, A; Pepin, M; Byers, P

    2002-01-01

    To evaluate if laboratory testing for osteogenesis imperfecta (OI) identifies children unrecognised by clinical examination in instances where non-accidental injury (NAI) is suspected as the likely cause of fracture, we carried out a retrospective review of available medical records and biochemical test results from 262 patients. Cultured fibroblasts were received for biochemical testing for OI from children in whom the diagnosis of NAI was suspected. Eleven of the samples had alterations in the amount or structure of type I collagen synthesised, consistent with the diagnosis of OI, and in 11 others we could not exclude OI. Referring physicians correctly identified children with OI in six of the 11 instances established by biochemical studies, did not identify OI by clinical examination in three, and there was inadequate clinical information to know in two others. Biochemical testing was inconclusive in 11 infants in whom the diagnosis of OI could not be excluded, none of whom were thought to be affected by the referring clinicians. Four children believed to have OI by clinical examination had normal biochemical studies, a false positive clinical diagnosis attributed, in large part, to the use of scleral hue (a feature that is age dependent) as a major diagnostic criterion. Given the inability to identify all children with OI by clinical examination in situations of suspected NAI, laboratory testing for OI (and other genetic predispositions for fractures) is a valuable adjunct in discerning the basis for fractures and may identify a small group of children with previously undiagnosed OI. PMID:12070242

  11. Novel Deletion of SERPINF1 Causes Autosomal Recessive Osteogenesis Imperfecta Type VI in Two Brazilian Families

    PubMed Central

    Moldenhauer Minillo, Renata; Sobreira, Nara; de Fatima de Faria Soares, Maria; Jurgens, Julie; Ling, Hua; Hetrick, Kurt N.; Doheny, Kimberly F.; Valle, David; Brunoni, Decio; Alvarez Perez, Ana B.

    2014-01-01

    Autosomal recessive osteogenesis imperfecta (OI) accounts for 10% of all OI cases, and, currently, mutations in 10 genes (CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SERPINF1, SP7, BMP1, TMEM38B, and WNT1) are known to be responsible for this form of the disease. PEDF is a secreted glycoprotein of the serpin superfamily that maintains bone homeostasis and regulates osteoid mineralization, and it is encoded by SERPINF1, currently associated with OI type VI (MIM 172860). Here, we report a consanguineous Brazilian family in which multiple individuals from at least 4 generations are affected with a severe form of OI, and we also report an unrelated individual from the same small city in Brazil with a similar but more severe phenotype. In both families the same homozygous SERPINF1 19-bp deletion was identified which is not known in the literature yet. We described intra- and interfamilial clinical and radiological phenotypic variability of OI type VI caused by the same homozygous SERPINF1 19-bp deletion and suggest a founder effect. Furthermore, the SERPINF1 genotypes/phenotypes reported so far in the literature are reviewed. PMID:25565926

  12. Phenotypic Variability of Osteogenesis Imperfecta Type V Caused by an IFITM5 Mutation

    PubMed Central

    Shapiro, Jay R; Lietman, Caressa; Grover, Monica; Lu, James T; Nagamani, Sandesh CS; Dawson, Brian C; Baldridge, Dustin M; Bainbridge, Matthew N; Cohn, Dan H; Blazo, Maria; Roberts, Timothy T; Brennen, Feng-Shu; Wu, Yimei; Gibbs, Richard A; Melvin, Pamela; Campeau, Philippe M; Lee, Brendan H

    2013-01-01

    In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5′ untranslated region (5′UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.–14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation. PMID:23408678

  13. Osteogenesis imperfecta in children and adolescents-new developments in diagnosis and treatment.

    PubMed

    Trejo, P; Rauch, F

    2016-12-01

    Osteogenesis imperfecta (OI) is the most prevalent heritable bone fragility disorder in children. It has been known for three decades that the majority of individuals with OI have mutations in COL1A1 or COL1A2, the two genes coding for collagen type I alpha chains, but in the past 10 years defects in at least 17 other genes have been linked to OI. Almost all individuals with a typical OI phenotype have a mutation in one of the currently known genes. Regarding medical treatment, intravenous bisphosphonate therapy is the most widely used medical approach. This has a marked effect on vertebra in growing children and can lead to vertebral reshaping after compression fractures, but there is little effect of bisphosphonate therapy on the development of scoliosis. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. Newer medications with anti-resorptive and bone anabolic action are being investigated in an attempt to improve on the efficacy of bisphosphonates but the safety and efficacy of these new approaches in children with OI is not yet established.

  14. Mechanical and mineral properties of osteogenesis imperfecta human bones at the tissue level.

    PubMed

    Imbert, Laurianne; Aurégan, Jean-Charles; Pernelle, Kélig; Hoc, Thierry

    2014-08-01

    Osteogenesis imperfecta (OI) is a genetic disorder characterized by an increase in bone fragility on the macroscopic scale, but few data are available to describe the mechanisms involved on the tissue scale and the possible correlations between these scales. To better understand the effects of OI on the properties of human bone, we studied the mechanical and chemical properties of eight bone samples from children suffering from OI and compared them to the properties of three controls. High-resolution computed tomography, nanoindentation and Raman microspectroscopy were used to assess those properties. A higher tissue mineral density was found for OI bone (1.131 gHA/cm3 vs. 1.032 gHA/cm3, p=0.032), along with a lower Young's modulus (17.6 GPa vs. 20.5 GPa, p=0.024). Obviously, the mutation-induced collagen defects alter the collagen matrix, thereby affecting the mineralization. Raman spectroscopy showed that the mineral-to-matrix ratio was higher in the OI samples, while the crystallinity was lower, suggesting that the mineral crystals were smaller but more abundant in the case of OI. This change in crystal size, distribution and composition contributes to the observed decrease in mechanical strength.

  15. Potential of human fetal chorionic stem cells for the treatment of osteogenesis imperfecta.

    PubMed

    Jones, Gemma N; Moschidou, Dafni; Abdulrazzak, Hassan; Kalirai, Bhalraj Singh; Vanleene, Maximilien; Osatis, Suchaya; Shefelbine, Sandra J; Horwood, Nicole J; Marenzana, Massimo; De Coppi, Paolo; Bassett, J H Duncan; Williams, Graham R; Fisk, Nicholas M; Guillot, Pascale V

    2014-02-01

    Osteogenesis imperfecta (OI) is a genetic bone pathology with prenatal onset, characterized by brittle bones in response to abnormal collagen composition. There is presently no cure for OI. We previously showed that human first trimester fetal blood mesenchymal stem cells (MSCs) transplanted into a murine OI model (oim mice) improved the phenotype. However, the clinical use of fetal MSC is constrained by their limited number and low availability. In contrast, human fetal early chorionic stem cells (e-CSC) can be used without ethical restrictions and isolated in high numbers from the placenta during ongoing pregnancy. Here, we show that intraperitoneal injection of e-CSC in oim neonates reduced fractures, increased bone ductility and bone volume (BV), increased the numbers of hypertrophic chondrocytes, and upregulated endogenous genes involved in endochondral and intramembranous ossification. Exogenous cells preferentially homed to long bone epiphyses, expressed osteoblast genes, and produced collagen COL1A2. Together, our data suggest that exogenous cells decrease bone brittleness and BV by directly differentiating to osteoblasts and indirectly stimulating host chondrogenesis and osteogenesis. In conclusion, the placenta is a practical source of stem cells for the treatment of OI.

  16. Child abuse and osteogenesis imperfecta: how can they be still misdiagnosed? A case report

    PubMed Central

    D’Eufemia, Patrizia; Palombaro, Marta; Lodato, Valentina; Zambrano, Anna; Celli, Mauro; Persiani, Pietro; De Bari, Maria Pia; Sangiorgi, Luca

    2012-01-01

    Summary Osteogenesis imperfecta (OI) is a rare hereditary disease caused by mutations in genes coding for type I collagen, resulting in bone fragility. In literature are described forms lethal in perinatal period, forms which are moderate and slight forms where the only sign of disease is osteopenia. Child abuse is an important social and medical problem. Fractures are the second most common presentation after skin lesions and may present specific patterns. The differential diagnosis between slight-moderate forms of OI and child abuse could be very challenging especially when other signs typical of abuse are absent, since both could present with multiple fractures without reasonable explanations. We report a 20 months-old female with a history of 4 fractures occurred between the age of three and eighteen months, brought to authorities’ attention as a suspected child abuse. However when she came to our department physical examination, biochemical tests, total body X-ray and a molecular analysis of DNA led the diagnosis of OI. Thus, a treatment with bisphosphonate and a physical rehabilitation process, according to Vojta method, were started with improvement in bony mineralization, gross motor skills and absence of new fracture. In conclusion our case demonstrates how in any child presenting fractures efforts should be made to consider, besides child abuse, all the other hypothesis even the rarest as OI. PMID:23289038

  17. Phenotypic Variation in Dentinogenesis Imperfecta/Dentin Dysplasia Linked to 4q21

    PubMed Central

    Beattie, M.L.; Kim, J.-W.; Gong, S.-G.; Murdoch-Kinch, C.A.; Simmer, J.P.; Hu, J.C.-C.

    2008-01-01

    Dentinogenesis imperfecta (DGI) and dentin dysplasia (DD) are allelic disorders that primarily affect the formation of tooth dentin. Both conditions are autosomal-dominant and can be caused by mutations in the dentin sialophospho-protein gene (DSPP, 4q21.3). We recruited 23 members of a four-generation kindred, including ten persons with dentin defects, and tested the hypothesis that these defects are linked to DSPP. The primary dentition showed amber discoloration, pulp obliteration, and severe attrition. The secondary dentition showed either pulp obliteration with bulbous crowns and gray discoloration or thistle-tube pulp configurations, normal crowns, and mild gray discoloration. Haplotype analyses showed no recombination between three 4q21-q24 markers and the disease locus. Mutational analyses identified no coding or intron junction sequence variations associated with affection status in DMP1, MEPE, or the DSP portion of DSPP. The defects in the permanent dentition were typically mild and consistent with a diagnosis of DD-II, but some dental features associated with DGI-II were also present. We conclude that DD-II and DGI-II are milder and more severe forms, respectively, of the same disease. PMID:16567553

  18. Microstructural and Photoacoustic Infrared Spectroscopic Studies of Human Cortical Bone with Osteogenesis Imperfecta

    NASA Astrophysics Data System (ADS)

    Gu, Chunju; Katti, Dinesh R.; Katti, Kalpana S.

    2016-04-01

    The molecular basis of bone disease osteogenesis imperfecta (OI) and the mineralization of hydroxyapatite in OI bone have been of significant research interest. To further investigate the mechanism of OI disease and bone mineralization, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy, and x-ray diffraction (XRD) are used in the present study to describe the structural and compositional differences between OI and healthy bone. OI bone exhibits more porous, fibrous features, abnormal collagen fibrils, and abnormal mineral deposits. Likewise, photoacoustic-FTIR experiments indicate an aberrant collagen structure and an altered mineral structure in OI. In contrast, there is neither significant difference in the non-collagenous proteins (NCPs) composition observed nor apparent change in the crystal structure between OI and healthy bone minerals as shown in XRD and energy-dispersive x-ray spectroscopy (EDS) results. This observation indicates that the biomineralization process is more controlled by the bone cells and non-collagenous phosphorylated proteins. The present study also confirms that there is an orientational influence on the stoichiometry of the mineral in OI bone. Also, a larger volume of the hydrated layer in the transverse plane than the longitudinal plane of the mineral crystal structure is proposed. The appearance of a new C-S band in the FTIR spectra in OI bone suggests the substitution of glycine by cysteine in collagen molecules or/and an increased amount of cysteine-rich osteonectin that relates to mineral nucleation and mineral crystal formation.

  19. Micro-CT characterization of human trabecular bone in osteogenesis imperfecta

    NASA Astrophysics Data System (ADS)

    Jameson, John; Albert, Carolyne; Smith, Peter; Molthen, Robert; Harris, Gerald

    2011-03-01

    Osteogenesis imperfecta (OI) is a genetic syndrome affecting collagen synthesis and assembly. Its symptoms vary widely but commonly include bone fragility, reduced stature, and bone deformity. Because of the small size and paucity of human specimens, there is a lack of biomechanical data for OI bone. Most literature has focused on histomorphometric analyses, which rely on assumptions to extrapolate 3-D properties. In this study, a micro-computed tomography (μCT) system was used to directly measure structural and mineral properties in pediatric OI bone collected during routine surgical procedures. Surface renderings suggested a poorly organized, plate-like orientation. Patients with a history of bone-augmenting drugs exhibited increased bone volume fraction (BV/TV), trabecular number (Tb.N), and connectivity density (Eu.Conn.D). The latter two parameters appeared to be related to OI severity. Structural results were consistently higher than those reported in a previous histomorphometric study, but these differences can be attributed to factors such as specimen collection site, drug therapy, and assumptions associated with histomorphometry. Mineral testing revealed strong correlations with several structural parameters, highlighting the importance of a dual approach in trabecular bone testing. This study reports some of the first quantitative μCT data of human OI bone, and it suggests compelling possibilities for the future of OI bone assessment.

  20. Gender-dependence of bone structure and properties in adult osteogenesis imperfecta murine model.

    PubMed

    Yao, Xiaomei; Carleton, Stephanie M; Kettle, Arin D; Melander, Jennifer; Phillips, Charlotte L; Wang, Yong

    2013-06-01

    Osteogenesis imperfecta (OI) is a dominant skeletal disorder characterized by bone fragility and deformities. Though the oim mouse model has been the most widely studied of the OI models, it has only recently been suggested to exhibit gender-dependent differences in bone mineralization. To characterize the impact of gender on the morphometry/ultra-structure, mechanical properties, and biochemical composition of oim bone on the congenic C57BL/J6 background, 4-month-old oim/oim, +/oim, and wild-type (wt) female and male tibiae were evaluated using micro-computed tomography, three-point bending, and Raman spectroscopy. Dramatic gender differences were evident in both cortical and trabecular bone morphological and geometric parameters. Male mice had inherently more bone and increased moment of inertia than genotype-matched female counterparts with corresponding increases in bone biomechanical strength. The primary influence of gender was structure/geometry in bone growth and mechanical properties, whereas the mineral/matrix composition and hydroxyproline content of bone were influenced primarily by the oim collagen mutation. This study provides evidence of the importance of gender in the evaluation and interpretation of potential therapeutic strategies when using mouse models of OI.

  1. The effect of SERPINF1 in-frame mutations in osteogenesis imperfecta type VI.

    PubMed

    Al-Jallad, Hadil; Palomo, Telma; Roughley, Peter; Glorieux, Francis H; McKee, Marc D; Moffatt, Pierre; Rauch, Frank

    2015-07-01

    Osteogenesis imperfecta type VI is caused by mutations in SERPINF1, which codes for pigment-epithelium derived factor (PEDF). Most of the reported SERPINF1 mutations lead to premature termination codons, but three in-frame insertion or deletion mutations have also been reported. It is not clear how such in-frame mutations lead to OI type VI. In the present study we therefore investigated how SERPINF1 in-frame mutations affect the intracellular localization and secretion of PEDF. Skin fibroblasts affected by SERPINF1 in-frame mutations transcribed SERPINF1 at slightly reduced levels but secretion of PEDF was markedly diminished. Two deletions (p.F277del and the deletion of SERPINF1 exon 5) were associated with retention of PEDF in the endoplasmic reticulum and a stress response in osteoblastic cells. A recurrent in-frame duplication of three amino acids (p.Ala91_Ser93dup) appeared to lead to intracellular degradation but no retention in the endoplasmic reticulum or stress response. Immunofluorescence imaging in transiently transfected osteoblastic MC3T3-E1 cells suggested that PEDF affected by in-frame mutations was not transported along the secretory pathway. MC3T3-E1 osteoblasts stably overexpressing SERPINF1 with the p.Ala91_Ser93dup mutation had decreased collagen type I deposition and mineralization. Thus, the assessed homozygous in-frame deletions or insertions lead to retention or degradation within cellular compartments and thereby interfere with PEDF secretion.

  2. Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta.

    PubMed

    Sinder, Benjamin P; Eddy, Mary M; Ominsky, Michael S; Caird, Michelle S; Marini, Joan C; Kozloff, Kenneth M

    2013-01-01

    Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia and easy susceptibility to fracture. Symptoms are most prominent during childhood. Although antiresorptive bisphosphonates have been widely used to treat pediatric OI, controlled trials show improved vertebral parameters but equivocal effects on long-bone fracture rates. New treatments for OI are needed to increase bone mass throughout the skeleton. Sclerostin antibody (Scl-Ab) therapy is potently anabolic in the skeleton by stimulating osteoblasts via the canonical wnt signaling pathway, and may be beneficial for treating OI. In this study, Scl-Ab therapy was investigated in mice heterozygous for a typical OI-causing Gly→Cys substitution in col1a1. Two weeks of Scl-Ab successfully stimulated osteoblast bone formation in a knock-in model for moderately severe OI (Brtl/+) and in WT mice, leading to improved bone mass and reduced long-bone fragility. Image-guided nanoindentation revealed no alteration in local tissue mineralization dynamics with Scl-Ab. These results contrast with previous findings of antiresorptive efficacy in OI both in mechanism and potency of effects on fragility. In conclusion, short-term Scl-Ab was successfully anabolic in osteoblasts harboring a typical OI-causing collagen mutation and represents a potential new therapy to improve bone mass and reduce fractures in pediatric OI.

  3. Full-mouth rehabilitation for a patient with dentinogenesis imperfecta: a clinical report.

    PubMed

    Bencharit, Sompop; Border, Michael B; Mack, C Russell; Byrd, Warren C; Wright, John T

    2014-10-01

    Dentinogenesis imperfecta (DI) is a genetic disorder affecting the structural integrity of the dentin that can result in weakened dentin. The affected teeth, especially posterior teeth, often need to be extracted due to severe wear or fracture. This frequently yields a loss of posterior occlusion and occlusal vertical dimension. Besides wear and fracture, anterior teeth often have an unesthetic appearance because of discoloration. Current treatments of choice, including composite bonding restorations and, more recently, all-ceramic restorations, are typically suggested to preserve the remaining teeth and tooth structure. However, there are a limited number of studies on dental implants in patients with DI. The effectiveness of dentin bonding and dental implants in patients with DI is not known. This clinical report describes a 32-year-old Asian woman with DI who underwent full-mouth rehabilitation. The posterior occlusion, mostly in the molar areas, was restored with dental implants and ceramometal restorations. The anterior teeth and premolars were restored with bonded lithium disilicate glass-ceramic pressed veneers and crowns made with computer-aided design/computer-aided manufacturing. This case demonstrates that restoring functional occlusion and esthetics for a patient with DI can be completed successfully using contemporary implant therapy and adhesive dentistry.

  4. Clinical, cellular, microscopic, and ultrastructural studies of a case of fibrogenesis imperfecta ossium

    PubMed Central

    Barron, Melissa L; Rybchyn, Mark S; Ramesh, Sutharshani; Mason, Rebecca S; Fiona Bonar, S; Stalley, Paul; Khosla, Sundeep; Hudson, Bernie; Arthur, Christopher; Kim, Edward; Clifton-Bligh, Roderick J; Clifton-Bligh, Phillip B

    2017-01-01

    Fibrogenesis imperfecta ossium is a rare disorder of bone usually characterized by marked osteopenia and associated with variable osteoporosis and osteosclerosis, changing over time. Histological examination shows that newly formed collagen is abnormal, lacking birefringence when examined by polarized light. The case presented demonstrates these features and, in addition, a previously undocumented finding of a persistent marked reduction of the serum C3 and C4. Osteoblasts established in culture from a bone biopsy showed abnormal morphology on electron microscopy and increased proliferation when cultured with benzoylbenzoyl-ATP and 1,25-dihydroxyvitamin D, contrasting with findings in normal osteoblasts in culture. A gene microarray study showed marked upregulation of the messenger RNA (mRNA) for G-protein-coupled receptor 128 (GPR 128), an orphan receptor of unknown function and also of osteoprotegerin in the patient’s osteoblasts in culture. When normal osteoblasts were cultured with the patient’s serum, there was marked upregulation of the mRNA for aquaporin 1. A single pathogenetic factor to account for the features of this disorder has not been defined, but the unique findings described here may facilitate more definitive investigation of the abnormal bone cell function. PMID:28326223

  5. Quantitative changes in human epithelial cancers and osteogenesis imperfecta disease detected using nonlinear multicontrast microscopy

    NASA Astrophysics Data System (ADS)

    Adur, Javier; Pelegati, Vitor B.; de Thomaz, Andre A.; D'Souza-Li, Lilia; Assunção, Maria do Carmo; Bottcher-Luiz, Fátima; Andrade, Liliana A. L. A.; Cesar, Carlos L.

    2012-08-01

    We show that combined multimodal nonlinear optical (NLO) microscopies, including two-photon excitation fluorescence, second-harmonic generation (SHG), third harmonic generation, and fluorescence lifetime imaging microscopy (FLIM) can be used to detect morphological and metabolic changes associated with stroma and epithelial transformation during the progression of cancer and osteogenesis imperfecta (OI) disease. NLO microscopes provide complementary information about tissue microstructure, showing distinctive patterns for different types of human breast cancer, mucinous ovarian tumors, and skin dermis of patients with OI. Using a set of scoring methods (anisotropy, correlation, uniformity, entropy, and lifetime components), we found significant differences in the content, distribution and organization of collagen fibrils in the stroma of breast and ovary as well as in the dermis of skin. We suggest that our results provide a framework for using NLO techniques as a clinical diagnostic tool for human cancer and OI. We further suggest that the SHG and FLIM metrics described could be applied to other connective or epithelial tissue disorders that are characterized by abnormal cells proliferation and collagen assembly.

  6. Limb lengthening and correction of deformity in the lower limbs of children with osteogenesis imperfecta.

    PubMed

    Saldanha, K A N; Saleh, M; Bell, M J; Fernandes, J A

    2004-03-01

    We performed limb lengthening and correction of deformity of nine long bones of the lower limb in six children (mean age, 14.7 years) with osteogenesis imperfecta (OI). All had femoral lengthening and three also had ipsilateral tibial lengthening. Angular deformities were corrected simultaneously. Five limb segments were treated using a monolateral external fixator and four with the Ilizarov frame. In three children, lengthening was done over previously inserted femoral intramedullary rods. The mean lengthening achieved was 6.26 cm (mean healing index, 33.25 days/cm). Significant complications included one deep infection, one fracture of the femur and one anterior angulation deformity of the tibia. The abnormal bone of OI tolerated the external fixators throughout the period of lengthening without any episodes of migration of wires or pins through the soft bone. The regenerate bone formed within the time which is normally expected in limb-lengthening procedures performed for other conditions. We conclude that despite the abnormal bone characteristics, distraction osteogenesis to correct limb-length discrepancy and angular deformity can be performed safely in children with OI.

  7. Quantitative second-harmonic generation imaging to detect osteogenesis imperfecta in human skin samples

    NASA Astrophysics Data System (ADS)

    Adur, J.; Ferreira, A. E.; D'Souza-Li, L.; Pelegati, V. B.; de Thomaz, A. A.; Almeida, D. B.; Baratti, M. O.; Carvalho, H. F.; Cesar, C. L.

    2012-03-01

    Osteogenesis Imperfecta (OI) is a genetic disorder that leads to bone fractures due to mutations in the Col1A1 or Col1A2 genes that affect the primary structure of the collagen I chain with the ultimate outcome in collagen I fibrils that are either reduced in quantity or abnormally organized in the whole body. A quick test screening of the patients would largely reduce the sample number to be studied by the time consuming molecular genetics techniques. For this reason an assessment of the human skin collagen structure by Second Harmonic Generation (SHG) can be used as a screening technique to speed up the correlation of genetics/phenotype/OI types understanding. In the present work we have used quantitative second harmonic generation (SHG) imaging microscopy to investigate the collagen matrix organization of the OI human skin samples comparing with normal control patients. By comparing fibril collagen distribution and spatial organization, we calculated the anisotropy and texture patterns of this structural protein. The analysis of the anisotropy was performed by means of the two-dimensional Discrete Fourier Transform and image pattern analysis with Gray-Level Co-occurrence Matrix (GLCM). From these results, we show that statistically different results are obtained for the normal and disease states of OI.

  8. Multiparametric Classification of Skin from Osteogenesis Imperfecta Patients and Controls by Quantitative Magnetic Resonance Microimaging

    PubMed Central

    Carter, Erin M.; Lin, Ping-Chang; Pleshko, Nancy; Raggio, Cathleen L.; Spencer, Richard G.

    2016-01-01

    The purpose of this study is to evaluate the ability of quantitative magnetic resonance imaging (MRI) to discriminate between skin biopsies from individuals with osteogenesis imperfecta (OI) and skin biopsies from individuals without OI. Skin biopsies from nine controls (unaffected) and nine OI patients were imaged to generate maps of five separate MR parameters, T1, T2, km, MTR and ADC. Parameter values were calculated over the dermal region and used for univariate and multiparametric classification analysis. A substantial degree of overlap of individual MR parameters was observed between control and OI groups, which limited the sensitivity and specificity of univariate classification. Classification accuracies ranging between 39% and 67% were found depending on the variable of investigation, with T2 yielding the best accuracy of 67%. When several MR parameters were considered simultaneously in a multivariate analysis, the classification accuracies improved up to 89% for specific combinations, including the combination of T2 and km. These results indicate that multiparametric classification by quantitative MRI is able to detect differences between the skin of OI patients and of unaffected individuals, which motivates further study of quantitative MRI for the clinical diagnosis of OI. PMID:27416032

  9. Analysis of cyanogen bromide peptides of type I collagen from a patient with lethal osteogenesis imperfecta.

    PubMed Central

    Kirsch, E; Glanville, R W; Krieg, T; Müller, P

    1983-01-01

    The CNBr peptides of type I collagen from bone of a patient with lethal osteogenesis imperfecta and age-matched controls were isolated by molecular-sieve chromatography and their amino acid compositions were determined. No differences were found between the compositions of the peptides from the patient and those from the controls, except for an increase in the degree of hydroxylation of lysine in all peptides from the patient. Type I collagen CNBr peptides from chick-embryo skin [Barnes, Constable Morton & Kodicek (1971) Biochem. J. 125, 925--928] and guinea-pig scar tissue [Shuttleworth, Forrest & Jackson (1975) Biochim. Biophys. Acta 379, 207--216] also have an increased degree of hydroxylation of lysine with an otherwise normal amino acid composition, and it was believed that this could be an embryonic form of collagen. As a similar collagen was present in the bones of the patient studied, it seems possible that the same 'embryonic' collagen is synthesized during development, in repair process and also in genetic disorders of collagen metabolism. Images Fig. 3. Fig. 4. PMID:6411063

  10. Structure-mechanics relationships of collagen fibrils in the osteogenesis imperfecta mouse model.

    PubMed

    Andriotis, O G; Chang, S W; Vanleene, M; Howarth, P H; Davies, D E; Shefelbine, S J; Buehler, M J; Thurner, P J

    2015-10-06

    The collagen molecule, which is the building block of collagen fibrils, is a triple helix of two α1(I) chains and one α2(I) chain. However, in the severe mouse model of osteogenesis imperfecta (OIM), deletion of the COL1A2 gene results in the substitution of the α2(I) chain by one α1(I) chain. As this substitution severely impairs the structure and mechanics of collagen-rich tissues at the tissue and organ level, the main aim of this study was to investigate how the structure and mechanics are altered in OIM collagen fibrils. Comparing results from atomic force microscopy imaging and cantilever-based nanoindentation on collagen fibrils from OIM and wild-type (WT) animals, we found a 33% lower indentation modulus in OIM when air-dried (bound water present) and an almost fivefold higher indentation modulus in OIM collagen fibrils when fully hydrated (bound and unbound water present) in phosphate-buffered saline solution (PBS) compared with WT collagen fibrils. These mechanical changes were accompanied by an impaired swelling upon hydration within PBS. Our experimental and atomistic simulation results show how the structure and mechanics are altered at the individual collagen fibril level as a result of collagen gene mutation in OIM. We envisage that the combination of experimental and modelling approaches could allow mechanical phenotyping at the collagen fibril level of virtually any alteration of collagen structure or chemistry.

  11. Deep tissue single cell MSC ablation using a fiber laser source to evaluate therapeutic potential in osteogenesis imperfecta

    NASA Astrophysics Data System (ADS)

    Tehrani, Kayvan F.; Pendleton, Emily G.; Lin, Charles P.; Mortensen, Luke J.

    2016-04-01

    Osteogenesis imperfecta (OI) is a currently uncurable disease where a mutation in collagen type I yields brittle bones. One potential therapy is transplantation of mesenchymal stem cells (MSCs), but controlling and enhancing transplanted cell survival has proven challenging. Therefore, we use a 2- photon imaging system to study individual transplanted cells in the living bone marrow. We ablated cells deep in the bone marrow and observed minimal collateral damage to surrounding tissue. Future work will evaluate the local impact of transplanted MSCs on bone deposition in vivo.

  12. Unusual Femur Stress Fractures in Children With Osteogenesis Imperfecta and Intramedullary Rods on Long-term Intravenous Pamidronate Therapy.

    PubMed

    Hegazy, Abdelsalam; Kenawey, Mohamed; Sochett, Etienne; Tile, Lianne; Cheung, Angela M; Howard, Andrew W

    2016-01-01

    In this report, we describe 6 children with osteogenesis imperfecta with unusual stress femoral fractures. All children were on long-term cyclic pamidronate treatment. All fractures occurred without trauma or with minimal trauma and were located in the subtrochanteric or the diaphyseal regions of the femur over preexisting intramedullary rods. These fractures have very similar features to the reported minimal trauma atypical femoral fractures in adults on long-term bisphosphonate treatment. These fractures raise concerns about the role of prolonged remodeling suppression and microdamage accumulation and the risk of increased bone fragility.

  13. A novel COL1A1 mutation in a family with osteogenesis imperfecta associated with phenotypic variabilities

    PubMed Central

    Seto, Toshiyuki; Yamamoto, Toshiyuki; Shimojima, Keiko; Shintaku, Haruo

    2017-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous disorder that is characterized by bone fragility and systemic complications, and is mainly caused by gene mutations in COL1A1 or COL1A2. A novel COL1A1 splicing mutation, c.750+2T>A, was identified in a Japanese OI family. Only the proband in this family showed various complications, such as heart valve diseases and severe scoliosis. The clinical heterogeneity in the family is discussed in this study. PMID:28326186

  14. A novel homozygous variant in SERPINH1 associated with a severe, lethal presentation of osteogenesis imperfecta with hydranencephaly.

    PubMed

    Marshall, Charlotte; Lopez, Jaime; Crookes, Laura; Pollitt, Rebecca C; Balasubramanian, Meena

    2016-12-20

    Osteogenesis imperfecta (OI) is a genetic disorder characterised by low bone mineral density resulting in fractures. 85-90% of patients with OI carry a variant in the type 1 collagen genes, COL1A1 and COL1A2, which follows an autosomal dominant pattern of inheritance. However, within the last two decades, there have been growing number of variants identified in genes that follow an autosomal recessive pattern of inheritance. Our proband is a child born in Mexico with multiple fractures of ribs, minimal calvarial mineralisation, platyspondyly, marked compression and deformed long bones. He also presented with significant hydranencephaly, requiring ventilatory support from birth, and died at 8days of age. A homozygous c.338_357delins22 variant in exon 2 of SERPINH1 was identified. This gene encodes heat shock protein 47, a collagen-specific chaperone which binds to the procollagen triple helix and is responsible for collagen stabilisation in the endoplasmic reticulum. There is minimal literature on the mechanism of action for variants in SERPINH1 resulting in osteogenesis imperfecta. Here we discuss this rare, previously unreported variant, and expand on the phenotypic presentation of this novel variant resulting in a severe, lethal phenotype of OI in association with hydranencephaly.

  15. A cross-sectional multicenter study of osteogenesis imperfecta in North America - results from the linked clinical research centers.

    PubMed

    Patel, R M; Nagamani, S C S; Cuthbertson, D; Campeau, P M; Krischer, J P; Shapiro, J R; Steiner, R D; Smith, P A; Bober, M B; Byers, P H; Pepin, M; Durigova, M; Glorieux, F H; Rauch, F; Lee, B H; Hart, T; Sutton, V R

    2015-02-01

    Osteogenesis imperfecta (OI) is the most common skeletal dysplasia that predisposes to recurrent fractures and bone deformities. In spite of significant advances in understanding the genetic basis of OI, there have been no large-scale natural history studies. To better understand the natural history and improve the care of patients, a network of Linked Clinical Research Centers (LCRC) was established. Subjects with OI were enrolled in a longitudinal study, and in this report, we present cross-sectional data on the largest cohort of OI subjects (n = 544). OI type III subjects had higher prevalence of dentinogenesis imperfecta, severe scoliosis, and long bone deformities as compared to those with OI types I and IV. Whereas the mean lumbar spine area bone mineral density (LS aBMD) was low across all OI subtypes, those with more severe forms had lower bone mass. Molecular testing may help predict the subtype in type I collagen-related OI. Analysis of such well-collected and unbiased data in OI can not only help answering questions that are relevant to patient care but also foster hypothesis-driven research, especially in the context of 'phenotypic expansion' driven by next-generation sequencing.

  16. Clinical Aspects, Imaging Features, and Considerations on Bisphosphonate-Related Osteonecrosis Risk in a Pediatric Patient with Osteogenesis Imperfecta

    PubMed Central

    Costa, Fábio Wildson Gurgel; Nogueira, Alexandre Simões; Rodrigues Carvalho, Francisco Samuel; Pereira, Karuza Maria Alves; Kurita, Lúcio Mitsuo; Rodrigues, Rodrigo Rodrigues; Fonteles, Cristiane Sá Roriz

    2014-01-01

    Osteogenesis imperfecta (OI) is a rare hereditary condition caused by changes in collagen metabolism. It is classified into four types according to clinical, genetic, and radiological criteria. Clinically, bone fragility, short stature, blue sclerae, and locomotion difficulties may be observed in this disease. OI is often associated to severe dental problems, such as dentinogenesis imperfecta (DI) and malocclusions. Radiographically, affected teeth may have crowns with bulbous appearance, accentuated constriction in the cementoenamel junction, narrowed roots, large root canals due to defective dentin formation, and taurodontism (enlarged pulp chambers). There is no definitive cure, but bisphosphonate therapy is reported to improve bone quality; however, there is a potential risk of bisphosphonate-related osteonecrosis of the jaw. In this study we report a case of OI in a male pediatric patient with no family history of OI who was receiving ongoing treatment with intravenous perfusion of bisphosphonate and who required dental surgery. In addition, we discussed the clinical and imaging findings and briefly reviewed the literature. PMID:25215248

  17. An unusual pattern of peptide-bound lysine metabolism in collagen from an infant with lethal perinatal osteogenesis imperfecta.

    PubMed Central

    Petrovic, O M; Miller, E J

    1984-01-01

    Collagens extracted from bones, cartilage, dermis, and dura mater of an infant with type II (lethal perinatal) osteogenesis imperfecta were evaluated with respect to chain composition and chemical characteristics of their constituent chains. The results indicated that the various types of collagen were present in the indicated tissues in proportions that approximated normal tissues. Nevertheless, the constituent chains of collagens extracted from dermis, i.e., alpha 1(I), alpha 2(I), alpha 1(III), alpha 1(V), and alpha 2(V), chromatographed on carboxymethyl cellulose as though they possessed substantially lower overall positive charge than the homologous chains of normal tissues. Amino acid analyses of the chains confirmed this observation and showed that the chains lacked five to seven residues of lysine (plus hydroxylysine). It was subsequently shown that the apparent deficiency in lysyl residues was due, at least in part, to the presence of unusually high levels of allysine , a cross-link precursor formed from peptide-bound lysine under the catalytic action of lysyl oxidase. These results, in conjunction with previous results obtained on collagens from type II osteogenesis imperfecta tissues, suggest that aberrant fibril formation in this syndrome allows increased lysyl oxidase activity. Images PMID:6427276

  18. Fluoroscopy-guided Sacroiliac Joint Steroid Injection for Low Back Pain in a Patient with Osteogenesis Imperfecta

    PubMed Central

    Dawson, PUA; Rose, REC; Wade, NA

    2015-01-01

    ABSTRACT Background: Osteogenesis imperfecta, also known as ‘brittle bone disease’, is a genetic connective tissue disease. It is characterized by bone fragility and osteopenia (low bone density). In this case, a 57-year old female presented to the University Hospital of the West Indies (UHWI), Physical Medicine and Rehabilitation Clinic with left low back pain rated 6/10 on the numeric rating scale (NRS). Clinically, the patient had sacroiliac joint-mediated pain although X-rays did not show the sacroiliac joint changes. Fluoroscopy-guided left sacroiliac joint steroid injection was done. Methods: Numeric rating scale and Oswestry Disability Index (ODI) questionnaire were used to evaluate outcome. This was completed at baseline, one week follow-up and at eight weeks post fluoroscopy-guided sacroiliac joint steroid injection. Results: Numeric rating scale improved from 6/10 before the procedure to 0/10 post procedure, and ODI questionnaire score improved from a moderate disability score of 40% to a minimal disability score of 13%. Up to eight weeks, the NRS was 0/10 and ODI remained at minimal disability of 15%. Conclusion: Fluoroscopy-guided sacroiliac joint injection is a known diagnostic and treatment method for sacroiliac joint mediated pain. To our knowledge, this is the first case published on the use of fluoroscopy-guided sacroiliac joint steroid injection in the treatment of sacroiliac joint mediated low back pain in a patient with osteogenesis imperfecta. PMID:26624601

  19. Evaluation of a Modified Pamidronate Protocol for the Treatment of Osteogenesis Imperfecta.

    PubMed

    Palomo, Telma; Andrade, Maria C; Peters, Barbara S E; Reis, Fernanda A; Carvalhaes, João Tomás A; Glorieux, Francis H; Rauch, Frank; Lazaretti-Castro, Marise

    2016-01-01

    Intravenous pamidronate is widely used to treat children with osteogenesis imperfecta (OI). In a well-studied protocol ('standard protocol'), pamidronate is given at a daily dose of 1 mg per kg body weight over 4 h on 3 successive days; infusion cycles are repeated every 4 months. Here, we evaluated renal safety of a simpler protocol for intravenous pamidronate infusions (2 mg per kg body weight given in a single infusion over 2 h, repeated every 4 months; 'modified protocol'). Results of 18 patients with OI types I, III, or IV treated with the modified protocol for 12 months were compared to 18 historic controls, treated with standard protocol. In the modified protocol, mild transient post-infusion increases in serum creatinine were found during each infusion but after 12 months serum creatinine remained similar from baseline [0.40 mg/dl (SD: 0.13)] to the end of the study [0.41 mg/dl (SD: 0.11)] (P = 0.79). The two protocols led to similar changes in serum creatinine during the first pamidronate infusion [modified protocol: +2% (SD: 21%); standard protocol: -3% (SD: 8%); P = 0.32]. Areal lumbar spine bone mineral density Z-scores increased from -2.7 (SD: 1.5) to -1.8 (SD: 1.4) with the modified protocol, and from -4.1 (SD: 1.4) to -3.1 (SD: 1.1) with standard protocol (P = 0.68 for group differences in bone density Z-score changes). The modified pamidronate protocol is safe and may have similar effects on bone density as the standard pamidronate protocol. More studies are needed with longer follow-up to prove anti-fracture efficacy.

  20. Bone Collagen: New Clues to its Mineralization Mechanism From Recessive Osteogenesis Imperfecta

    PubMed Central

    Eyre, David R.; Ann Weis, Mary

    2013-01-01

    Until 2006 the only mutations known to cause osteogenesis imperfecta (OI) were in the two genes coding for type I collagen chains. These dominant mutations affecting the expression or primary sequence of collagen α1(I) and α2(I) chains account for over 90% of OI cases. Since then a growing list of mutant genes causing the 5–10% of recessive cases has rapidly emerged. They include CRTAP, LEPRE1 and PPIB, which encode three proteins forming the prolyl 3-hydroxylase complex; PLOD2 and FKBP10, which encode respectively lysyl hydroxylase 2 and a foldase required for its activity in forming mature cross-links in bone collagen; SERPIN H1, which encodes the collagen chaperone HSP47; SERPIN F1, which encodes pigment epithelium-derived factor required for osteoid mineralization; and BMP1, which encodes the type I procollagen C-propeptidase. All cause fragile bone in infancy, which can include over-mineralization or under-mineralization defects as well as abnormal collagen post-translational modifications. Consistently both dominant and recessive variants lead to abnormal cross-linking chemistry in bone collagen. These recent discoveries strengthen the potential for a common pathogenic mechanism of misassembled collagen fibrils. Of the new genes identified, eight encode proteins required for collagen post-translational modification, chaperoning of newly synthesized collagen chains into native molecules or transport through the endoplasmic reticulum and Golgi for polymerization, cross-linking and mineralization. In reviewing these findings, we conclude that a common theme is emerging in the pathogenesis of brittle bone disease of mishandled collagen assembly with important insights on post-translational features of bone collagen that have evolved to optimize it as a biomineral template. PMID:23508630

  1. COL1 C-propeptide Cleavage Site Mutations Cause High Bone Mass Osteogenesis Imperfecta

    PubMed Central

    Lindahl, Katarina; Barnes, Aileen M.; Fratzl-Zelman, Nadja; Whyte, Michael P.; Hefferan, Theresa E.; Makareeva, Elena; Brusel, Marina; Yaszemski, Michael J.; Rubin, Carl-Johan; Kindmark, Andreas; Roschger, Paul; Klaushofer, Klaus; McAlister, William H.; Mumm, Steven; Leikin, Sergey; Kessler, Efrat; Boskey, Adele L.; Ljunggren, Östen; Marini, Joan C.

    2011-01-01

    Osteogenesis imperfecta (OI) is most often caused by mutations in the type I procollagen genes (COL1A1/COL1A2). We identified two children with substitutions in the type I procollagen C-propeptide cleavage site, which disrupt a unique processing step in collagen maturation and define a novel phenotype within OI. The patients have mild OI caused by mutations in COL1A1 (Patient 1: p.Asp1219Asn) or COL1A2 (Patient 2: p.Ala1119Thr), respectively. Patient 1 L1-L4 DXA z-score was +3.9 and pQCT vBMD was +3.1; Patient 2 had L1-L4 DXA z-score of 0.0 and pQCT vBMD of −1.8. Patient BMD contrasts with radiographic osteopenia and histomorphometry without osteosclerosis. Mutant procollagen processing is impaired in pericellular and in vitro assays. Patient dermal collagen fibrils have irregular borders. Incorporation of pC-collagen into matrix leads to increased bone mineralization. FT-IR imaging confirms elevated mineral/matrix ratios in both patients, along with increased collagen maturation in trabecular bone, compared to normal or OI controls. Bone mineralization density distribution revealed a marked shift toward increased mineralization density for both patients. Patient 1 has areas of higher and lower bone mineralization than controls; Patient 2’s bone matrix has a mineral content exceeding even classical OI bone. These patients define a new phenotype of high BMD OI and demonstrate that procollagen C-propeptide cleavage is crucial to normal bone mineralization. PMID:21344539

  2. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta

    SciTech Connect

    Orioli, I.M.; Castilla, E.E.; Scarano, G.; Mastroiacovo, P.

    1995-11-06

    The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite (IPIMC) and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congenitas (ECLAMC) series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 {plus_minus} 6.74 years in the IPIMC, and 37.19 {plus_minus} 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 {plus_minus} 7.08 years in the IPIMC, and 36.41 {plus_minus} 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 {plus_minus} 9.25 years, but not in the IPIMC, 32.26 {plus_minus} 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area. 28 refs., 1 fig., 6 tabs.

  3. Decrease in serum FGF23 levels after intravenous infusion of pamidronate in patients with osteogenesis imperfecta.

    PubMed

    Kitaoka, Taichi; Namba, Noriyuki; Miura, Kohji; Kubota, Takuo; Ohata, Yasuhisa; Fujiwara, Makoto; Hirai, Haruhiko; Yamamoto, Takehisa; Ozono, Keiichi

    2011-09-01

    Fibroblast growth factor 23 (FGF23) plays a central role in phosphate (P) homeostasis. However, the precise mechanism of how FGF23 secretion is regulated remains to be elucidated. In the present study, we examined the effect of intravenous pamidronate administration on serum levels of FGF23. Thirteen patients with osteogenesis imperfecta were treated with two cycles of 3-day pamidronate infusion. Blood samples at pre- and post-drip pamidronate infusion were evaluated for serum calcium, P, intact PTH (iPTH), 1,25(OH)(2)D, intact FGF23 (FGF23), type I collagen cross-linked N-telopeptides (NTx), bone-specific alkaline phosphatase (BAP), and TmP/GFR. During the two cycles, FGF23 levels decreased significantly preceding the decline in P levels. Although the change in P levels became less apparent during the second cycle, the reduction in FGF23 levels was similar during both cycles. Moreover, absence of correlation between FGF23 and P indicates that FGF23 attenuation is independent of the decrease in P levels during pamidronate infusion. Significant correlation between NTx suppression and the decrease in FGF23 levels during the 1st cycle (r = 0.665, P = 0.013) suggests that inhibition of osteoclast function may have some role in suppressing FGF23 levels. Because pamidronate dose was most associated with the decrease in FGF23 levels during the second cycle, pamidronate may directly attenuate osteocyte/osteoblast-mediated FGF23 production. This is the first evidence of a rapid fall in FGF23 levels following pamidronate infusion, raising the possibility that inhibition of bone resorption and/or direct effects of pamidronate may suppress secretion of FGF23.

  4. Pamidronate alters the growth plate in the oim mouse model for osteogenesis imperfecta.

    PubMed

    Evans, K D; Sheppard, L E; Rao, S H; Martin, R B; Oberbauer, A M

    2009-12-01

    Bisphosphonates alleviate bone pain and fractures associated with osteogenesis imperfecta (OI). Using the oim mouse model to simulate variations in OI severity, the effect of pamidronate on bone growth was assessed. Homozygous (oim/oim) and heterozygous (oim/wt) mice from 4 to 12 weeks of age were given pamidronate at 0 mg/kg/wk (control), 1.25 mg/kg/wk (low) and 2.5 mg/kg/wk (high). Humerus and ulna lengths were reduced in oim/oim mice relative to those of the oim/wt. Further, the oim/oim genotype exhibited a 23.5% prevalence of fractures in these bones as compared to the 2.8% prevalence observed in the oim/wt mice. Pamidronate tended to reduce fracture prevalence in a dose dependent manner for the oim/oim genotype (p<0.08) but had no effect on the low fracture prevalence in oim/wtmice. The high dose of pamidronate reduced bone length in females of both genotypes but not males when compared to control (p<0.01). Pamidronate increased growth plate area (p<0.05) by increasing growth plate height, particularly the proliferative and hypertrophic zones, in both genotypes indicating reduced growth plate cell turnover. The increased area coincided with increased osteoclast numbers in the metaphyseal region (p<0.05) though when corrected for the greater mineralized surface area that accompanies bisphosphonate treatment, osteoclasts per surface area were reduced indicating reduced resorptive capacity. This study demonstrated that the effects of pamidronate were independent of the degree of collagen deficit and fracture prevalence was improved in the most severe OI model, the oim/oim genotype.

  5. Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta.

    PubMed

    Jacobsen, Christina M; Barber, Lauren A; Ayturk, Ugur M; Roberts, Heather J; Deal, Lauren E; Schwartz, Marissa A; Weis, MaryAnn; Eyre, David; Zurakowski, David; Robling, Alexander G; Warman, Matthew L

    2014-10-01

    The cell surface receptor low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5(p.A214V) ) that is orthologous to a human HBM-causing mutation have increased bone mass and strength. Osteogenesis imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5(+/p.A214V) mice to Col1a2(+/p.G610C) mice, which model human type IV OI. We found that Col1a2(+/p.G610C) ;Lrp5(+/p.A214V) offspring had significantly increased bone mass and strength compared to Col1a2(+/p.G610C) ;Lrp5(+/+) littermates. The improved bone properties were not a result of altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2(+/p.G610C) mice with a monoclonal antibody that inhibits sclerostin activity (Scl-Ab). We found that antibody-treated mice had significantly increased bone mass and strength compared to vehicle-treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI.

  6. Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta.

    PubMed

    Roschger, Andreas; Roschger, Paul; Keplingter, Petra; Klaushofer, Klaus; Abdullah, Sami; Kneissel, Michaela; Rauch, Frank

    2014-09-01

    Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I production in osteoblasts. Stimulation of bone formation through sclerostin antibody treatment (Sost-ab) has shown promising results in mouse models of relatively mild OI. We assessed the effect of once-weekly intravenous Sost-ab injections for 4weeks in male Col1a1(Jrt)/+mice, a model of severe dominant OI, starting either at 4weeks (growing mice) or at 20weeks (adult mice) of age. Sost-ab had no effect on weight or femur length. In OI mice, no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity, procollagen type I N-propeptide) or resorption (C-telopeptide of collagen type I) were found. Micro-CT analyses at the femur showed that Sost-ab treatment was associated with higher trabecular bone volume and higher cortical thickness in wild type mice at both ages and in growing OI mice, but not in adult OI mice. Three-point bending tests of the femur showed that in wild type but not in OI mice, Sost-ab was associated with higher ultimate load and work to failure. Quantitative backscattered electron imaging of the femur did not show any effect of Sost-ab on CaPeak (the most frequently occurring calcium concentration in the bone mineral density distribution), regardless of genotype, age or measurement location. Thus, Sost-ab had a larger effect in wild type than in Col1a1(Jrt)/+mice. Previous studies had found marked improvements of Sost-ab on bone mass and strength in an OI mouse model with a milder phenotype. Our data therefore suggest that Sost-ab is less effective in a more severely affected OI mouse model.

  7. Copy number variants in association with type 1 collagenopathy: Atypical osteogenesis imperfecta.

    PubMed

    Balasubramanian, Meena; Cartwright, Ashley; Smith, Kath; Arundel, Paul; Bishop, Nicholas J

    2016-02-01

    We report a sibling-pair and a 4-year old child from two families with an atypical presentation in Osteogenesis imperfecta (OI). In the sib-pair, the older sibling initially came to medical attention due to a fracture history (Patient 1) and she was shown to have a COL1A2 mutation. In addition, she also had developmental delay, facial dysmorphism, and a history of frequent infections which led to a search for an alternate diagnosis. ArrayCGH revealed a 4.3 Mb duplication on chromosome 19q13.42q13.43, which was confirmed by FISH analysis. On further familial analysis, the younger sibling who had no previous fracture history was also found to have the COL1A2 mutation and tested positive for the 19q13.42q13.43 duplication (Patient 2). The 19q13 duplication appears to be the cause of intellectual disability in these siblings but given that this is a chromosomal duplication, it is still possible that there is an as yet unidentified cause that may account for the combined phenotype in this family. Patient 3 was a 4-year old child presenting with a femoral fracture, blue sclerae, developmental delay, and joint hypermobility. Genetic analyses confirmed a COL1A2 mutation but also revealed an 8.8 Mb deletion of 11q24.2q25, confirmed by G-band chromosome analysis. We discuss the differing phenotypes in patients presenting with atypical OI and stress the need to consider ancillary investigations in individuals presenting with heterogeneous phenotypic symptoms, not entirely attributable to OI.

  8. Tracing the pathway between mutation and phenotype in osteogenesis imperfecta: Isolation of mineralization-specific genes

    SciTech Connect

    Culbert, A.A.; Wallis, G.A.; Kadler, K.E.

    1996-05-03

    The brittleness of bone in people with lethal (type II) osteogenesis imperfecta, a heritable disorder caused by mutations in the type I collagen genes, arises from the deposition of abnormal collagen in the bone matrix. The inability of the abnormal collagen to participate in mineralization may be caused by its failure to interact with other bone proteins. Here, we have designed a strategy to isolate the genes important for mineralization of collagen during bone formation. Cells isolated from 16-day embryonic chick calvaria and seeded post-confluence in culture deposited a mineralized matrix over a period of 2 weeks. Chick skin fibroblasts seeded and cultured under the same conditions did not mineralize. Using RT-PCR, we prepared short cDNAs ({approximately}300 bp) corresponding to the 3{prime} ends of mRNA from fibroblasts and separately from the mineralizing calvarial cells. Subtractive cDNA hybridization generated a pool of cDNAs that were specific to mineralizing calvarial cells but not to fibroblasts. Screening of 100,000 plaques of a chick bone ZAP Express cDNA library with this pool of mineralizing-specific cDNAs identified ten clones which comprised full-length cDNAs for the bone proteins osteopontin (eight of the ten positives), bone sialoprotein II (one of the ten positives), and cystatin (one of the ten positives). cDNAs for type I collagen, fibronectin, alkaline phosphatase, house-keeping genes, and other genes expressed in fibroblasts were not identified in this preliminary screen. The pool of short cDNAs is likely to comprise cDNAs for further bone-specific genes and will be used to screen the entire bone cDNA library of 4.2 million clones. 30 refs., 4 figs.

  9. Intrafibrillar Mineral May be Absent in Dentinogenesis Imperfecta Type II (DI-II)

    SciTech Connect

    Pople, John A.

    2001-03-29

    High-resolution synchrotron radiation computed tomography (SRCT) and small angle x-ray scattering (SAXS) were performed on normal and dentinogenesis imperfecta type II (DI-II) teeth. Three normal and three DI-II human third molars were used in this study. The normal molars were unerupted and had intact enamel; donors were female and ranged in age from 18-21y. The DI-II specimens, which were also unerupted with intact enamel, came from a single female donor age 20y. SRCT showed that the mineral concentration was 33% lower on average in the DI-II dentin with respect to normal dentin. The SAXS spectra from normal dentin exhibited low-angle diffraction peaks at harmonics of 67.6 nm, consistent with nucleation and growth of the apatite phase within gaps in the collagen fibrils (intrafibrillar mineralization). In contrast, the low-angle peaks were almost nonexistent in the DI-II dentin. Crystallite thickness was independent of location in both DI-II and normal dentin, although the crystallites were significantly thicker in DI-II dentin (6.8 nm (s.d. = 0.5) vs 5.1 nm (s.d. = 0.6)). The shape factor of the crystallites, as determined by SAXS, showed a continuous progression in normal dentin from roughly one-dimensional (needle-like) near the pulp to two-dimensional (plate-like) near the dentin-enamel junction. The crystallites in DI-II dentin, on the other hand, remained needle-like throughout. The above observations are consistent with an absence of intrafibrillar mineral in DI-II dentin.

  10. Targeting the LRP5 pathway improves bone properties in a mouse model of Osteogenesis Imperfecta

    PubMed Central

    Jacobsen, Christina M.; Barber, Lauren A.; Ayturk, Ugur M.; Roberts, Heather J.; Deal, Lauren E.; Schwartz, Marissa A.; Weis, MaryAnn; Eyre, David; Zurakowski, David; Robling, Alexander G.; Warman, Matthew L.

    2014-01-01

    The cell surface receptor low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5p.A214V) that is orthologous to a human HBM-causing mutation have increased bone mass and strength. Osteogenesis Imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5+/p.A214V mice to Col1a2+/p.G610C mice, which model human type IV OI. We found that Col1a2+/p.G610C;Lrp5+/p.A214V offspring had significantly increased bone mass and strength compared to Col1a2+/p.G610C;Lrp5+/+ littermates. The improved bone properties were not due to altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2+/p.G610C mice with a monoclonal antibody that inhibits sclerostin activity (Scl-Ab). We found that antibody treated mice had significantly increased bone mass and strength compared to vehicle treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI. PMID:24677211

  11. Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice

    PubMed Central

    Muir, Alison M.; Ren, Yinshi; Butz, Delana Hopkins; Davis, Nicholas A.; Blank, Robert D.; Birk, David E.; Lee, Se-Jin; Rowe, David; Feng, Jian Q.; Greenspan, Daniel S.

    2014-01-01

    Osteogenesis imperfecta (OI), or brittle bone disease, is most often caused by dominant mutations in the collagen I genes COL1A1/COL1A2, whereas rarer recessive OI is often caused by mutations in genes encoding collagen I-interacting proteins. Recently, mutations in the gene for the proteinase bone morphogenetic 1 (BMP1) were reported in two recessive OI families. BMP1 and the closely related proteinase mammalian tolloid-like 1 (mTLL1) are co-expressed in various tissues, including bone, and have overlapping activities that include biosynthetic processing of procollagen precursors into mature collagen monomers. However, early lethality of Bmp1- and Tll1-null mice has precluded use of such models for careful study of in vivo roles of their protein products. Here we employ novel mouse strains with floxed Bmp1 and Tll1 alleles to induce postnatal, simultaneous ablation of the two genes, thus avoiding barriers of Bmp1−/− and Tll1−/− lethality and issues of functional redundancy. Bones of the conditionally null mice are dramatically weakened and brittle, with spontaneous fractures—defining features of OI. Additional skeletal features include osteomalacia, thinned/porous cortical bone, reduced processing of procollagen and dentin matrix protein 1, remarkably high bone turnover and defective osteocyte maturation that is accompanied by decreased expression of the osteocyte marker and Wnt-signaling inhibitor sclerostin, and by marked induction of canonical Wnt signaling. The novel animal model presented here provides new opportunities for in-depth analyses of in vivo roles of BMP1-like proteinases in bone and other tissues, and for their roles, and for possible therapeutic interventions, in OI. PMID:24419319

  12. Abnormal type I collagen metabolism by cultured fibroblasts in lethal perinatal osteogenesis imperfecta.

    PubMed Central

    Bateman, J F; Mascara, T; Chan, D; Cole, W G

    1984-01-01

    Cultured skin fibroblasts from seven consecutive cases of lethal perinatal osteogenesis imperfecta (OI) expressed defects of type I collagen metabolism. The secretion of [14C]proline-labelled collagen by the OI cells was specifically reduced (51-79% of control), and collagen degradation was increased to twice that of control cells in five cases and increased by approx. 30% in the other two cases. Sodium dodecyl sulphate/polyacrylamide-gel electrophoresis revealed that four of the OI cell lines produced two forms of type I collagen consisting of both normally and slowly migrating forms of the alpha 1(I)- and alpha 2(I)-chains. In the other three OI cell lines only the 'slow' alpha (I)'- and alpha 2(I)'-chains were detected. In both groups inhibition of the post-translational modifications of proline and lysine resulted in the production of a single species of type I collagen with normal electrophoretic migration. Proline hydroxylation was normal, but the hydroxylysine contents of alpha 1(I)'- and alpha 2(I)'-chains purified by h.p.l.c. were greater than in control alpha-chains. The glucosylgalactosylhydroxylysine content was increased approx. 3-fold while the galactosylhydroxylysine content was only slightly increased in the alpha 1(I)'-chains relative to control alpha 1(I)-chains. Peptide mapping of the CNBr-cleavage peptides provided evidence that the increased post-translational modifications were distributed throughout the alpha 1(I)'- and alpha 2(I)'-chains. It is postulated that the greater modification of these chains was due to structural defects of the alpha-chains leading to delayed helix formation. The abnormal charge heterogeneity observed in the alpha 1 CB8 peptide of one patient may reflect such a structural defect in the type I collagen molecule. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. PMID:6421277

  13. The United States Army Medical Department Journal. The United States Army Dental Corps: A Century of Commitment, Service, and Care

    DTIC Science & Technology

    2011-03-01

    amelogenesis imperfecta , congenital erythropoietic porphyria, Kostmann’s condition (conditions leading to early tooth loss), cyclic neutropenia, Chediak...Patient with Dentinogensis Imperfecta : A Clinical Report 95 COL David A. Mott; COL Minaxi I. Patel; LTC Dong Soo Park Solid Ameloblastoma, Resection...describe a 19-year-old Soldier’s presentation with a condition known as dentinogenesis imperfecta , a genetic disorder that affects the majority of the

  14. What type of valve is most appropriate for osteogenesis imperfecta patients?

    PubMed

    Dimitrakakis, Georgios; Challoumas, Dimitrios; von Oppell, Ulrich Otto

    2014-09-01

    A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was in osteogenesis imperfecta (OI) patients with valve disease undergoing valve replacement which type of valve (bioprosthetic or mechanical) is most appropriate in terms of safety, complications and survival. Altogether more than 77 papers were found as a result of the reported search, of which 43 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Previous review articles have presented case reports up to 2009. As all published data are based on case reports, we conducted a more detailed analysis that included the aforementioned series, reports that were missed prior to 2009 and all published data from 2009 to October 2013. Our analysis identified 43 OI patients. Mechanical valves were used in the majority of cases (31 patients), bioprosthetic valves in 10 patients and homografts in 2 patients. We conclude that based on the best available evidence, it appears that bioprosthetic valves have had better outcomes (mortality rate 10%) and a lower valve-related complication rate (0%) compared with mechanical valves (mortality rate 16.1%, complication rate 16.1%), even though differences were not statistically significant. Although the existing evidence is solely based on case reports of a relatively small number, we would suggest the use of bioprosthetic valves in OI patients with valve disease, as they appear to be safer according to our analysis. Moreover, considering the surgical difficulties related to the friability and weakness of the tissues in terms of suture lines and implantation of the valve as well as the high risk of perioperative bleeding which can be related to tissue friability, capillary fragility and platelet dysfunction followed by the risk of major traumatic fractures and a

  15. Therapeutic impact of low amplitude high frequency whole body vibrations on the osteogenesis imperfecta mouse bone.

    PubMed

    Vanleene, Maximilien; Shefelbine, Sandra J

    2013-04-01

    Osteogenesis imperfecta (OI) is characterized by extremely brittle bone. Currently, bisphosphonate drugs allow a decrease of fracture by inhibiting bone resorption and increasing bone mass but with possible long term side effects. Whole body mechanical vibrations (WBV) treatment may offer a promising route to stimulate bone formation in OI patients as it has exhibited health benefits on both muscle and bone mass in human and animal models. The present study has investigated the effects of WBV (45Hz, 0.3g, 15minutes/days, 5days/week) in young OI (oim) and wild type female mice from 3 to 8weeks of age. Vibration therapy resulted in a significant increase in the cortical bone area and cortical thickness in the femur and tibia diaphysis of both vibrated oim and wild type mice compared to sham controls. Trabecular bone was not affected by vibration in the wild type mice; vibrated oim mice, however, exhibited significantly higher trabecular bone volume fraction in the proximal tibia. Femoral stiffness and yield load in three point bending were greater in the vibrated wild type mice than in sham controls, most likely attributed to the increase in femur cortical cross sectional area observed in the μCT morphology analyses. The vibrated oim mice showed a trend toward improved mechanical properties, but bending data had large standard deviations and there was no significant difference between vibrated and non-vibrated oim mice. No significant difference of the bone apposition was observed in the tibial metaphyseal trabecular bone for both the oim and wild type vibrated mice by histomorphometry analyses of calcein labels. At the mid diaphysis, the cortical bone apposition was not significantly influenced by the WBV treatment in both the endosteum and periosteum of the oim vibrated mice while a significant change is observed in the endosteum of the vibrated wild type mice. As only a weak impact in bone apposition between the vibrated and sham groups is observed in the

  16. Ultrastructural and histological findings on examination of skin in osteogenesis imperfecta: a novel study.

    PubMed

    Balasubramanian, Meena; Wagner, Bart E; Peres, Luiz C; Sobey, Glenda J; Parker, Michael J; Dalton, Ann; Arundel, Paul; Bishop, Nicholas J

    2015-04-01

    Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity for fractures. It is a variable condition with a range of clinical severities. The histological and ultrastructural findings in the skin of patients with OI have not been described in detail in the previously published literature. Although protein analysis of cultured fibroblasts has historically been used in the diagnostic work-up of OI patients, other aspects of skin examination are not routinely performed as part of the diagnostic pathway in patients with OI. The aims of this study were to perform histological and ultrastructural examination of skin biopsies in patients with OI. This was to identify common and distinguishing features in the numerous genetically distinct subtypes of OI and compare the findings with those in patients who did not present with fractures, and to enable the use of the results thus obtained to aid in the diagnostic work-up of patients with OI. As part of a larger research study set-up to identify clinical features and natural history in patients with atypical features of OI, skin biopsy and examination (histology and electron microscopy) were undertaken. Genetic analysis and ancillary investigations were also performed to identify similarities within this group and to differentiate this group from the 'normal' population. At the end of this study, we were able to demonstrate that the histological and electron microscopic findings on a skin biopsy may be an indicator of the likelihood of identifying a pathogenic mutation in type 1 collagen genes. This is because patients with specific findings on examination, such as elastic fibre area fraction (on histological analysis), collagen fibril diameter variability, deviation from the expected mean and collagen flowers (on electron microscopy), are more likely to be positive on genetic analyses. This has, in turn, provided more insight into the

  17. Severe osteogenesis imperfecta Type-III and its challenging treatment in newborn and preschool children. A systematic review.

    PubMed

    Sinikumpu, Juha-Jaakko; Ojaniemi, Marja; Lehenkari, Petri; Serlo, Willy

    2015-08-01

    Osteogenesis imperfecta (OI) is a group of genetic disorders, of which Type III is the most severe among survivors. The disease is characterised in particular by bone fragility, decreased bone mass and increased incidence of fractures. Other usual findings are muscle hypotonia, joint hypermobility and short stature. Fractures and weak bones may consequently cause limb and spinal deformity and chronic physical disability. Bisphosphonates have revolutionised the treatment of newborn children with severe OI type III. Surgery is still needed in most patients due to high frequency of the fractures. In this systematic review we describe the present state-of-art in treating the most severe type of OI in newborn and preschool children with their bone fractures.

  18. Microstructure and compressive mechanical properties of cortical bone in children with osteogenesis imperfecta treated with bisphosphonates compared with healthy children.

    PubMed

    Imbert, Laurianne; Aurégan, Jean-Charles; Pernelle, Kélig; Hoc, Thierry

    2015-06-01

    Osteogenesis imperfecta (OI) is a genetic disorder characterized by a change in bone tissue quality, but little data are available to describe the factors involved at the macroscopic scale. To better understand the effect of microstructure alterations on the mechanical properties at the sample scale, we studied the structural and mechanical properties of six cortical bone samples from children with OI treated with bisphosphonates and compared them to the properties of three controls. Scanning electron microscopy, high resolution computed tomography and compression testing were used to assess these properties. More resorption cavities and a higher osteocyte lacunar density were observed in OI bone compared with controls. Moreover, a higher porosity was measured for OI bones along with lower macroscopic Young's modulus, yield stress and ultimate stress. The microstructure was impaired in OI bones; the higher porosity and osteocyte lacunar density negatively impacted the mechanical properties and made the bone more prone to fracture.

  19. Transcriptional Repression of the Dspp Gene Leads to Dentinogenesis Imperfecta Phenotype in Col1a1-Trps1 Transgenic Mice

    PubMed Central

    Napierala, Dobrawa; Sun, Yao; Maciejewska, Izabela; Bertin, Terry K; Dawson, Brian; D'Souza, Rena; Qin, Chunlin; Lee, Brendan

    2012-01-01

    Dentinogenesis imperfecta (DGI) is a hereditary defect of dentin, a calcified tissue that is the most abundant component of teeth. Most commonly, DGI is manifested as a part of osteogenesis imperfecta (OI) or the phenotype is restricted to dental findings only. In the latter case, DGI is caused by mutations in the DSPP gene, which codes for dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). Although these two proteins together constitute the majority of noncollagenous proteins of the dentin, little is known about their transcriptional regulation. Here we demonstrate that mice overexpressing the Trps1 transcription factor (Col1a1-Trps1 mice) in dentin-producing cells, odontoblasts, present with severe defects of dentin formation that resemble DGI. Combined micro–computed tomography (µCT) and histological analyses revealed tooth fragility due to severe hypomineralization of dentin and a diminished dentin layer with irregular mineralization in Col1a1-Trps1 mice. Biochemical analyses of noncollagenous dentin matrix proteins demonstrated decreased levels of both DSP and DPP proteins in Col1a1-Trps1 mice. On the molecular level, we demonstrated that sustained high levels of Trps1 in odontoblasts lead to dramatic decrease of Dspp expression as a result of direct inhibition of the Dspp promoter by Trps1. During tooth development Trps1 is highly expressed in preodontoblasts, but in mature odontoblasts secreting matrix its expression significantly decreases, which suggests a Trps1 role in odontoblast development. In these studies we identified Trps1 as a potent inhibitor of Dspp expression and the subsequent mineralization of dentin. Thus, we provide novel insights into mechanisms of transcriptional dysregulation that leads to DGI. © 2012 American Society for Bone and Mineral Research. PMID:22508542

  20. Osteogenesis imperfecta Type I caused by a novel mutation in the start codon of the COL1A1 gene in a Korean family.

    PubMed

    Cho, Sung Yoon; Lee, Ji-Ho; Ki, Chang-Seok; Chang, Mi Sun; Jin, Dong-Kyu; Han, Heon-Seok

    2015-01-01

    Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders characterized by susceptibility to bone fractures ranging in severity from perinatal death to a subtle increase in fracture frequency. We report the case of a patient who appeared healthy at birth and did not experience any fractures until 12 months of age. We observed blue sclera, frequent fractures without commensurate trauma, nearly normal stature, the absence of dentinogenesis imperfecta, no bony deformity, and no limitation of mobility in the patient--all characteristics suggestive of OI Type I. The patient's mother also had blue sclera and a history of frequent fracture episodes until the age of 15 years. A novel COL1A1 missense mutation (c.2T>G) disrupting the start codon of the gene (ATG to AGG (Met1Arg)) was found in the patient and his mother.

  1. Two novel distinct COL1A2 mutations highlight the complexity of genotype-phenotype correlations in osteogenesis imperfecta and related connective tissue disorders.

    PubMed

    Reuter, Miriam S; Schwabe, Georg C; Ehlers, Christian; Marschall, Christoph; Reis, André; Thiel, Christian; Graul-Neumann, Luitgard

    2013-12-01

    Osteogenesis imperfecta is a heritable connective tissue disorder characterized by variable symptoms including predisposition to fractures. Despite the identification of numerous mutations, a reliable genotype-phenotype correlation has remained notoriously difficult. We now describe two patients with osteogenesis imperfecta and novel, so far undescribed mutations in the COL1A2 gene, further highlighting this complexity. A 3-year-old patient presented with features reminiscent of a connective tissue disorder, with joint hypermobility, Wormian bones, streaky lucencies in the long bones and relative macrocephaly. The patient carried a heterozygous c.1316G > A (p.Gly439Asp) mutation in the COL1A2 gene located in a triple-helix region, in which glycine substitutions have been assumed to cause perinatal lethal OI (Sillence type II). A second family with type I osteogenesis imperfecta carried a heterozygous nonsense mutation c.4060C > T (p.Gln1354X) within the last exon of COL1A2. Whereas other heterozygous nonsense mutations in COL1A2 do not lead to a phenotype, in this case the mRNA is presumed to escape nonsense-mediated decay. Therefore the predicted COL1A2 propeptide lacks the last 13 C-terminal amino acids, suggesting that the OI phenotype results from decelerated assembly and overmodification of the collagen triple helix. The presented COL1A2 mutations exemplify the complexity of COL1A2 genotype-phenotype correlation in genetic counselling in OI.

  2. Kohlschütter-Tönz Syndrome – Report of an additional case

    PubMed Central

    González-Arriagada, Wilfredo A.; Carlos-Bregni, Román; Contreras, Elisa; Almeida, Oslei P.

    2013-01-01

    Kohlschütter-Tönz Syndrome is a rare disorder clinically characterized by amelogenesis imperfecta, epilepsy and progressive mental deterioration. We present an additional case of this syndrome of a nine year-old boy who was referred by pigmented teeth. The mental deterioration was associated with speech delay, impulsive behavior, attention-deficit/hyperactivity disorder, and learning problems. The physical examination revealed a reduction of lower third, slightly palpebral fissures, low ear and hair implantation, coarse hair and hypertrichosis. The intraoral examination showed alteration in teeth pigmentation diagnosed as amelogenesis imperfecta. Although rare, the present case report illustrates a syndrome that has dental anomalies and systemic alterations. It is important to recognize this syndrome as early as possible and paediatric dentist may contribute to the diagnosis and consequently to better manage the patients. Key words:Kohlschütter-Tönz syndrome, amelogenesis imperfecta, seizures, mental deterioration. PMID:24455057

  3. Kohlschütter-Tönz Syndrome - Report of an additional case.

    PubMed

    González-Arriagada, Wilfredo A; Carlos-Bregni, Román; Contreras, Elisa; Almeida, Oslei P; Lopes, Marcio A

    2013-04-01

    Kohlschütter-Tönz Syndrome is a rare disorder clinically characterized by amelogenesis imperfecta, epilepsy and progressive mental deterioration. We present an additional case of this syndrome of a nine year-old boy who was referred by pigmented teeth. The mental deterioration was associated with speech delay, impulsive behavior, attention-deficit/hyperactivity disorder, and learning problems. The physical examination revealed a reduction of lower third, slightly palpebral fissures, low ear and hair implantation, coarse hair and hypertrichosis. The intraoral examination showed alteration in teeth pigmentation diagnosed as amelogenesis imperfecta. Although rare, the present case report illustrates a syndrome that has dental anomalies and systemic alterations. It is important to recognize this syndrome as early as possible and paediatric dentist may contribute to the diagnosis and consequently to better manage the patients. Key words:Kohlschütter-Tönz syndrome, amelogenesis imperfecta, seizures, mental deterioration.

  4. Osteogenesis Imperfecta with Celiac Disease and Type II Diabetes Mellitus Associated: Improvement with a Gluten-Free Diet

    PubMed Central

    Rodrigo, Luis; Pérez-Martinez, Isabel

    2012-01-01

    Osteogenesis imperfecta (OI) is a genetic disease, with a connective tissue alteration, consisting in the presence of multiple spontaneous fractures or after minimal traumatism. Its association with other metabolic processes is rarely described. We present the clinical case of a female adult patient of 43 years. From her infancy, she has had multiple fractures, needing several surgical interventions, and she was diagnosed of OI type 2 at adolescence age. Due mainly to difficulties in walking remaining in wheel-chair in the last three years, she was overweight with morbid obesity (BMI = 45.4) and had a type-II DM associated. She suffered from recurrent abdominal pain and chronic diarrhea and was diagnosed of celiac disease (CD) with increased intraepithelial duodenal infiltration, being classified as lymphocytic enteritis, Marsh I type. She was put on a gluten-free diet (GFD), having lost 6 kg of weight after 6 months, with a good control of DM-II and presenting a significant clinical improvement. It is rewarding to search the presence of two coincidental metabolic diseases associated to OI, specially CD, because of the dramatic clinical benefit in the general found after putting on a GFD. PMID:22481956

  5. Identification of a Mutation Causing Deficient BMP1/mTLD Proteolytic Activity in Autosomal Recessive Osteogenesis Imperfecta

    PubMed Central

    Martínez-Glez, Víctor; Valencia, Maria; Caparrós-Martín, José A.; Aglan, Mona; Temtamy, Samia; Tenorio, Jair; Pulido, Veronica; Lindert, Uschi; Rohrbach, Marianne; Eyre, David; Giunta, Cecilia; Lapunzina, Pablo; Ruiz-Perez, Victor L.

    2013-01-01

    Herein, we have studied a consanguineous Egyptian family with two children diagnosed with severe autosomal recessive osteogenesis imperfecta (AR-OI) and a large umbilical hernia. Homozygosity mapping in this family showed lack of linkage to any of the previously known AR-OI genes, but revealed a 10.27 MB homozygous region on chromosome 8p in the two affected sibs, which comprised the procollagen I C-terminal propeptide (PICP) endopeptidase gene BMP1. Mutation analysis identified both patients with a Phe249Leu homozygous missense change within the BMP1 protease domain involving a residue, which is conserved in all members of the astacin group of metalloproteases. Type I procollagen analysis in supernatants from cultured fibroblasts demonstrated abnormal PICP processing in patient-derived cells consistent with the mutation causing decreased BMP1 function. This was further confirmed by overexpressing wild type and mutant BMP1 longer isoform (mammalian Tolloid protein [mTLD]) in NIH3T3 fibroblasts and human primary fibroblasts. While overproduction of normal mTLD resulted in a large proportion of proα1(I) in the culture media being C-terminally processed, proα1(I) cleavage was not enhanced by an excess of the mutant protein, proving that the Phe249Leu mutation leads to a BMP1/mTLD protein with deficient PICP proteolytic activity. We conclude that BMP1 is an additional gene mutated in AR-OI. PMID:22052668

  6. Defective pro alpha 2(I) collagen synthesis in a recessive mutation in mice: a model of human osteogenesis imperfecta.

    PubMed Central

    Chipman, S D; Sweet, H O; McBride, D J; Davisson, M T; Marks, S C; Shuldiner, A R; Wenstrup, R J; Rowe, D W; Shapiro, J R

    1993-01-01

    Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue associated with fractures, osteopenia, and short stature. OI results from mutations affecting the pro alpha 1 or pro alpha 2 gene of type I collagen. We describe a strain of mice with a nonlethal recessively inherited mutation (oim) that results in phenotypic and biochemical features that simulate moderate to severe human OI. The phenotype of homozygous oim mice includes skeletal fractures, limb deformities, generalized osteopenia, and small body size. Their femurs are smaller and demonstrate marked cortical thinning and fewer medullary trabeculae than those of wild-type mice. Breeding studies show the mutation is inherited in most crosses as a single recessive gene on chromosome 6, near the murine Cola-2 gene. Biochemical analysis of skin and bone, as well as isolated dermal fibroblast cultures, demonstrate that alpha 1(I) homotrimeric collagen accumulates in these tissues and is secreted by fibroblasts. Short labeling studies in fibroblasts demonstrate an absence of pro alpha 2(I) collagen chains. Nucleotide sequencing of the cDNA encoding the COOH-propeptide reveals a G deletion at pro alpha 2(I) nucleotide 3983; this results in an alteration of the sequence of the last 48 amino acids. The oim mouse will facilitate the study of type I collagen-related skeletal disease. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8446583

  7. Pigment epithelium-derived factor (PEDF) normalizes matrix defects in iPSCs derived from Osteogenesis imperfecta Type VI.

    PubMed

    Belinsky, Glenn S; Ward, Leanne; Chung, Chuhan

    2016-01-01

    Osteogenesis imperfecta (OI) Type VI is characterized by a defect in bone mineralization, which results in multiple fractures early in life. Null mutations in the PEDF gene, Serpinf1, are the cause of OI VI. Whether PEDF restoration in a murine model of OI Type VI could improve bone mass and function was previously unknown. In Belinsky et al, we provided evidence that PEDF delivery enhanced bone mass and improved parameters of bone function in vivo. Further, we demonstrated that PEDF temporally inhibits Wnt signaling to enhance osteoblast differentiation. Here, we demonstrate that generation of induced pluripotent stem cells (iPSCs) from a PEDF null patient provides additional evidence for PEDF's role in regulating extracellular matrix proteins secreted from osteoblasts. PEDF null iPSCs have marked abnormalities in secreted matrix proteins, capturing a key feature of human OI Type VI, which were normalized by exogenous PEDF. Lastly, we place our recent findings within the broader context of PEDF biology and the developmental signaling pathways that are implicated in its actions.

  8. Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms.

    PubMed

    Otsuru, Satoru; Gordon, Patricia L; Shimono, Kengo; Jethva, Reena; Marino, Roberta; Phillips, Charlotte L; Hofmann, Ted J; Veronesi, Elena; Dominici, Massimo; Iwamoto, Masahiro; Horwitz, Edwin M

    2012-08-30

    Transplantation of whole bone marrow (BMT) as well as ex vivo-expanded mesenchymal stromal cells (MSCs) leads to striking clinical benefits in children with osteogenesis imperfecta (OI); however, the underlying mechanism of these cell therapies has not been elucidated. Here, we show that non-(plastic)-adherent bone marrow cells (NABMCs) are more potent osteoprogenitors than MSCs in mice. Translating these findings to the clinic, a T cell-depleted marrow mononuclear cell boost (> 99.99% NABMC) given to children with OI who had previously undergone BMT resulted in marked growth acceleration in a subset of patients, unambiguously indicating the therapeutic potential of bone marrow cells for these patients. Then, in a murine model of OI, we demonstrated that as the donor NABMCs differentiate to osteoblasts, they contribute normal collagen to the bone matrix. In contrast, MSCs do not substantially engraft in bone, but secrete a soluble mediator that indirectly stimulates growth, data which provide the underlying mechanism of our prior clinical trial of MSC therapy for children with OI. Collectively, our data indicate that both NABMCs and MSCs constitute effective cell therapy for OI, but exert their clinical impact by different, complementary mechanisms. The study is registered at www.clinicaltrials.gov as NCT00187018.

  9. Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment.

    PubMed

    Sinder, Benjamin P; Salemi, Joseph D; Ominsky, Michael S; Caird, Michelle S; Marini, Joan C; Kozloff, Kenneth M

    2015-02-01

    Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk that presents most severely in children. Anti-resorptive bisphosphonates are frequently used to treat pediatric OI and controlled clinical trials have shown that bisphosphonate therapy improves vertebral outcomes but has little benefit on long bone fracture rate. New treatments which increase bone mass throughout the pediatric OI skeleton would be beneficial. Sclerostin antibody (Scl-Ab) is a potential candidate anabolic therapy for pediatric OI and functions by stimulating osteoblastic bone formation via the canonical Wnt signaling pathway. To explore the effect of Scl-Ab on the rapidly growing OI skeleton, we treated rapidly growing 3week old Brtl/+ mice, harboring a typical heterozygous OI-causing Gly→Cys substitution on col1a1, for 5weeks with Scl-Ab. Scl-Ab had anabolic effects in Brtl/+ and led to new cortical bone formation and increased cortical bone mass. This anabolic action resulted in improved mechanical strength to WT Veh levels without altering the underlying brittle nature of the material. While Scl-Ab was anabolic in trabecular bone of the distal femur in both genotypes, the effect was less strong in these rapidly growing Brtl/+ mice compared to WT. In conclusion, Scl-Ab was able to stimulate bone formation in a rapidly growing Brtl/+ murine model of OI, and represents a potential new therapy to improve bone mass and reduce fracture risk in pediatric OI.

  10. Anesthetic management of an 8-month-old infant with osteogenesis imperfecta undergoing liver transplantation: a case report

    PubMed Central

    Lee, Jiwon; Kim, Anna; Yoo, Seokha; Shin, Seung-Yeon; Kang, Sun-Hye; Jeong, Jinyoung; Yoo, Yongjae

    2014-01-01

    Anesthetic management of pediatric liver transplantation in a patient with osteogenesis imperfecta (OI) requires tough decisions and comprehensive considerations of the cascade of effects that may arise and the required monitoring. Total intravenous anesthesia (TIVA) with propofol and remifentanil was chosen as the main anesthetic strategy. Malignant hyperthermia (MH), skeletal fragility, anhepatic phase during liver transplantation, uncertainties of TIVA in children, and propofol infusion syndrome were considered and monitored. There were no adverse events during the operation. Despite meticulous precautions with regard to the risk of MH, there was an episode of high fever (40℃) in the ICU a few hours after the operation, which was initially feared as MH. Fortunately, MH was ruled out as the fever subsided soon after hydration and antipyretics were given. Although the delivery of supportive care and the administration of dantrolene are the core principles in the management of MH, perioperative fever does not always mean a MH in patients at risk for MH, and other common causes of fever should also be considered. PMID:25006373

  11. Osteogenesis imperfecta model peptides: incorporation of residues replacing Gly within a triple helix achieved by renucleation and local flexibility.

    PubMed

    Xiao, Jianxi; Madhan, Balaraman; Li, Yingjie; Brodsky, Barbara; Baum, Jean

    2011-07-20

    Missense mutations, which replace one Gly with a larger residue in the repeating sequence of the type I collagen triple helix, lead to the hereditary bone disorder osteogenesis imperfecta (OI). Previous studies suggest that these mutations may interfere with triple-helix folding. NMR was used to investigate triple-helix formation in a series of model peptides where the residue replacing Gly, as well as the local sequence environment, was varied. NMR measurement of translational diffusion coefficients allowed the identification of partially folded species. When Gly was replaced by Ala, the Ala residue was incorporated into a fully folded triple helix, whereas replacement of Gly by Ser or Arg resulted in the presence of some partially folded species, suggesting a folding barrier. Increasing the triple-helix stability of the sequence N-terminal to a Gly-to-Ser replacement allowed complete triple-helix folding, whereas with the substitution of Arg, with its large side chain, the peptide achieved full folding only after flexible residues were introduced N-terminal to the mutation site. These studies shed light on the factors important for accommodation of Gly mutations within the triple helix and may relate to the varying severity of OI.

  12. Delivery by Cesarean Section is not Associated With Decreased at-Birth Fracture Rates in Osteogenesis Imperfecta

    PubMed Central

    Bellur, S; Jain, M; Cuthbertson, D; Krakow, D; Shapiro, JR; Steiner, RD; Smith, PA; Bober, MB; Hart, T; Krischer, J; Mullins, M; Byers, PH; Pepin, M; Durigova, M; Glorieux, FH; Rauch, F; Sutton, VR; Lee, B; Nagamani, SC

    2015-01-01

    Purpose Osteogenesis imperfecta (OI) predisposes to recurrent fractures. The moderate-to-severe forms of OI present with antenatal fractures and the mode of delivery that would be safest for the fetus is not known. Methods We conducted systematic analyses on the largest cohort of individuals (n=540) with OI enrolled to-date in the OI Linked Clinical Research Centers. Self-reported at-birth fracture rates were compared in individuals with OI types I, III, and IV. Multivariate analyses utilizing backward-elimination logistic regression model building were performed to assess the effect of multiple covariates including method of delivery on fracture-related outcomes. Results When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was by vaginal route or by cesarean section (CS). Increased birth weight conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing CS for delivery. Conclusion Our study, the largest to analyze the effect of various factors on at-birth fracture rates in OI shows that delivery by CS is not associated with decreased fracture rate. With the limitation that the fracture data were self-reported in this cohort, these results suggest that CS should be performed only for other maternal or fetal indications, but not for the sole purpose of fracture prevention in OI. PMID:26426884

  13. Biochemical analysis of callus tissue in osteogenesis imperfecta type IV. Evidence for transient overmodification in collagen types I and III.

    PubMed Central

    Brenner, R E; Vetter, U; Nerlich, A; Wörsdorfer, O; Teller, W M; Müller, P K

    1989-01-01

    We analyzed tissue and cells from a stationary and a rapidly growing hyperplastic callus from a patient with osteogenesis imperfecta (OI) type IV and compared the results with those of compact bone and skin fibroblasts of an age-matched control. Collagen and protein contents per cell were low in the callus tissues and collagen I and III were overmodified as evidenced by an elevated level of hydroxylysine. The degree of lysyl hydroxylation was highest in those regions that appeared most immature by histological examination. Lysyl hydroxylation approached normal levels in collagen from the stationary callus and from the center of the growing callus. Overmodification of collagen was not seen in compact bone or cell cultures (neither skin fibroblasts nor callus cells) from the patient. Elevation of hydroxylysine in collagen from OI patients is generally attributed to mutations that delay triple helix formation. Our observations suggest that the varying degree of collagen modifications may occur in consequence of regulatory mechanisms during bone development and tissue repair. These mechanisms may be defective in some patients with OI as seen in this case with hyperplastic callus formation. Images PMID:2760218

  14. Rapidly Growing Brtl/+ Mouse Model of Osteogenesis Imperfecta Improves Bone Mass and Strength with Sclerostin Antibody Treatment

    PubMed Central

    Sinder, Benjamin P.; Salemi, Joseph D.; Ominsky, Michael S.; Caird, Michelle S.; Marini, Joan C.; Kozloff, Kenneth M.

    2014-01-01

    Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk that presents most severely in children. Anti-resorptive bisphosphonates are frequently used to treat pediatric OI and controlled clinical trials have shown bisphosphonate therapy improves vertebral outcomes but has little benefit on long bone fracture rate. New treatments which increase bone mass throughout the pediatric OI skeleton would be beneficial. Sclerostin antibody (Scl-Ab) is a potential candidate anabolic therapy for pediatric OI and functions by stimulating osteoblastic bone formation via the canonical wnt signaling pathway. To explore the effect of Scl-Ab on the rapidly growing OI skeleton, we treated rapidly growing 3 week old Brtl/+ mice, harboring a typical heterozygous OI-causing Gly->Cys substitution on col1a1, for 5 weeks with Scl-Ab. Scl-Ab had anabolic effects in Brtl/+ and led to new cortical bone formation and increased cortical bone mass. This anabolic action resulted in improved mechanical strength to WT Veh levels without altering the underlying brittle nature of the material. While Scl-Ab was anabolic in trabecular bone of the distal femur in both genotypes, the effect was less strong in these rapidly growing Brtl/+ mice compared to WT. In conclusion, Scl-Ab was able to stimulate bone formation in a rapidly growing Brtl/+ murine model of OI, and represents a potential new therapy to improve bone mass and reduce fracture risk in pediatric OI. PMID:25445450

  15. Adult Brtl/+ Mouse Model of Osteogenesis Imperfecta Demonstrates Anabolic Response to Sclerostin Antibody Treatment with Increased Bone Mass and Strength

    PubMed Central

    Sinder, Benjamin P.; White, Logan E.; Salemi, Joseph D.; Ominsky, Michael S.; Caird, Michelle S.; Marini, Joan C.; Kozloff, Kenneth M.

    2015-01-01

    Purpose Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk. Although OI fracture risk is greatest before puberty, adults with OI remain at risk of fracture. Anti-resorptive bisphosphonates are commonly used to treat adult OI, but have shown mixed efficacy. New treatments which consistently improve bone mass throughout the skeleton may improve patient outcomes. Neutralizing antibodies to sclerostin (Scl-Ab) are a novel anabolic therapy that have shown efficacy in preclinical studies by stimulating bone formation via the canonical wnt signaling pathway. The purpose of this study was to evaluate Scl-Ab in an adult 6 mo old Brtl/+ model of OI that harbors a typical heterozygous OI-causing Gly>Cys substitution on Col1a1. Methods 6mo old WT and Brtl/+ mice were treated with Scl-Ab (25mg/kg, 2x/week) or Veh for 5 weeks. OCN and TRACP5b serum assays, dynamic histomorphometry, microCT and mechanical testing were performed. Results Adult Brtl/+ mice demonstrated a strong anabolic response to Scl-Ab with increased serum osteocalcin and bone formation rate. This anabolic response led to improved trabecular and cortical bone mass in the femur. Mechanical testing revealed Scl-Ab increased Brtl/+ femoral stiffness and strength. Conclusion Scl-Ab was successfully anabolic in an adult Brtl/+ model of OI. PMID:24803333

  16. Evolution of the radiographic appearance of the metaphyses over the first year of life in type V osteogenesis imperfecta: clues to pathogenesis.

    PubMed

    Arundel, Paul; Offiah, Amaka; Bishop, Nicholas J

    2011-04-01

    We present the first report of the development of characteristic radiologic appearances of long bones during the first year of life in an infant with type V osteogenesis imperfecta (OI). We show the evolution of metaphyseal abnormalities from a rickets-like appearance to the classically described dense metaphyseal bands. These abnormalities suggest that the underlying defect in type V OI may involve a molecule common to both bone and cartilage that is involved in the regulation of growth plate development and metadiaphyseal ossification. Our findings provide new insights into skeletal development in type V OI and potentially yield useful clues to the identity of the defect underpinning the condition.

  17. Mutation in a gene for type I procollagen (COL1A2) in a woman with postmenopausal osteoporosis: Evidence for phenotypic and genotypic overlap with mild osteogenesis imperfecta

    SciTech Connect

    Spotila, L.D.; Constantinou, C.D.; Sereda, L.; Ganguly, A.; Prockop, D.J. ); Riggs, B.L. )

    1991-06-15

    Mutations in the two genes for type I collagen (COL1A1 or COL1A2) cause osteogenesis imperfecta (OI), a heritable disease characterized by moderate to extreme brittleness of bone early in life. Here, the authors show that a 52-year-old post menopausal woman with severe osteopenia and a compression fracture of a thoracic vertebra had a mutation in the gene for the {alpha}2(I) chain of type I collagen (COL1A2) similar to mutations that cause OI. cDNA was prepared from the woman's skin fibroblast RNA and assayed for the presence of a mutation by treating DNA heteroduplexes with carbodiimide. The results indicated a sequence variation in the region encoding amino acid residues 660-667 of the {alpha}2(I) chain. Further analysis demonstrated a single-base mutation that caused a serine-for-glycine substitution at position 661 of the {alpha}2(I) triple-helical domain. The substitution produced posttranslational overmodification of the collagen triple helix, as is seen with most glycine substitutions that cause OI. The patient had a history of five previous fractures, slightly blue sclerae, and slight hearing loss. Therefore, the results suggest that there may be phenotypic and genotypic overlap between mild osteogenesis imperfecta and postmenopausal osteoporosis, and that a subset of women with postmenopausal osteoporosis may have mutations in the genes for type I procollagen.

  18. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone

    PubMed Central

    Horwitz, Edwin M.; Gordon, Patricia L.; Koo, Winston K. K.; Marx, Jeffrey C.; Neel, Michael D.; McNall, Rene Y.; Muul, Linda; Hofmann, Ted

    2002-01-01

    Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affecting mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplantation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the first 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex-matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically significant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect engraftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors. PMID:12084934

  19. Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(+/mov13) mouse model of type I Osteogenesis Imperfecta.

    PubMed

    Jacobsen, Christina M; Schwartz, Marissa A; Roberts, Heather J; Lim, Kyung-Eun; Spevak, Lyudmila; Boskey, Adele L; Zurakowski, David; Robling, Alexander G; Warman, Matthew L

    2016-09-01

    Osteogenesis Imperfecta (OI) comprises a group of genetic skeletal fragility disorders. The mildest form of OI, Osteogenesis Imperfecta type I, is frequently caused by haploinsufficiency mutations in COL1A1, the gene encoding the α1(I) chain of type 1 collagen. Children with OI type I have a 95-fold higher fracture rate compared to unaffected children. Therapies for OI type I in the pediatric population are limited to anti-catabolic agents. In adults with osteoporosis, anabolic therapies that enhance Wnt signaling in bone improve bone mass, and ongoing clinical trials are determining if these therapies also reduce fracture risk. We performed a proof-of-principle experiment in mice to determine whether enhancing Wnt signaling in bone could benefit children with OI type I. We crossed a mouse model of OI type I (Col1a1(+/Mov13)) with a high bone mass (HBM) mouse (Lrp5(+/p.A214V)) that has increased bone strength from enhanced Wnt signaling. Offspring that inherited the OI and HBM alleles had higher bone mass and strength than mice that inherited the OI allele alone. However, OI+HBM and OI mice still had bones with lower ductility compared to wild-type mice. We conclude that enhancing Wnt signaling does not make OI bone normal, but does improve bone properties that could reduce fracture risk. Therefore, agents that enhance Wnt signaling are likely to benefit children and adults with OI type 1.

  20. Subarachnoid hemorrhage secondary to a ruptured middle cerebral aneurysm in a patient with osteogenesis imperfecta: a case report

    PubMed Central

    2014-01-01

    Background Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders that occur owing to the abnormalities in type 1 collagen, and is characterized by increased bone fragility and other extraskeletal manifestations. We report the case of a patient who was diagnosed with OI following subarachnoid hemorrhage (SAH) secondary to a ruptured saccular intracranial aneurysm (IA). Case Presentation A 37-year-old woman was referred to our hospital because of sudden headache and vomiting. She was diagnosed with SAH (World Federation of Neurosurgical Society grade 2) owing to an aneurysm of the middle cerebral artery. She then underwent surgical clipping of the aneurysm successfully. She had blue sclerae, a history of several fractures of the extremities, and a family history of bone fragility and blue sclerae in her son. According to these findings, she was diagnosed with OI type 1. We performed genetic analysis for a single nucleotide G/C polymorphism (SNP) of exon 28 of the gene encoding for alpha-2 polypeptide of collagen 1, which is a potential risk factor for IA. However, this SNP was not detected in this patient or in five normal control subjects. Other genetic analyses did not reveal any mutations of the COL1A1 or COL1A2 gene. The cerebrovascular system is less frequently involved in OI. OI is associated with increased vascular weakness owing to collagen deficiency in and around the blood vessels. SAH secondary to a ruptured IA with OI has been reported in only six cases. Conclusion The patient followed a good clinical course after surgery. It remains controversial whether IAs are caused by OI or IAs are coincidentally complicated with OI. PMID:25056440

  1. Identification of a novel heterozygous mutation in exon 50 of the COL1A1 gene causing osteogenesis imperfecta

    PubMed Central

    Aftab, S A S; Reddy, N; Owen, N L; Pollitt, R; Harte, A; McTernan, P G; Tripathi, G; Barber, T M

    2013-01-01

    Summary A 19-year-old woman was diagnosed with osteogenesis imperfecta (OI). She had sustained numerous low-trauma fractures throughout her childhood, including a recent pelvic fracture (superior and inferior ramus) following a low-impact fall. She had the classical blue sclerae, and dual energy X-ray absorptiometry (DEXA) bone scanning confirmed low bone mass for her age in the lumbar spine (Z-score was −2.6). However, despite these classical clinical features, the diagnosis of OI had not been entertained throughout the whole of her childhood. Sequencing of her genomic DNA revealed that she was heterozygous for the c.3880_3883dup mutation in exon 50 of the COL1A1 gene. This mutation is predicted to result in a frameshift at p.Thr1295, and truncating stop codon 3 amino acids downstream. To our knowledge, this mutation has not previously been reported in OI. Learning points OI is a rare but important genetic metabolic bone and connective tissue disorder that manifests a diverse clinical phenotype that includes recurrent low-impact fractures.Most mutations that underlie OI occur within exon 50 of the COL1A1 gene (coding for protein constituents of type 1 pro-collagen).The diagnosis of OI is easily missed in its mild form. Early diagnosis is important, and there is a need for improved awareness of OI among health care professionals.OI is a diagnosis of exclusion, although the key diagnostic criterion is through genetic testing for mutations within the COL1A1 gene.Effective management of OI should be instituted through a multidisciplinary team approach that includes a bone specialist (usually an endocrinologist or rheumatologist), a geneticist, an audiometrist and a genetic counsellor. Physiotherapy and orthopaedic surgery may also be required. PMID:24616757

  2. Tissue level material composition and mechanical properties in Brtl/+ mouse model of Osteogenesis Imperfecta after sclerostin antibody treatment

    NASA Astrophysics Data System (ADS)

    Lloyd, William R.; Sinder, Benjamin P.; Salemi, Joseph; Ominsky, Michael S.; Marini, Joan C.; Caird, Michelle S.; Morris, Michael D.; Kozloff, Kenneth M.

    2015-02-01

    Osteogenesis imperfecta (OI) is a genetic disorder resulting in defective collagen or collagen-associated proteins and fragile, brittle bones. To date, therapies to improve OI bone mass, such as bisphosphonates, have increased bone mass in the axial skeleton of OI patients, but have shown limited effects at reducing long bone fragility. Sclerostin antibody (Scl- Ab), currently in clinical trials for osteoporosis, stimulates bone formation and may have the potential to reduce long bone fracture rates in OI patients. Scl-Ab has been investigated as an anabolic therapy for OI in the Brtl/+ mouse model of moderately severe Type IV OI. While Scl-Ab increases long bone mass in the Brtl/+ mouse, it is not known whether material properties and composition changes also occur. Here, we report on the effects of Scl-Ab on wild type and Brtl/+ young (3 week) and adult (6 month) male mice. Scl-Ab was administered over 5 weeks (25mg/kg, 2x/week). Raman microspectroscopy and nanoindentation are used for bone composition and biomechanical bone property measurements in excised bone. Fluorescent labels (calcein and alizarin) at 4 time points over the entire treatment period are used to enable measurements at specific tissue age. Differences between wild type and Brtl/+ groups included variations in the mineral and matrix lattices, particularly the phosphate v1, carbonate v1, and the v(CC) proline and hydroxyproline stretch vibrations. Results of Raman spectroscopy corresponded to nanoindentation findings which indicated that old bone (near midcortex) is stiffer (higher elastic modulus) than new bone. We compare and contrast mineral to matrix and carbonate to phosphate ratios in young and adult mice with and without treatment.

  3. Pre- and postnatal transplantation of fetal mesenchymal stem cells in osteogenesis imperfecta: a two-center experience.

    PubMed

    Götherström, Cecilia; Westgren, Magnus; Shaw, S W Steven; Aström, Eva; Biswas, Arijit; Byers, Peter H; Mattar, Citra N Z; Graham, Gail E; Taslimi, Jahan; Ewald, Uwe; Fisk, Nicholas M; Yeoh, Allen E J; Lin, Ju-Li; Cheng, Po-Jen; Choolani, Mahesh; Le Blanc, Katarina; Chan, Jerry K Y

    2014-02-01

    Osteogenesis imperfecta (OI) can be recognized prenatally with ultrasound. Transplantation of mesenchymal stem cells (MSCs) has the potential to ameliorate skeletal damage. We report the clinical course of two patients with OI who received prenatal human fetal MSC (hfMSC) transplantation and postnatal boosting with same-donor MSCs. We have previously reported on prenatal transplantation for OI type III. This patient was retransplanted with 2.8 × 10(6) same-donor MSCs per kilogram at 8 years of age, resulting in low-level engraftment in bone and improved linear growth, mobility, and fracture incidence. An infant with an identical mutation who did not receive MSC therapy succumbed at 5 months despite postnatal bisphosphonate therapy. A second fetus with OI type IV was also transplanted with 30 × 10(6) hfMSCs per kilogram at 31 weeks of gestation and did not suffer any new fractures for the remainder of the pregnancy or during infancy. The patient followed her normal growth velocity until 13 months of age, at which time longitudinal length plateaued. A postnatal infusion of 10 × 10(6) MSCs per kilogram from the same donor was performed at 19 months of age, resulting in resumption of her growth trajectory. Neither patient demonstrated alloreactivity toward the donor hfMSCs or manifested any evidence of toxicities after transplantation. Our findings suggest that prenatal transplantation of allogeneic hfMSCs in OI appears safe and is of likely clinical benefit and that retransplantation with same-donor cells is feasible. However, the limited experience to date means that it is not possible to be conclusive and that further studies are required.

  4. Ossotide promotes cell differentiation of human osteoblasts from osteogenesis imperfecta patients by up-regulating miR-145.

    PubMed

    Sun, Keming; Wang, Junjian; Liu, Fangna; Ji, Zejuan; Guo, Zhanhao; Zhang, Chunxu; Yao, Manye

    2016-10-01

    Ossotide as an effective bone formation compound preparation has been proved to promote osteoblasts differentiation. MiR-145 is significantly decreased in osteogenesis imperfecta (OI) patients, but it is still unknown whether ossotide performed its effect by regulating miR-145. In this study, we investigated the effect of ossotide on regulating miR-145 expression and osteoblasts differentiation. The primary osteoblasts cells were isolated from OI patients and then cultured with different concentrations (0, 25, 50, 100, 200μg/l) of ossotide. The cell proliferation was detected with CCK-8 Elisa kit after ossotide treatment. The level of miR-145 expression was determined using qRT-PCR. In order to study whether ossotide up regulated miR-145, miR-145 mimic and miR-145 inhibitor were used to up regulate and down regulate the miR-145 levels in osteoblasts. The expressions of Runx2, Osx, β-catenin, TCF-1 were detected using Western blot and qRT-PCR. We observed that miR-145 was up regulated by ossotide treatment in miR-145 mimic or miR-145 inhibitor treated osteoblasts. What's more, up regulated miR-145 increased the expression of osteoblasts differentiation regulated protein Runx2 and Osx. In addition, Wnt signaling related β-catenin, TCF-1 were activated by up-regulated miR-145 which was induced by ossotide treatment. In summary, ossotide induced cell differentiation and Wnt signaling activation in osteoblasts by up regulating miR-145.

  5. Pre- and Postnatal Transplantation of Fetal Mesenchymal Stem Cells in Osteogenesis Imperfecta: A Two-Center Experience

    PubMed Central

    Westgren, Magnus; Shaw, S.W. Steven; Åström, Eva; Biswas, Arijit; Byers, Peter H.; Mattar, Citra N.Z.; Graham, Gail E.; Taslimi, Jahan; Ewald, Uwe; Fisk, Nicholas M.; Yeoh, Allen E.J.; Lin, Ju-Li; Cheng, Po-Jen; Choolani, Mahesh; Le Blanc, Katarina; Chan, Jerry K.Y.

    2014-01-01

    Osteogenesis imperfecta (OI) can be recognized prenatally with ultrasound. Transplantation of mesenchymal stem cells (MSCs) has the potential to ameliorate skeletal damage. We report the clinical course of two patients with OI who received prenatal human fetal MSC (hfMSC) transplantation and postnatal boosting with same-donor MSCs. We have previously reported on prenatal transplantation for OI type III. This patient was retransplanted with 2.8 × 106 same-donor MSCs per kilogram at 8 years of age, resulting in low-level engraftment in bone and improved linear growth, mobility, and fracture incidence. An infant with an identical mutation who did not receive MSC therapy succumbed at 5 months despite postnatal bisphosphonate therapy. A second fetus with OI type IV was also transplanted with 30 × 106 hfMSCs per kilogram at 31 weeks of gestation and did not suffer any new fractures for the remainder of the pregnancy or during infancy. The patient followed her normal growth velocity until 13 months of age, at which time longitudinal length plateaued. A postnatal infusion of 10 × 106 MSCs per kilogram from the same donor was performed at 19 months of age, resulting in resumption of her growth trajectory. Neither patient demonstrated alloreactivity toward the donor hfMSCs or manifested any evidence of toxicities after transplantation. Our findings suggest that prenatal transplantation of allogeneic hfMSCs in OI appears safe and is of likely clinical benefit and that retransplantation with same-donor cells is feasible. However, the limited experience to date means that it is not possible to be conclusive and that further studies are required. PMID:24342908

  6. Altered cytoskeletal organization characterized lethal but not surviving Brtl+/− mice: insight on phenotypic variability in osteogenesis imperfecta

    PubMed Central

    Bianchi, Laura; Gagliardi, Assunta; Maruelli, Silvia; Besio, Roberta; Landi, Claudia; Gioia, Roberta; Kozloff, Kenneth M.; Khoury, Basma M.; Coucke, Paul J.; Symoens, Sofie; Marini, Joan C.; Rossi, Antonio; Bini, Luca; Forlino, Antonella

    2015-01-01

    Osteogenesis imperfecta (OI) is a heritable bone disease with dominant and recessive transmission. It is characterized by a wide spectrum of clinical outcomes ranging from very mild to lethal in the perinatal period. The intra- and inter-familiar OI phenotypic variability in the presence of an identical molecular defect is still puzzling to the research field. We used the OI murine model Brtl+/− to investigate the molecular basis of OI phenotypic variability. Brtl+/− resembles classical dominant OI and shows either a moderately severe or a lethal outcome associated with the same Gly349Cys substitution in the α1 chain of type I collagen. A systems biology approach was used. We took advantage of proteomic pathway analysis to functionally link proteins differentially expressed in bone and skin of Brtl+/− mice with different outcomes to define possible phenotype modulators. The skin/bone and bone/skin hybrid networks highlighted three focal proteins: vimentin, stathmin and cofilin-1, belonging to or involved in cytoskeletal organization. Abnormal cytoskeleton was indeed demonstrated by immunohistochemistry to occur only in tissues from Brtl+/− lethal mice. The aberrant cytoskeleton affected osteoblast proliferation, collagen deposition, integrin and TGF-β signaling with impairment of bone structural properties. Finally, aberrant cytoskeletal assembly was detected in fibroblasts obtained from lethal, but not from non-lethal, OI patients carrying an identical glycine substitution. Our data demonstrated that compromised cytoskeletal assembly impaired both cell signaling and cellular trafficking in mutant lethal mice, altering bone properties. These results point to the cytoskeleton as a phenotypic modulator and potential novel target for OI treatment. PMID:26264579

  7. Osteogenesis imperfecta: Ultrastructural and histological findings on examination of skin revealing novel insights into genotype-phenotype correlation.

    PubMed

    Balasubramanian, M; Sobey, G J; Wagner, B E; Peres, L C; Bowen, J; Bexon, J; Javaid, M K; Arundel, P; Bishop, N J

    2016-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. Over 90% of patients with OI have a mutation in COL1A1/COL1A2, which shows an autosomal dominant pattern of inheritance. In-depth phenotyping and in particular, studies involving manifestations in the skin connective tissue have not previously been undertaken in OI. The aims of the study were to perform histological and ultrastructural examination of skin biopsies in a cohort of patients with OI; to identify common and distinguishing features in order to inform genotype-phenotype correlation; and to identify common and distinguishing features between the different subtypes of OI. As part of the RUDY (Rare Diseases in Bone, Joints and/or Blood Vessels) study, in collaboration with the NIHR Rare Diseases Translational Research Collaboration, we undertook a national study of skin biopsies in patients with OI. We studied the manifestations in the skin connective tissue and undertook in-depth clinical and molecular phenotyping of 16 patients with OI. We recruited 16 patients: analyses have shown that in type 1 collagen mutation positive patients (COL1A1/ COL1A2) (n-4/16) consistent findings included: variable collagen fibril diameter (CFD) and presence of collagen flowers. Histological examination in these patients showed an increase in elastic fibers that are frequently fragmented and clumped. These observations provide evidence that collagen flowers and CFD variability are consistent features in OI due to type 1 collagen defects and reinforce the need for accurate phenotyping in conjunction with genomic analyses.

  8. Molecular Consequences of the SERPINH1/HSP47 Mutation in the Dachshund Natural Model of Osteogenesis Imperfecta.

    PubMed

    Lindert, Uschi; Weis, Mary Ann; Rai, Jyoti; Seeliger, Frank; Hausser, Ingrid; Leeb, Tosso; Eyre, David; Rohrbach, Marianne; Giunta, Cecilia

    2015-07-17

    Osteogenesis imperfecta (OI) is a heritable connective tissue disease characterized by bone fragility and increased risk of fractures. Up to now, mutations in at least 18 genes have been associated with dominant and recessive forms of OI that affect the production or post-translational processing of procollagen or alter bone homeostasis. Among those, SERPINH1 encoding heat shock protein 47 (HSP47), a chaperone exclusive for collagen folding in the ER, was identified to cause a severe form of OI in dachshunds (L326P) as well as in humans (one single case with a L78P mutation). To elucidate the disease mechanism underlying OI in the dog model, we applied a range of biochemical assays to mutant and control skin fibroblasts as well as on bone samples. These experiments revealed that type I collagen synthesized by mutant cells had decreased electrophoretic mobility. Procollagen was retained intracellularly with concomitant dilation of ER cisternae and activation of the ER stress response markers GRP78 and phospho-eIF2α, thus suggesting a defect in procollagen processing. In line with the migration shift detected on SDS-PAGE of cell culture collagen, extracts of bone collagen from the OI dog showed a similar mobility shift, and on tandem mass spectrometry, the chains were post-translationally overmodified. The bone collagen had a higher content of pyridinoline than control dog bone. We conclude that the SERPINH1 mutation in this naturally occurring model of OI impairs how HSP47 acts as a chaperone in the ER. This results in abnormal post-translational modification and cross-linking of the bone collagen.

  9. Effect of high-dose vitamin D supplementation on bone density in youth with osteogenesis imperfecta: A randomized controlled trial.

    PubMed

    Plante, Laura; Veilleux, Louis-Nicolas; Glorieux, Francis H; Weiler, Hope; Rauch, Frank

    2016-05-01

    Osteogenesis imperfecta (OI) is a heritable condition characterized by fragile bones. Our previous studies indicated that serum 25-hydroxyvitamin D (25OHD) concentrations were positively associated with lumbar spine areal bone mineral density (LS-aBMD) in children and adolescents with OI. Here we assessed whether one year of high-dose vitamin D supplementation results in higher LS-aBMD z-scores in youth with OI. A one-year double-blind randomized controlled trial conducted at a pediatric orthopedic hospital in Montreal, Canada. Sixty patients (age: 6.0 to 18.9years; 35 female) were randomized in equal numbers to receive either 400 or 2000international units (IU) of vitamin D, stratified according to baseline bisphosphonate treatment status and pubertal stage. At baseline, the average serum 25OHD concentration was 65.6nmol/L (SD 20.4) with no difference between treatment groups (p=0.77); 21% of patients had results <50nmol/L. Vitamin D supplementation was associated with higher serum 25OHD concentrations in 90% of participants. The increase in mean 25OHD was significantly higher (p=0.02) in the group receiving 2000IU of vitamin D (mean [95% CI]=30.5nmol/L [21.3; 39.6]) than in the group receiving 400IU (15.2nmol/L [6.4; 24.1]). No significant differences in LS-aBMD z-score changes were detected between treatment groups. Thus, supplementation with vitamin D at 2000IU increased serum 25OHD concentrations in children with OI more than supplementation with 400IU. However, in this study where about 80% of participants had baseline serum 25OHD concentrations ≥50nmol/L, this difference had no detectable effect on LS-aBMD z-scores.

  10. Mutational characterization of the P3H1/CRTAP/CypB complex in recessive osteogenesis imperfecta.

    PubMed

    Barbirato, C; Trancozo, M; Almeida, M G; Almeida, L S; Santos, T O; Duarte, J C G; Rebouças, M R G O; Sipolatti, V; Nunes, V R R; Paula, F

    2015-12-03

    Osteogenesis imperfecta (OI) is a genetic disease characterized by bone deformities and fractures. Most cases are caused by autosomal dominant mutations in the type I collagen genes COL1A1 and COL1A2; however, an increasing number of recessive mutations in other genes have been reported. The LEPRE1, CRTAP, and PPIB genes encode proteins that form the P3H1/CRTAP/CypB complex, which is responsible for posttranslational modifications of type I collagen. In general, mutations in these genes lead to severe and lethal phenotypes of recessive OI. Here, we describe sixteen genetic variations detected in LEPRE1, CRTAP, and PPIB from 25 Brazilian patients with OI. Samples were screened for mutations on single-strand conformation polymorphism gels and variants were determined by automated sequencing. Seven variants were detected in patients but were absent in control samples. LEPRE1 contained the highest number of variants, including the previously described West African allele (c.1080+1G>T) found in one patient with severe OI as well as a previously undescribed p.Trp675Leu change that is predicted to be disease causing. In CRTAP, one patient carried the c.558A>G homozygous mutation, predicted as disease causing through alteration of a splice site. Genetic variations detected in the PPIB gene are probably not pathogenic due to their localization or because of their synonymous effect. This study enhances our knowledge about the mutational pattern of the LEPRE1, CRTAP, and PPIB genes. In addition, the results strengthen the proposition that LEPRE1 should be the first gene analyzed in mutation detection studies in patients with recessive OI.

  11. Allele Dependent Silencing of Collagen Type I Using Small Interfering RNAs Targeting 3'UTR Indels - a Novel Therapeutic Approach in Osteogenesis Imperfecta

    PubMed Central

    Lindahl, Katarina; Kindmark, Andreas; Laxman, Navya; Åström, Eva; Rubin, Carl-Johan; Ljunggren, Östen

    2013-01-01

    Osteogenesis imperfecta, also known as “brittle bone disease”, is a heterogeneous disorder of connective tissue generally caused by dominant mutations in the genes COL1A1 and COL1A2, encoding the α1 and α2 chains of type I (pro)collagen. Symptomatic patients are usually prescribed bisphosphonates, but this treatment is neither curative nor sufficient. A promising field is gene silencing through RNA interference. In this study small interfering RNAs (siRNAs) were designed to target each allele of 3'UTR insertion/deletion polymorphisms (indels) in COL1A1 (rs3840870) and COL1A2 (rs3917). For both indels, the frequency of heterozygous individuals was determined to be approximately 50% in Swedish cohorts of healthy controls as well as in patients with osteogenesis imperfecta. Cultures of primary human bone derived cells were transfected with siRNAs through magnet-assisted transfection. cDNA from transfected cells was sequenced in order to measure targeted allele/non-targeted allele ratios and the overall degree of silencing was assessed by quantitative PCR. Successful allele dependent silencing was observed, with promising results for siRNAs complementary to both the insertion and non-insertion harboring alleles. In COL1A1 cDNA the indel allele ratios were shifted from 1 to 0.09 and 0.19 for the insertion and non-insertion allele respectively while the equivalent resulting ratios for COL1A2 were 0.05 and 0.01. Reductions in mRNA abundance were also demonstrated; in cells treated with siRNAs targeting the COL1A1 alleles the average COL1A1 mRNA levels were reduced 65% and 78% compared to negative control levels and in cells treated with COL1A2 siRNAs the average COL1A2 mRNA levels were decreased 26% and 49% of those observed in the corresponding negative controls. In conclusion, allele dependent silencing of collagen type I utilizing 3'UTR indels common in the general population constitutes a promising mutation independent therapeutic approach for osteogenesis

  12. Fracture Rates and Fracture Sites in Patients With Osteogenesis Imperfecta: A Nationwide Register-Based Cohort Study.

    PubMed

    Folkestad, Lars; Hald, Jannie Dahl; Ersbøll, Annette Kjaer; Gram, Jeppe; Hermann, Anne Pernille; Langdahl, Bente; Abrahamsen, Bo; Brixen, Kim

    2017-01-01

    Osteogenesis imperfecta (OI) is a hereditary, clinically heterogeneous, connective tissue disorder. The population prevalence of OI in Denmark is 10.6 in 100,000. A hallmark of the disease is frequent fractures that are often precipitated by minimal trauma. The aim of the current study was to compare the fracture rates across the lifespan of patients with OI with that of a reference population from the general population. The present study was a Danish nationwide, population-based, cohort study using register data. We identified 644 (55.6% females) patients in the OI cohort through the Danish National Patient Register and 3361 (55.2% females) persons, randomly selected from the Civil Registry System. A total of 416 patients with OI experienced a total of 1566 fractures during the observation period of median 17.9 years (interquartile range [IQR], 12.4 to 18.0 years), summing to 10137 person years. In comparison, 709 persons in the reference population experienced a total of 1018 fractures during follow-up. Both male and female patients with OI had an increased fracture rate throughout their life. The fracture rate ratio for participants aged 0 to 19 years was 10.7, for participants aged 20 to 54 years 17.2, and for participants aged 55 years and over 4.1 when compared to the reference population. The highest fracture rate was seen in males with OI aged 0 to 19 years (257 fractures per 1000 person-years). The fractures appear to follow the same pattern as in the general population, with a peak during the toddler and adolescent years (incidence rate [IR] 233.9 per 1000 person years), fewer fractures during adulthood (IR 84.5 per 1000 person years), and increased fracture rates in older women (IR 111.9 per 1000 person years). This is the largest register-based nationwide study on the fracture epidemiology of patients with OI. The risk of fractures seems largest in the childhood and adolescent years, and the relative risk of fracture declines with age in patients with

  13. Mortality and Causes of Death in Patients With Osteogenesis Imperfecta: A Register-Based Nationwide Cohort Study.

    PubMed

    Folkestad, Lars; Hald, Jannie Dahl; Canudas-Romo, Vladimir; Gram, Jeppe; Hermann, Anne Pernille; Langdahl, Bente; Abrahamsen, Bo; Brixen, Kim

    2016-12-01

    Osteogenesis imperfecta (OI) is a hereditary connective tissue disease that causes frequent fractures. Little is known about causes of death and length of survival in OI. The objective of this work was to calculate the risk and cause of death, and the median survival time in patients with OI. This study was a Danish nationwide, population-based and register-based cohort study. We used National Patient Register data from 1977 until 2013 with complete long-term follow-up. Participants comprised all patients registered with the diagnosis of OI from 1977 until 2013, and a reference population matched five to one to the OI cohort. We calculated hazard ratios for all-cause mortality and subhazard ratios for cause-specific mortality in a comparison of the OI cohort and the reference population. We also calculated all-cause mortality hazard ratios for males, females, and age groups (0 to 17.99 years, 18.00 to 34.99 years, 35.00 to 54.99 years, 55.00 to 74.99 years, and >75 years). We identified 687 cases of OI (379 women) and included 3435 reference persons (1895 women). A total of 112 patients with OI and 257 persons in the reference population died during the observation period. The all-cause mortality hazard ratio between the OI cohort and the reference population was 2.90. The median survival time for males with OI was 72.4 years, compared to 81.9 in the reference population. The median survival time for females with OI was 77.4 years, compared to 84.5 years in the reference population. Patients with OI had a higher risk of death from respiratory diseases, gastrointestinal diseases, and trauma. We were limited by the lack of clinical information about phenotype and genotype of the included patients. Patients with OI had a higher mortality rate throughout their life compared to the general population. © 2016 American Society for Bone and Mineral Research.

  14. Beneficial effects of intravenous pamidronate treatment in children with osteogenesis imperfecta under 24 months of age.

    PubMed

    Kusumi, Kirsten; Ayoob, Rose; Bowden, Sasigarn A; Ingraham, Susan; Mahan, John D

    2015-09-01

    Osteogenesis imperfecta (OI) is an inherited disorder characterized by bone fragility and low bone mass. Low bone density and fracture is a cause of morbidity. Limited data exists on bisphosphonate treatment in patients under 24 months of age. The objective of the study was to examine the safety and efficacy of pamidronate in children under 24 months with OI. To do so, we carried out a retrospective chart review and analysis of OI patients started on intravenous pamidronate under 24 months of age. Pamidronate was administered in three-day cycles. Growth, the number of fractures, and lumbar bone mineral densities were recorded both prior to and after treatment initiation. A total of 18 patients were reviewed. Five were classified as OI type I, seven were type III, and six were type IV. The mean age at treatment initiation was 12 months (range 11 days to 23 months). The mean lumbar z score at baseline was -3.63, which improved to -1.53 at one year (P < 0.01) and 0.79 (P < 0.01) at the end of the study. The fracture rate improved from 68 fractures in 209 months (0.32 fractures/patient-month) before treatment to 41 fractures in 1,248 months (0.03 fractures/patient-month) post-treatment (P < 0.05). Height standard deviation score (SDS) was conserved from baseline to end of study (-2.12 ± 2.45 vs. -2.45 ± 2.73) (P = 0.05) with an average follow-up of 73 months. The only adverse effect recorded in six infants was fever during the initial pamidronate infusion. Treatment with intravenous pamidronate is safe, significantly improves lumbar bone mineral density (L-BMD), and reduces fracture rates in young infants with OI while preserving linear growth.

  15. Impairment of diastolic function in adult patients affected by osteogenesis imperfecta clinically asymptomatic for cardiac disease: casuality or causality?

    PubMed

    Migliaccio, Silvia; Barbaro, Giuseppe; Fornari, Rachele; Di Lorenzo, Gabriella; Celli, Mauro; Lubrano, Carla; Falcone, Stefania; Fabbrini, Elisa; Greco, Emanuela; Zambrano, Anna; Brama, Marina; Prossomariti, Giancarlo; Marzano, Sara; Marini, Mario; Conti, Francesco; D'Eufemia, Patrizia; Spera, Giovanni

    2009-01-09

    Osteogenesis imperfecta (OI) is a rare inherited connective disorder causing increased bone fragility and low bone mass. OI includes severe bone fragility, impaired dentinogenesis, with less common alterations in the joints, blood vessels, heart valves, skin. Interestingly, description of left ventricular rupture, aortic dissection and heart valves incompetence has been previously described. Death may occur in OI patients for cardiac disease in asyntomatic subjects. Aim of our study has been to evaluate the presence of potential subclinical cardiac disorders and to characterize cardiac functional parameters by echocardiography in adults with OI in absence of cardiac symptoms. Forty patients (21 females and 19 males) affected by type I, III, IV OI and 40 control subjects (20 females and 20 males) were evaluated in the study. Patients and controls underwent clinical examination, screening for endocrine and metabolic disorders, 12-lead electrocardiogram and echocardiogram. In particular, all subjects were evaluated by two-dimensional echocardiography with continuous- and pulse-wave Doppler. Patients and controls belonged to NYHA class I and no significant electrocardiographic alteration was documented in both groups. Thirty-eight patients (95%) showed valvular regurgitation compared to one control subject (2.5%; P<0.001). As regards the diastolic function parameters, in OI patients E wave velocity was reduced by 23% (95% CI: 9% to 29%; P<0.001), E/A ratio was reduced by 17% (95% CI: 15% to 26%; P<0.001) while isovolumetric relaxation time (IRT) was increased by 47% (95% CI: 26% to 53%; P<0.001) and E wave deceleration time (DT) was increased by 18% (95% CI: 13% to 26%; P<0.001) compared to controls. In conclusion, our data indicate that adult patients affected by OI have an altered diastolic function in absence of other metabolic alterations. These diastolic echocardiographic parameters might worsen over time, especially if other cardiovascular risk factors (e

  16. Genomic organization of the human osteopontin gene: Exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II.

    SciTech Connect

    Crosby, A.H.; Edwards, S.J.; Murray, J.C.

    1995-05-01

    Osteopontin (SPP1) is the principal phosphorylated glycoprotein of bone that is also expressed in a limited number of other tissues including dentine. In the current investigation the authors report the genomic organization of the SPP1 gene, which comprises seven exons, six of which contain coding sequence. The splice sites for exon donor and acceptor positions are in close agreement with previously published consensus sequences. Comparison of the human gene with its murine and bovine counterparts revealed a highly homologous organization. A highly informative short tandem repeat polymorphism isolated at the SPP1 locus showed no recombination with the autosomal dominant disorder dentinogenesis imperfecta type II. Nevertheless, sequencing of each exon in individuals affected by this disorder failed to reveal any disease-specific mutations. 25 refs., 2 figs., 2 tabs.

  17. WDR72 models of structure and function: A stage-specific regulator of enamel mineralization

    PubMed Central

    Katsura, K.A.; Horst, J.A.; Chandra, D.; Le, T.Q.; Nakano, Y.; Zhang, Y.; Horst, O.V.; Zhu, L.; Le, M.H.

    2014-01-01

    Amelogenesis Imperfecta (AI) is a clinical diagnosis that encompasses a group of genetic mutations, each affecting processes involved in tooth enamel formation and thus, result in various enamel defects. The hypomaturation enamel phenotype has been described for mutations involved in the later stage of enamel formation, including Klk4, Mmp20, C4orf26, and Wdr72. Using a candidate gene approach we discovered a novel Wdr72 human mutation in association with AI to be a 5-base pair deletion (c.806_810delGGCAG; p.G255VfsX294). To gain insight into the function of WDR72, we used computer modeling of the full-length human WDR72 protein structure and found that the predicted N-terminal sequence forms two beta-propeller folds with an alpha-solenoid tail at the C-terminus. This domain iteration is characteristic of vesicle coat proteins, such as beta′-COP, suggesting a role for WDR72 in the formation of membrane deformation complexes to regulate intracellular trafficking. Our Wdr72 knockout mouse model (Wdr72−/−), containing a LacZ reporter knock-in, exhibited hypomineralized enamel similar to the AI phenotype observed in humans with Wdr72 mutations. MicroCT scans of Wdr72−/− mandibles affirmed the hypomineralized enamel phenotype occurring at the onset of the maturation stage. H&E staining revealed a shortened height phenotype in the Wdr72−/− ameloblasts with retained proteins in the enamel matrix during maturation stage. H+/Cl− exchange transporter 5 (CLC5), an early endosome acidifier, was co-localized with WDR72 in maturation-stage ameloblasts and decreased in Wdr72−/− maturation-stage ameloblasts. There were no obvious differences in RAB4A and LAMP1 immunostaining of Wdr72−/− mice as compared to wildtype controls. Moreover, Wdr72−/− ameloblasts had reduced amelogenin immunoreactivity, suggesting defects in amelogenin fragment resorption from the matrix. These data demonstrate that WDR72 has a major role in enamel mineralization, most notably

  18. FAM83H — EDRN Public Portal

    Cancer.gov

    FAM83H is a member of the FAM83 family and plays an important role in the structural development and calcification of tooth enamel. Defects in this gene are a cause of amelogenesis imperfecta type 3 (AI3). Lack of a recognizable signal peptide indicates that the protein functions within the cell. It is expressed in the tooth follicle.

  19. Learning about Osteogenesis Imperfecta

    MedlinePlus

    ... Database Newsroom Calendar of Events Current News Releases Image Gallery GenomeTV Media Contacts Media Resources NHGRI-Related News Journal Articles from NHGRI Social Media Careers Educational Programs Health Professional Education Intramural ...

  20. Osteogenesis Imperfecta Overview

    MedlinePlus

    ... Inheritance Factors Treatment Prognosis Resource For Your Information Prevalence Although the number of people affected with OI ... recessive OI have a 25-percent chance per pregnancy of having another child with OI. Siblings of ...

  1. Osteogenesis Imperfecta Foundation

    MedlinePlus

    ... Spirit® Awareness Week Fine Wines Strong Bones Bone China Tea Blue Jeans for Better Bones Calendar Online ... information about Blue Jeans for Better Bones, Bone China Tea, and more! Learn More OI Foundation National ...

  2. Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome

    PubMed Central

    2013-01-01

    Background Whereas mutations affecting the helical domain of type I procollagen classically cause Osteogenesis Imperfecta (OI), helical mutations near the amino (N)-proteinase cleavage site have been suggested to result in a mixed OI/Ehlers-Danlos syndrome (EDS)-phenotype. Methods We performed biochemical and molecular analysis of type I (pro-) collagen in a cohort of seven patients referred with a clinical diagnosis of EDS and showing only subtle signs of OI. Transmission electron microscopy of the dermis was available for one patient. Results All of these patients harboured a COL1A1 / COL1A2 mutation residing within the most N-terminal part of the type I collagen helix. These mutations affect the rate of type I collagen N-propeptide cleavage and disturb normal collagen fibrillogenesis. Importantly, patients with this type of mutation do not show a typical OI phenotype but mainly present as EDS patients displaying severe joint hyperlaxity, soft and hyperextensible skin, abnormal wound healing, easy bruising, and sometimes signs of arterial fragility. In addition, they show subtle signs of OI including blue sclerae, relatively short stature and osteopenia or fractures. Conclusion Recognition of this distinct phenotype is important for accurate genetic counselling, clinical management and surveillance, particularly in relation to the potential risk for vascular rupture associated with these mutations. Because these patients present clinical overlap with other EDS subtypes, biochemical collagen analysis is necessary to establish the correct diagnosis. PMID:23692737

  3. A case of fetal osteogenesis imperfecta type 2A: longitudinal observation of natural course in utero and pitfalls for prenatal ultrasound diagnosis.

    PubMed

    Kimura, Ibuki; Araki, Ryota; Yoshizato, Toshiyuki; Miyamoto, Shingo

    2015-10-01

    We present a case of osteogenesis imperfecta (OI) type 2A in which a natural course in utero was observed from 23 weeks' gestation to term. At 23 weeks' gestation, a sonographic examination showed a cloverleaf skull-like head, a narrow thorax, and marked shortening of the long bones with bowing of the femurs and humeri. Follow-up examinations showed that the cloverleaf skull-like head was not evident at 28 weeks' gestation. Discontinuity of the ribs and femurs was observed at 26 and 30 weeks' gestation, respectively. This finding suggested bone fractures, which were confirmed by three-dimensional computed tomography at 32 weeks' gestation. Ultrasonographic findings of bones, including the long bones and calvarium, changed with advancing gestation during the second trimester. Characteristic features of OI type 2A were evident during the late second to early third trimesters. Repeated ultrasonographic examinations together with three-dimensional computed tomography are necessary for the definitive diagnosis of OI type 2A in the second trimester.

  4. Targeted exome sequencing identifies novel compound heterozygous mutations in P3H1 in a fetus with osteogenesis imperfecta type VIII.

    PubMed

    Huang, Yanru; Mei, Libin; Lv, Weigang; Li, Haoxian; Zhang, Rui; Pan, Qian; Tan, Hu; Guo, Jing; Luo, Xiaomei; Chen, Chen; Liang, Desheng; Wu, Lingqian

    2017-01-01

    Osteogenesis imperfecta (OI) is a highly clinically and genetically heterogeneous group of disorders. It is difficult to identify severe OI in the perinatal period. Here, a Chinese woman with a suspected history of fetal OI was referred to our institution at 19weeks of gestation, due to ultrasound inspection during antenatal screening, which revealed bulbous metaphyses, short humeri, and short thick bent femora in the fetus. Using targeted exome sequencing of 248 genes known to be involved in skeletal system diseases, we identified novel compound heterozygous mutation in the P3H1 gene in the fetus with OI type VIII: c.105_120del (p.D36Rfs*16) and c.2164C>T (p.Q722*). These two mutations were inherited from the father and mother, respectively. The mRNA level of P3H1 wasn't changed suggested that mRNA with this mutation escaped from nonsense-mediated RNA decay. Besides, the level of P3H1 was absence while the CRTAP was mildly decreased. In conclusion, our findings imply this novel compound heterozygous mutation as the molecular pathogenetic in a Chinese fetus with OI type VIII, and demonstrate that targeted next-generation sequencing (NGS) is an accurate, rapid, and cost-effective method in the genetic diagnosis of fetal skeletal dysplasia with genetic and clinical heterogeneity, especially for autosomal recessive skeletal disorders.

  5. In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta

    PubMed Central

    Panaroni, Cristina; Gioia, Roberta; Lupi, Anna; Besio, Roberta; Goldstein, Steven A.; Kreider, Jaclynn; Leikin, Sergey; Vera, Juan Carlos; Mertz, Edward L.; Perilli, Egon; Baruffaldi, Fabio; Villa, Isabella; Farina, Aurora; Casasco, Marco; Cetta, Giuseppe; Rossi, Antonio; Frattini, Annalisa; Marini, Joan C.; Vezzoni, Paolo

    2009-01-01

    Autosomal dominant osteogenesis imperfecta (OI) caused by glycine substitutions in type I collagen is a paradigmatic disorder for stem cell therapy. Bone marrow transplantation in OI children has produced a low engraftment rate, but surprisingly encouraging symptomatic improvements. In utero transplantation (IUT) may hold even more promise. However, systematic studies of both methods have so far been limited to a recessive mouse model. In this study, we evaluated intrauterine transplantation of adult bone marrow into heterozygous BrtlIV mice. Brtl is a knockin mouse with a classical glycine substitution in type I collagen [α1(I)-Gly349Cys], dominant trait transmission, and a phenotype resembling moderately severe and lethal OI. Adult bone marrow donor cells from enhanced green fluorescent protein (eGFP) transgenic mice engrafted in hematopoietic and nonhematopoietic tissues differentiated to trabecular and cortical bone cells and synthesized up to 20% of all type I collagen in the host bone. The transplantation eliminated the perinatal lethality of heterozygous BrtlIV mice. At 2 months of age, femora of treated Brtl mice had significant improvement in geometric parameters (P < .05) versus untreated Brtl mice, and their mechanical properties attained wild-type values. Our results suggest that the engrafted cells form bone with higher efficiency than the endogenous cells, supporting IUT as a promising approach for the treatment of genetic bone diseases. PMID:19414862

  6. Substitution of cysteine for glycine at residue 415 of one allele of the alpha 1(I) chain of type I procollagen in type III/IV osteogenesis imperfecta.

    PubMed Central

    Nicholls, A C; Oliver, J; Renouf, D V; Keston, M; Pope, F M

    1991-01-01

    We have examined the type I collagen in a patient with type III/IV osteogenesis imperfecta. Two forms of alpha 1(I) chain were produced, one normal and the other containing a cysteine residue within the triple helical domain of the molecule. Cysteine is not normally present in this domain of type I collagen. Peptide mapping experiments localised the mutation to peptide alpha 1(I)CB3 which spans residues 403 to 551 of the triple helix. Subsequent PCR amplification of cDNA covering this region followed by sequencing showed a G to T single base change in the GGC codon for glycine 415 generating TGC, the codon for cysteine. The effect of the mutation on the protein is to delay secretion from the cell, reduce the thermal stability of the molecule by 2 degrees C, and cause excessive post-translational modification of all chains in molecules containing one or more mutant alpha 1(I) chains. The clinical phenotype observed in this patient and the position of the mutation conform to the recent prediction of Starman et al that Gly----Cys mutations in the alpha 1(I) chain have a gradient of severity decreasing from the C-terminus to the N-terminus. Images PMID:1770532

  7. Premature chain termination is a unifying mechanism for COL1A1 null alleles in osteogenesis imperfecta type I cell strains

    SciTech Connect

    Willing, M.C.; Deschenes, S.P.; Roberts, E.J.

    1996-10-01

    Nonsense and frameshift mutations, which predict premature termination of translation, often cause a dramatic reduction in the amount of transcript from the mutant allele (nonsense-mediated mRNA decay). In some genes, these mutations also influence RNA splicing and induce skipping of the exon that contains the nonsense codon. To begin to dissect how premature termination alters the metabolism of RNA from the COL1A1 gene, we studied nonsense and frameshift mutations distributed over exons 11-49 of the gene. These mutations were originally identified in 10 unrelated families with osteogenesis imperfecta (OI) type I. We observed marked reduction in steady-state amounts of mRNA from the mutant allele in both total cellular and nuclear RNA extracts of cells from affected individuals, suggesting that nonsense-mediated decay of COL1A1 RNA is a nuclear phenomenon. Position of the mutation within the gene did not influence this observation. None of the mutations induced skipping of either the exon containing the mutation or, for the frameshifts, the downstream exons with the new termination sites. Our data suggest that nonsense and frameshift mutations throughout most of the COL1A1 gene result in a null allele, which is associated with the predictable mild clinical phenotype, OI type I. 42 refs., 6 figs., 1 tab.

  8. Augmentation of the mandible via a "tent-pole" procedure and implant treatment in a patient with type III osteogenesis imperfecta: clinical and histologic considerations.

    PubMed

    Wannfors, Karin; Johansson, Carina; Donath, Karl

    2009-01-01

    The present report describes the oral rehabilitation of a female patient suffering from type III osteogenesis imperfecta. Agenesis of the mandibular anterior teeth and malocclusion caused partly by heavily worn teeth made dental rehabilitation necessary. Before a decision to use implants following a grafting procedure, the osseointegration of microimplants was tested. After 4 and 12 months, bone plugs containing two microimplants were retrieved from the patient. Histologic evaluation showed very sparse/poor osseointegration, and the healing time seemed to be much longer than normal. A decision was made to use the "tent-pole" procedure described by Marx et al, followed by prolonged healing. Surgery was uneventful, and the patient was provided with four implants that were partly covered with bone obtained from the iliac crest. Platelet-rich plasma was used to accelerate bone healing. After 9 months, the implants were uncovered and the prosthetic construction was completed. The implant-supported metal-ceramic restoration was serving well at the 1-year and 3-year follow-ups. Minimal resorption of marginal bone was detected during the first year.

  9. Four patients with Sillence type I osteogenesis imperfecta and mild bone fragility, complicated by left ventricular cardiac valvular disease and cardiac tissue fragility caused by type I collagen mutations.

    PubMed

    Vandersteen, Anthony M; Lund, Allan M; Ferguson, David J P; Sawle, Philip; Pollitt, Rebecca C; Holder, Susan E; Wakeling, Emma; Moat, Neil; Pope, F Michael

    2014-02-01

    Osteogenesis imperfecta (OI) type I is a hereditary disorder of connective tissue (HDCT) characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurrent fractures from infancy. We present four examples of OI type I complicated by valvular heart disease and associated with tissue fragility. The diagnosis of a type I collagen disorder was confirmed by abnormal COL1A1 or COL1A2 gene sequencing. One patient was investigated with electrophoresis of collagens from cultured skin fibroblasts, showing structurally abnormal collagen type I, skin biopsy showed unusual histology and abnormal collagen fibril ultra-structure at electron microscopy. The combined clinical, surgical, histological, ultra-structural, and molecular genetic data suggest the type I collagen defect as contributory to cardiac valvular disease. The degree of tissue fragility experienced at cardiac surgery in these individuals, also reported in a small number of similar case reports, suggests that patients with OI type I need careful pre-operative assessment and consideration of the risks and benefits of cardiac surgery.

  10. Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen

    PubMed Central

    Schwarze, Ulrike; Cundy, Tim; Pyott, Shawna M.; Christiansen, Helena E.; Hegde, Madhuri R.; Bank, Ruud A.; Pals, Gerard; Ankala, Arunkanth; Conneely, Karen; Seaver, Laurie; Yandow, Suzanne M.; Raney, Ellen; Babovic-Vuksanovic, Dusica; Stoler, Joan; Ben-Neriah, Ziva; Segel, Reeval; Lieberman, Sari; Siderius, Liesbeth; Al-Aqeel, Aida; Hannibal, Mark; Hudgins, Louanne; McPherson, Elizabeth; Clemens, Michele; Sussman, Michael D.; Steiner, Robert D.; Mahan, John; Smith, Rosemarie; Anyane-Yeboa, Kwame; Wynn, Julia; Chong, Karen; Uster, Tami; Aftimos, Salim; Sutton, V. Reid; Davis, Elaine C.; Kim, Lammy S.; Weis, Mary Ann; Eyre, David; Byers, Peter H.

    2013-01-01

    Although biallelic mutations in non-collagen genes account for <10% of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes. We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis–trans isomerase, FKBP65, in 38 members of 21 families with OI. These include 10 families from the Samoan Islands who share a founder mutation. Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability. In four families missense mutations result in loss of most of the protein. The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families. The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues. These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result. PMID:22949511

  11. A Novel IFITM5 Mutation in Severe Atypical Osteogenesis Imperfecta Type VI Impairs Osteoblast Production of Pigment Epithelium-Derived Factor

    PubMed Central

    Farber, Charles R; Reich, Adi; Barnes, Aileen M; Becerra, Patricia; Rauch, Frank; Cabral, Wayne A; Bae, Alison; Quinlan, Aaron; Glorieux, Francis H; Clemens, Thomas L; Marini, Joan C

    2015-01-01

    Osteogenesis imperfecta (OI) types V and VI are caused, respectively, by a unique dominant mutation in IFITM5, encoding BRIL, a transmembrane ifitm-like protein most strongly expressed in the skeletal system, and recessive null mutations in SERPINF1, encoding pigment epithelium-derived factor (PEDF). We identified a 25-year-old woman with severe OI whose dermal fibroblasts and cultured osteoblasts displayed minimal secretion of PEDF, but whose serum PEDF level was in the normal range. SERPINF1 sequences were normal despite bone histomorphometry consistent with type VI OI and elevated childhood serum alkaline phosphatase. We performed exome sequencing on the proband, both parents, and an unaffected sibling. IFITM5 emerged as the candidate gene from bioinformatics analysis, and was corroborated by membership in a murine bone co-expression network module containing all currently known OI genes. The de novo IFITM5 mutation was confirmed in one allele of the proband, resulting in a p.S40L substitution in the intracellular domain of BRIL but was absent in unaffected family members. IFITM5 expression was normal in proband fibroblasts and osteoblasts, and BRIL protein level was similar to control in differentiated proband osteoblasts on Western blot and in permeabilized mutant osteoblasts by microscopy. In contrast, SERPINF1 expression was decreased in proband osteoblasts; PEDF was barely detectable in conditioned media of proband cells. Expression and secretion of type I collagen was similarly decreased in proband osteoblasts; the expression pattern of several osteoblast markers largely overlapped reported values from cells with a primary PEDF defect. In contrast, osteoblasts from a typical case of type V OI, with an activating mutation at the 5′-terminus of BRIL, have increased SERPINF1 expression and PEDF secretion during osteoblast differentiation. Together, these data suggest that BRIL and PEDF have a relationship that connects the genes for types V and VI OI and

  12. Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta

    PubMed Central

    Cabral, Wayne A.; Ishikawa, Masaki; Garten, Matthias; Makareeva, Elena N.; Sargent, Brandi M.; Weis, MaryAnn; Barnes, Aileen M.; Webb, Emma A.; Shaw, Nicholas J.; Ala-Kokko, Leena; Lacbawan, Felicitas L.; Högler, Wolfgang; Leikin, Sergey; Blank, Paul S.; Zimmerberg, Joshua; Eyre, David R.; Yamada, Yoshihiko; Marini, Joan C.

    2016-01-01

    Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B. TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca2+-dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50–70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes. PMID:27441836

  13. Scoliosis in osteogenesis imperfecta caused by COL1A1/COL1A2 mutations - genotype-phenotype correlations and effect of bisphosphonate treatment.

    PubMed

    Sato, Atsuko; Ouellet, Jean; Muneta, Takeshi; Glorieux, Francis H; Rauch, Frank

    2016-05-01

    Bisphosphonates are widely used to treat children with osteogenesis imperfecta (OI), a bone fragility disorder that is most often caused by mutations in COL1A1 or COL1A2. However, it is unclear whether this treatment decreases the risk of developing scoliosis. We retrospectively evaluated spine radiographs and charts of 437 patients (227 female) with OI caused by mutations in COL1A1 or COL1A2 and compared the relationship between scoliosis, genotype and bisphosphonate treatment history. At the last follow-up (mean age 11.9 [SD: 5.9] years), 242 (55%) patients had scoliosis. The prevalence of scoliosis was highest in OI type III (89%), followed by OI type IV (61%) and OI type I (36%). Moderate to severe scoliosis (Cobb angle ≥25°) was rare in individuals with COL1A1 haploinsufficiency mutations but was present in about two fifth of patients with triple helical glycine substitutions or C-propeptide mutations. During the first 2 to 4years of bisphosphonate therapy, patients with OI type III had lower Cobb angle progression rates than before bisphosphonate treatment, whereas in OI types I and IV bisphosphonate treatment was not associated with a change in Cobb angle progression rates. At skeletal maturity, the prevalence of scoliosis (Cobb angle >10°) was similar in patients who had started bisphosphonate treatment early in life (before 5.0years of age) and in patients who had started therapy later (after the age of 10.0years) or had never received bisphosphonate therapy. Bisphosphonate treatment decreased progression rate of scoliosis in OI type III but there was no evidence of a positive effect on scoliosis in OI types I and IV. The prevalence of scoliosis at maturity was not influenced by the bisphosphonate treatment history in any OI type.

  14. Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta.

    PubMed

    Syx, Delfien; Guillemyn, Brecht; Symoens, Sofie; Sousa, Ana Berta; Medeira, Ana; Whiteford, Margo; Hermanns-Lê, Trinh; Coucke, Paul J; De Paepe, Anne; Malfait, Fransiska

    2015-08-01

    Whereas the vast majority of osteogenesis imperfecta (OI) is caused by autosomal dominant defects in the genes encoding type I procollagen, mutations in a myriad of genes affecting type I procollagen biosynthesis or bone formation and homeostasis have now been associated with rare autosomal recessive OI forms. Recently, homozygous or compound heterozygous mutations in BMP1, encoding the metalloproteases bone morphogenetic protein-1 (BMP1) and its longer isoform mammalian Tolloid (mTLD), were identified in 5 children with a severe autosomal recessive form of OI and in 4 individuals with mild to moderate bone fragility. BMP1/mTLD functions as the procollagen carboxy-(C)-proteinase for types I to III procollagen but was also suggested to participate in amino-(N)-propeptide cleavage of types V and XI procollagens and in proteolytic trimming of other extracellular matrix (ECM) substrates. We report the phenotypic characteristics and natural history of 4 adults with severe, progressive OI characterized by numerous fractures, short stature with rhizomelic shortening, and deformity of the limbs and variable kyphoscoliosis, in whom we identified novel biallelic missense and frameshift mutations in BMP1. We show that BMP1/mTLD-deficiency in humans not only results in delayed cleavage of the type I procollagen C-propeptide but also hampers the processing of the small leucine-rich proteoglycan prodecorin, a regulator of collagen fibrillogenesis. Immunofluorescent staining of types I and V collagen and transmission electron microscopy of the dermis show impaired assembly of heterotypic type I/V collagen fibrils in the ECM. Our study thus highlights the severe and progressive nature of BMP1-associated OI in adults and broadens insights into the functional consequences of BMP1/mTLD-deficiency on ECM organization.

  15. Bone geometry, density, and microarchitecture in the distal radius and tibia in adults with osteogenesis imperfecta type I assessed by high-resolution pQCT.

    PubMed

    Folkestad, Lars; Hald, Jannie Dahl; Hansen, Stinus; Gram, Jeppe; Langdahl, Bente; Abrahamsen, Bo; Brixen, Kim

    2012-06-01

    Osteogenesis imperfecta (OI) is a hereditary disorder characterized by decreased biosynthesis or impaired morphology of type I collagen that leads to decreased bone mass and increased bone fragility. We hypothesized that patients with OI have altered bone microstructure and bone geometry. In this cross-sectional study we compared patients with type I OI to age- and gender-matched healthy controls. A total of 39 (13 men and 26 women) patients with OI, aged 53 (range, 21-77) years, and 39 controls, aged 53 (range, 21-77) years, were included in the study. Twenty-seven of the patients had been treated with bisphosphonates. High-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and dual-energy X-ray absorptiometry of total hip, femoral neck, trochanteric region, and the lumbar spine (L1-L4) were performed. The patients were shorter than the controls (159 ± 10 cm versus 170 ± 9 cm, p < 0.001), but had similar body weight. In OI, areal bone mineral density (aBMD) was 8% lower at the hip (p < 0.05) and 13% lower at the spine (p < 0.001) compared with controls. The trabecular volumetric bone mineral density (vBMD) was 28% lower in radius (p < 0.001) and 38% lower in tibia (p < 0.001) in OI compared with controls. At radius, total bone area was 5% lower in OI than in controls (p < 0.05). In the tibia, cortical bone area was 18% lower in OI (p < 0.001). In both radius and tibia the number of trabeculae was lower in patients compared to the controls (35% and 38%, respectively, p < 0.001 at both sites). Furthermore, trabecular spacing was 55% higher in OI in both tibia and radius (p < 0.001 at both sites) when compared with controls. We conclude that patients with type I OI have lower aBMD, vBMD, bone area, and trabecular number when compared with healthy age- and gender-matched controls.

  16. Effect of Anti-Sclerostin Therapy and Osteogenesis Imperfecta on Tissue-level Properties in Growing and Adult Mice While Controlling for Tissue Age

    PubMed Central

    Sinder, Benjamin P.; Lloyd, William R.; Salemi, Joseph D.; Marini, Joan C.; Caird, Michelle S.; Morris, Michael D.; Kozloff, Kenneth M.

    2016-01-01

    Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as Osteogenesis Imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly→Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5 weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2–4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages >3wk) and rapidly growing Brtl/+ (at tissue ages > 4wk) mice compared to WT. At identical tissue ages defined by fluorescent labels adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age

  17. Abnormal Type I Collagen Post-translational Modification and Crosslinking in a Cyclophilin B KO Mouse Model of Recessive Osteogenesis Imperfecta

    PubMed Central

    Cabral, Wayne A.; Perdivara, Irina; Weis, MaryAnn; Terajima, Masahiko; Blissett, Angela R.; Chang, Weizhong; Perosky, Joseph E.; Makareeva, Elena N.; Mertz, Edward L.; Leikin, Sergey; Tomer, Kenneth B.; Kozloff, Kenneth M.; Eyre, David R.; Yamauchi, Mitsuo; Marini, Joan C.

    2014-01-01

    Cyclophilin B (CyPB), encoded by PPIB, is an ER-resident peptidyl-prolyl cis-trans isomerase (PPIase) that functions independently and as a component of the collagen prolyl 3-hydroxylation complex. CyPB is proposed to be the major PPIase catalyzing the rate-limiting step in collagen folding. Mutations in PPIB cause recessively inherited osteogenesis imperfecta type IX, a moderately severe to lethal bone dysplasia. To investigate the role of CyPB in collagen folding and post-translational modifications, we generated Ppib−/− mice that recapitulate the OI phenotype. Knock-out (KO) mice are small, with reduced femoral areal bone mineral density (aBMD), bone volume per total volume (BV/TV) and mechanical properties, as well as increased femoral brittleness. Ppib transcripts are absent in skin, fibroblasts, femora and calvarial osteoblasts, and CyPB is absent from KO osteoblasts and fibroblasts on western blots. Only residual (2–11%) collagen prolyl 3-hydroxylation is detectable in KO cells and tissues. Collagen folds more slowly in the absence of CyPB, supporting its rate-limiting role in folding. However, treatment of KO cells with cyclosporine A causes further delay in folding, indicating the potential existence of another collagen PPIase. We confirmed and extended the reported role of CyPB in supporting collagen lysyl hydroxylase (LH1) activity. Ppib−/− fibroblast and osteoblast collagen has normal total lysyl hydroxylation, while increased collagen diglycosylation is observed. Liquid chromatography/mass spectrometry (LC/MS) analysis of bone and osteoblast type I collagen revealed site-specific alterations of helical lysine hydroxylation, in particular, significantly reduced hydroxylation of helical crosslinking residue K87. Consequently, underhydroxylated forms of di- and trivalent crosslinks are strikingly increased in KO bone, leading to increased total crosslinks and decreased helical hydroxylysine- to lysine-derived crosslink ratios. The altered

  18. Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age.

    PubMed

    Sinder, Benjamin P; Lloyd, William R; Salemi, Joseph D; Marini, Joan C; Caird, Michelle S; Morris, Michael D; Kozloff, Kenneth M

    2016-03-01

    Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as osteogenesis imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly➔Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2-4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages>3wks) and rapidly growing Brtl/+ (at tissue ages>4wks) mice compared to WT. At identical tissue ages defined by fluorescent labels, adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age and

  19. Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations

    PubMed Central

    Jaureguiberry, Graciana; De la Dure-Molla, Muriel; Parry, David; Quentric, Mickael; Himmerkus, Nina; Koike, Toshiyasu; Poulter, James; Klootwijk, Enriko; Robinette, Steven L.; Howie, Alexander J.; Patel, Vaksha; Figueres, Marie-Lucile; Stanescu, Horia C.; Issler, Naomi; Nicholson, Jeremy K.; Bockenhauer, Detlef; Laing, Christopher; Walsh, Stephen B.; McCredie, David A.; Povey, Sue; Asselin, Audrey; Picard, Arnaud; Coulomb, Aurore; Medlar, Alan J.; Bailleul-Forestier, Isabelle; Verloes, Alain; Le Caignec, Cedric; Roussey, Gwenaelle; Guiol, Julien; Isidor, Bertrand; Logan, Clare; Shore, Roger; Johnson, Colin; Inglehearn, Christopher; Al-Bahlani, Suhaila; Schmittbuhl, Matthieu; Clauss, François; Huckert, Mathilde; Laugel, Virginie; Ginglinger, Emmanuelle; Pajarola, Sandra; Spartà, Giuseppina; Bartholdi, Deborah; Rauch, Anita; Addor, Marie-Claude; Yamaguti, Paulo M.; Safatle, Heloisa P.; Acevedo, Ana Carolina; Martelli-Júnior, Hercílio; dos Santos Netos, Pedro E.; Coletta, Ricardo D.; Gruessel, Sandra; Sandmann, Carolin; Ruehmann, Denise; Langman, Craig B.; Scheinman, Steven J.; Ozdemir-Ozenen, Didem; Hart, Thomas C.; Hart, P. Suzanne; Neugebauer, Ute; Schlatter, Eberhard; Houillier, Pascal; Gahl, William A.; Vikkula, Miikka; Bloch-Zupan, Agnès; Bleich, Markus; Kitagawa, Hiroshi; Unwin, Robert J.; Mighell, Alan; Berdal, Ariane; Kleta, Robert

    2013-01-01

    Background/Aims Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. Methods We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. Results All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. Conclusions This au-tosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis. PMID:23434854

  20. Fast Facts on Osteogenesis Imperfecta

    MedlinePlus

    ... healing process.) Calcification of the membrane between the radius and ulna (the bones of the forearm). This leads to restriction of forearm rotation. White sclera. Normal teeth. Bone has a “mesh-like” appearance when viewed under the microscope. ...

  1. Genetics Home Reference: osteogenesis imperfecta

    MedlinePlus

    ... most abundant protein in bone, skin, and other connective tissues that provide structure and strength to the body. ... in the structure of type I collagen weakens connective tissues, particularly bone, resulting in the characteristic features of ...

  2. Myths about OI (Osteogenesis Imperfecta)

    MedlinePlus

    ... OIF Research Grants 50,000 Lives, One Unbreakable Spirit © Jamie Kendall Fund My Personal Gift Membership Employer ... Wheel Regional Conference 50,000 Laps, One Unbreakable Spirit® Awareness Week Fine Wines Strong Bones Bone China ...

  3. Arachnoid cyst and chronic subdural haematoma in a child with osteogenesis imperfecta type III resulting from the substitution of glycine 1006 by alanine in the pro alpha 2(I) chain of type I procollagen.

    PubMed Central

    Cole, W G; Lam, T P

    1996-01-01

    The features of a child with osteogenesis imperfecta type III (OI III) resulting from the heterozygous substitution of glycine 1006 by alanine in the pro alpha 2(I) chain of type I procollagen were studied. He was born at term with the clinical features of severe OI, including deep grey-blue sclerae. He had severe osteopenia and all long bones were smaller than normal with cortical thinning, metaphyseal expansion, poor metaphyseal modelling, and multiple fractures. However, the vertebrae, pelvis, and shoulder girdle were of normal shape and there were few rib fractures. Histological examination of the calvarium and tibial shaft showed woven bone without lamellar bone or Haversian systems. The shafts of the long bones were widened owing to repeated fractures. Progressive enlargement of the calvarium occurred between 3 and 4.5 months of age owing to bilateral chronic subdural haematomata and a large arachnoid cyst in the Sylvian fissure. The cyst was probably developmental in origin while the subdural collections were probably the result of perinatal skull trauma. The cyst and the subdural collections resolved following drainage but ventricular dilatation with normal cerebrospinal fluid pressure followed. The proband is the first reported case of OI with a glycine substitution by alanine in the pro alpha 2(I) chain of type I procollagen. Images PMID:8728690

  4. An overlapping phenotype of Osteogenesis imperfecta and Ehlers-Danlos syndrome due to a heterozygous mutation in COL1A1 and biallelic missense variants in TNXB identified by whole exome sequencing.

    PubMed

    Mackenroth, Luisa; Fischer-Zirnsak, Björn; Egerer, Johannes; Hecht, Jochen; Kallinich, Tilmann; Stenzel, Werner; Spors, Birgit; von Moers, Arpad; Mundlos, Stefan; Kornak, Uwe; Gerhold, Kerstin; Horn, Denise

    2016-04-01

    Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G > A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin-X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype.

  5. Diagnostic conundrums in antenatal presentation of a skeletal dysplasia with description of a heterozygous C-propeptide mutation in COL1A1 associated with a severe presentation of osteogenesis imperfecta.

    PubMed

    Marshall, Charlotte J; Arundel, Paul; Mushtaq, Talat; Offiah, Amaka C; Pollitt, Rebecca C; Bishop, Nicholas J; Balasubramanian, Meena

    2016-12-01

    Prompt and accurate diagnosis of skeletal dysplasias can play a crucial role in ensuring appropriate counseling and management (both antenatal and postnatal). When a skeletal dysplasia is detected during the antenatal period, especially early in the pregnancy, it can be associated with a poor prognosis. It is important to make a diagnosis in antenatal presentation of skeletal dysplasias to inform diagnosis, predict prognosis, provide accurate recurrence risks, and options for prenatal genetic testing in future pregnancies. Prenatal ultrasound scanning is a useful tool to detect several skeletal dysplasias and sonographic measurements serve as reliable indicators of lethality. The lethality depends on various factors including gestational age at which features are identified, size of the chest and progression of malformations. Although, it is important to type the skeletal presentation as accurately as possible, this is not always possible in an antenatal presentation and it is important to acknowledge this uncertainty. In the case of a live birth, it is always important to reassess the infant. Osteogenesis imperfecta (OI) is a heterogeneous group of disorders characterized by fragile bones. Here, we report an infant with severe OI born following a twin pregnancy in whom the bone disease is caused by a heterozygous pathogenic mutation, c.4160C >T, p.(Ala1387Val) located in the C-propeptide region of COL1A1. An assumption of lethality antenatally complicated his management in early life. We discuss this patient with particular emphasis on the neonatal presentation of a severe skeletal dysplasia and the lessons that may be learned in such situations. © 2016 Wiley Periodicals, Inc.

  6. Alendronate Treatment of the Brtl Osteogenesis Imperfecta Mouse Improves Femoral Geometry and Load Response Before Fracture but Decreases Predicted Material Properties and Has Detrimental Effects on Osteoblasts and Bone Formation

    PubMed Central

    Uveges, Thomas E.; Kozloff, Kenneth M.; Ty, Jennifer M.; Ledgard, Felicia; Raggio, Cathleen L.; Gronowicz, Gloria; Goldstein, Steven A.; Marini, Joan C.

    2009-01-01

    Long courses of bisphosphonates are widely administered to children with osteogenesis imperfecta (OI), although bisphosphonates do not block mutant collagen secretion and may affect bone matrix composition or structure. The Brtl mouse has a glycine substitution in col1a1 and is ideal for modeling the effects of bisphosphonate in classical OI. We treated Brtl and wildtype mice with alendronate (Aln; 0.219 mg/kg/wk, SC) for 6 or 12 wk and compared treated and untreated femora of both genotypes. Mutant and wildtype bone had similar responses to Aln treatment. Femoral areal BMD and cortical volumetric BMD increased significantly after 12 wk, but femoral length and growth curves were unaltered. Aln improved Brtl diaphyseal cortical thickness and trabecular number after 6 wk and cross-sectional shape after 12 wk. Mechanically, Aln significantly increased stiffness in wildtype femora and load to fracture in both genotypes after 12 wk. However, predicted material strength and elastic modulus were negatively impacted by 12 wk of Aln in both genotypes, and metaphyseal remnants of mineralized cartilage also increased. Brtl femoral brittleness was unimproved. Brtl osteoclast and osteoblast surface were unchanged by treatment. However, decreased mineral apposition rate and bone formation rate/bone surface and the flattened morphology of Brtl osteoblasts suggested that Aln impaired osteoblast function and matrix synthesis. We conclude that Aln treatment improves Brtl femoral geometry and load to fracture but decreases bone matrix synthesis and predicted material modulus and strength, with striking retention of mineralized cartilage. Beneficial and detrimental changes appear concomitantly. Limiting cumulative bisphosphonate exposure of OI bone will minimize detrimental effects. PMID:19113917

  7. Rough Endoplasmic Reticulum (rER) Trafficking Errors by Different Classes of Mutant DSPP Cause the Dominant Negative Effects in both Dentinogenesis Imperfecta and Dentin Dysplasia by Entrapping Normal DSPP

    PubMed Central

    von Marschall, Zofia; Mok, Seeun; Phillips, Matthew D.; McKnight, Dianalee A.; Fisher, Larry W.

    2012-01-01

    Families with nonsyndromic dentinogenesis imperfecta (DGI) and the milder, dentin dysplasia (DD), have mutations in one allele of the dentin sialophosphoprotein (DSPP) gene. Because loss of a single Dspp allele in mice (and likely, humans) causes no dental phenotype, the mechanism(s) underling the dominant-negative effects were investigated. DSPP mutations occur in three classes. (The first class, the mid-leader missense mutation, Y6D, was not investigated in this report.) All other 5' mutations of DSPP result in changes/loss in the first three amino acids (IPV) of mature DSPP or, for A15V, some retention of the hydrophobic leader sequence. All of this second class of mutations caused mutant DSPP to be retained in the rER of transfected HEK293 cells. Trafficking out of the rER by co-expressed normal DSPP was reduced in a dose-responsive manner, probably due to formation of Ca2+-dependent complexes with the retained mutant DSPP. IPV-like sequences begin many secreted Ca2+-binding proteins, and changing the third amino acid to the charged aspartate (D) in three other acidic proteins also caused increased rER accumulation. Both the leader-retaining A15V and the long string of hydrophobic amino acids resulting from all known frameshift mutations within the 3'-encoded Ca2+-binding repeat domain (third class of mutations) caused retention by association of the mutant proteins with rER membranes. More 5' frameshift mutations result in longer mutant hydrophobic domains but the milder phenotype, DD, probably due to lower effectiveness of the remaining, shorter Ca2+-binding domain in capturing normal DSPP protein within the rER. This study presents evidence of a shared underlying mechanism of capturing of normal DSPP by two different classes of DSPP mutations and offers an explanation for the mild (DD-II) versus severe (DGI-II & III) nonsyndromic dentin phenotypes. Evidence is also presented that many acidic, Ca2+-binding proteins may use the same IPV-like receptor

  8. Planning for Your Child's Surgery (Osteogenesis Imperfecta)

    MedlinePlus

    ... out of bed, sit in a rocking chair. Deep breathing together can help your child relax tense ... response to the surgery and usually subsides. Taking deep breaths helps expand the lungs and minimize fever. ...

  9. What Are the Symptoms of Osteogenesis Imperfecta?

    MedlinePlus

    ... pdf?docID=7621 [top] Forlino A, Cabral WA, Barnes AM, & Marini JC. (2011). New Perspectives on Osteogenesis ... pubmed/21670757 [top] Forlino, A., Cabral, W. A., Barnes, A. M., & Marini, J. C. (2011). New perspectives ...

  10. What Are the Treatments for Osteogenesis Imperfecta?

    MedlinePlus

    ... between healing fractures and maintaining bone strength. [top] Physical Therapy Physical therapy aims to maintain functioning in as many aspects of life as possible. A usual program combines muscle strengthening with aerobic ... rehabilitation program can include strengthening of deltoids, biceps, ...

  11. Substitutions of aspartic acid for glycine-220 and of arginine for glycine-664 in the triple helix of the pro alpha 1(I) chain of type I procollagen produce lethal osteogenesis imperfecta and disrupt the ability of collagen fibrils to incorporate crystalline hydroxyapatite.

    PubMed Central

    Culbert, A A; Lowe, M P; Atkinson, M; Byers, P H; Wallis, G A; Kadler, K E

    1995-01-01

    We identified two infants with lethal (type II) osteogenesis imperfecta (OI) who were heterozygous for mutations in the COL1A1 gene that resulted in substitutions of aspartic acid for glycine at position 220 and arginine for glycine at position 664 in the product of one COL1A1 allele in each individual. In normal age- and site-matched bone, approximately 70% (by number) of the collagen fibrils were encrusted with plate-like crystallites of hydroxyapatite. In contrast, approximately 5% (by number) of the collagen fibrils in the probands' bone contained crystallites. In contrast with normal bone, the c-axes of hydroxyapatite crystallites were sometimes poorly aligned with the long axis of fibrils obtained from OI bone. Chemical analysis showed that the OI samples contained normal amounts of calcium. The probands' bone samples contained type I collagen, overmodified type I collagen and elevated levels of type III and V collagens. On the basis of biochemical and morphological data, the fibrils in the OI samples were co-polymers of normal and mutant collagen. The results are consistent with a model of fibril mineralization in which the presence of abnormal type I collagen prevents normal collagen in the same fibril from incorporating hydroxyapatite crystallites. Images Figure 1 Figure 2 Figure 3 PMID:7487936

  12. Tricho-Dento-Osseous Syndrome: Diagnosis and Dental Management

    PubMed Central

    Al-Batayneh, Ola B.

    2012-01-01

    Tricho-dento-osseous (TDO) syndrome is a rare, autosomal dominant disorder principally characterised by curly hair at infancy, severe enamel hypomineralization and hypoplasia and taurodontism of teeth, sclerotic bone, and other defects. Diagnostic criteria are based on the generalized enamel defects, severe taurodontism especially of the mandibular first permanent molars, an autosomal dominant mode of inheritance, and at least one of the other features (i.e., nail defects, bone sclerosis, and curly, kinky or wavy hair present at a young age that may straighten out later). Confusion with amelogenesis imperfecta is common; however, taurodontism is not a constant feature of any of the types of amelogenesis imperfecta. Management of TDO requires a team approach, proper documentation, and a long-term treatment and follow-up plan. The aim of treatment is to prevent problems such as sensitivity, caries, dental abscesses, and loss of occlusal vertical dimension through attrition of hypoplastic tooth structure. Another aim is to restore function of the dentition and enhance the esthetics and self-esteem of the patient. This paper proposes treatment approaches that include preventive, restorative, endodontic, prosthetic, and surgical options to management. In addition, it sheds light on the difficulties faced during dental treatment of such cases. PMID:22969805

  13. Partial rescue of the amelogenin null dental enamel phenotype.

    PubMed

    Li, Yong; Suggs, Cynthia; Wright, J Timothy; Yuan, Zhi-an; Aragon, Melissa; Fong, Hanson; Simmons, Darrin; Daly, Bill; Golub, Ellis E; Harrison, Gerald; Kulkarni, Ashok B; Gibson, Carolyn W

    2008-05-30

    The amelogenins are the most abundant secreted proteins in developing dental enamel. Enamel from amelogenin (Amelx) null mice is hypoplastic and disorganized, similar to that observed in X-linked forms of the human enamel defect amelogenesis imperfecta resulting from amelogenin gene mutations. Both transgenic strains that express the most abundant amelogenin (TgM180) have relatively normal enamel, but strains of mice that express a mutated amelogenin (TgP70T), which leads to amelogenesis imperfecta in humans, have heterogeneous enamel structures. When Amelx null (KO) mice were mated with transgenic mice that produce M180 (TgM180), the resultant TgM180KO offspring showed evidence of rescue in enamel thickness, mineral density, and volume in molar teeth. Rescue was not observed in the molars from the TgP70TKO mice. It was concluded that a single amelogenin protein was able to significantly rescue the KO phenotype and that one amino acid change abrogated this function during development.

  14. A solution NMR investigation into the impaired self-assembly properties of two murine amelogenins containing the point mutations T21→I or P41→T

    SciTech Connect

    Buchko, Garry W.; Lin, Genyao; Tarasevich, Barbara J.; Shaw, Wendy J.

    2013-08-26

    Amelogenesis imperfecta describes a group of inherited disorders that results in defective tooth enamel. Two disorders associated with human amelogenesis imperfecta are the point mutations T21?I or P40?T in amelogenin, the dominant protein present during the early stages of enamel biomineralization. The biophysical properties of wildtype murine amelogenin (M180) and two proteins containing the equivalent mutations in murine amelogenin, T21?I (M180-I) and P41?T (M180-T), were probed by NMR spectroscopy. At low protein concentration (0.1 mM), M180, M180-I, and M180-T are predomi- nately monomeric at pH 3.0 in 2% acetic acid and neither mutation produces a major structural change. Chemical shift perturbation studies as a function of protein (0.1–1.8 mM) or NaCl (0–400 mM) concentra- tions show that the mutations affect the self-association properties by causing self-assembly at lower protein or salt concentrations, relative to wildtype amelogenin, with the largest effect observed for M180-I. Under both conditions, the premature self-assembly is initiated near the N-terminus, providing further evidence for the importance of this region in the self-assembly process. The self-association of M180-I and M180-T at lower protein concentrations and lower ionic strengths than wildtype M180 may account for the clinical phenotypes of these mutations, defective enamel formation.

  15. Enamel-renal-gingival syndrome and FAM20A mutations.

    PubMed

    Kantaputra, Piranit Nik; Kaewgahya, Massupa; Khemaleelakul, Udomrat; Dejkhamron, Prapai; Sutthimethakorn, Suchitra; Thongboonkerd, Visith; Iamaroon, Anak

    2014-01-01

    The enamel-renal syndrome of amelogenesis imperfecta (AI) and nephrocalcinosis, and the amelogenesis imperfecta-gingival fibromatosis syndrome have both been associated with mutations in FAM20A. We report on two unrelated Thai patients with three novel and one previously reported mutations in FAM20A with findings suggesting both disorders, including hypoplastic AI, gingival fibromatosis, unerupted teeth, aggressive periodontitis, and nephrocalcinosis/nephrolithiasis. Additional findings consisted of a supernumerary premolar, localized aggressive periodontitis, thin alveolar bone, vitamin D deficiency-associated hyperparathyroidism, and heterotopic calcification in other tissues, including lungs, dental pulp, gingiva, dental follicles, and periodontal tissues, and early cessation of limited menstruation. Greater promotory activity of urine on calcium oxalate crystal growth compared to controls may help to explain the pathogenesis, and suggest that FAM20A mutations can contribute to nephrocalcinosis/nephrolithiasis. Our findings expand the phenotypic spectrum of FAM20A mutations. Since both of our patients and a large number of previously reported cases had all the important features of both syndromes, including AI, renal anomalies, and gingival fibromatosis, we are convinced that these two disorders actually are the same entity. The name of enamel-renal-gingival syndrome is suggested.

  16. Periodontal disease and FAM20A mutations.

    PubMed

    Kantaputra, Piranit Nik; Bongkochwilawan, Chotika; Lubinsky, Mark; Pata, Supansa; Kaewgahya, Massupa; Tong, Huei Jinn; Ketudat Cairns, James R; Guven, Yeliz; Chaisrisookumporn, Nipon

    2017-03-16

    Enamel-renal-gingival syndrome (ERGS; OMIM #204690), a rare autosomal recessive disorder caused by mutations in FAM20A, is characterized by nephrocalcinosis, nephrolithiasis, amelogenesis imperfecta, hypoplastic type, gingival fibromatosis and other dental abnormalities, including hypodontia and unerupted teeth with large dental follicles. We report three patients and their families with findings suggestive of ERGS. Mutation analysis of FAM20A was performed in all patients and their family members. Patients with homozygous frameshift and compound heterozygous mutations in FAM20A had typical clinical findings along with periodontitis. The other had a novel homozygous missense mutation in exon 10, mild gingival fibromatosis and renal calcifications. The periodontitis in our patients may be a syndrome component, and similar findings in previous reports suggest more than coincidence. Fam20a is an allosteric activator that increases Fam20c kinase activity. It is hypothesized that lack of FAM20A activation of FAM20C in our patients with FAM20A mutations might have caused amelogenesis imperfecta, abnormal bone remodeling and periodontitis. Nephrocalcinosis appears not to be a consistent finding of the syndrome and the missense mutation may correlate with mild gingival fibromatosis. Here we report three patients with homozygous or compound heterozygous mutations in FAM20A and findings that extend the phenotypic spectrum of this disorder, showing that protein truncation is associated with greater clinical severity.Journal of Human Genetics advance online publication, 16 March 2017; doi:10.1038/jhg.2017.26.

  17. A distinctive oral phenotype points to FAM20A mutations not identified by Sanger sequencing.

    PubMed

    Poulter, James A; Smith, Claire E L; Murrillo, Gina; Silva, Sandra; Feather, Sally; Howell, Marianella; Crinnion, Laura; Bonthron, David T; Carr, Ian M; Watson, Christopher M; Inglehearn, Chris F; Mighell, Alan J

    2015-11-01

    Biallelic FAM20A mutations cause two conditions where Amelogenesis Imperfecta (AI) is the presenting feature: Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome; and Enamel Renal Syndrome. A distinctive oral phenotype is shared in both conditions. On Sanger sequencing of FAM20A in cases with that phenotype, we identified two probands with single, likely pathogenic heterozygous mutations. Given the recessive inheritance pattern seen in all previous FAM20A mutation-positive families and the potential for renal disease, further screening was carried out to look for a second pathogenic allele. Reverse transcriptase-PCR on cDNA was used to determine transcript levels. CNVseq was used to screen for genomic insertions and deletions. In one family, FAM20A cDNA screening revealed only a single mutated FAM20A allele with the wild-type allele not transcribed. In the second family, CNV detection by whole genome sequencing (CNVseq) revealed a heterozygous 54.7 kb duplication encompassing exons 1 to 4 of FAM20A. This study confirms the link between biallelic FAM20A mutations and the characteristic oral phenotype. It highlights for the first time examples of FAM20A mutations missed by the most commonly used mutation screening techniques. This information informed renal assessment and ongoing clinical care.

  18. Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning by conformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15 patients with osteogenesis imperfecta type I: identification of common sequences of null-allele mutations.

    PubMed Central

    Körkkö, J; Ala-Kokko, L; De Paepe, A; Nuytinck, L; Earley, J; Prockop, D J

    1998-01-01

    Although >90% of patients with osteogenesis imperfecta (OI) have been estimated to have mutations in the COL1A1 and COL1A2 genes for type I procollagen, mutations have been difficult to detect in all patients with the mildest forms of the disease (i.e., type I). In this study, we first searched for mutations in type I procollagen by analyses of protein and mRNA in fibroblasts from 10 patients with mild OI; no evidence of a mutation was found in 2 of the patients by the protein analyses, and no evidence of a mutation was found in 5 of the patients by the RNA analyses. We then searched for mutations in the original 10 patients and in 5 additional patients with mild OI, by analysis of genomic DNA. To assay the genomic DNA, we established a consensus sequence for the first 12 kb of the COL1A1 gene and for 30 kb of new sequences of the 38-kb COL1A2 gene. The sequences were then used to develop primers for PCR for the 103 exons and exon boundaries of the two genes. The PCR products were first scanned for heteroduplexes by conformation-sensitive gel electrophoresis, and then products containing heteroduplexes were sequenced. The results detected disease-causing mutations in 13 of the 15 patients and detected two additional probable disease-causing mutations in the remaining 2 patients. Analysis of the data developed in this study and elsewhere revealed common sequences for mutations causing null alleles. PMID:9443882

  19. ENAM Mutations with Incomplete Penetrance

    PubMed Central

    Seymen, F.; Lee, K.-E.; Koruyucu, M.; Gencay, K.; Bayram, M.; Tuna, E.B.; Lee, Z.H.; Kim, J.-W.

    2014-01-01

    Amelogenesis imperfecta (AI) is a genetic disease affecting tooth enamel formation. AI can be an isolated entity or a phenotype of syndromes. To date, more than 10 genes have been associated with various forms of AI. We have identified 2 unrelated Turkish families with hypoplastic AI and performed mutational analysis. Whole-exome sequencing identified 2 novel heterozygous nonsense mutations in the ENAM gene (c.454G>T p.Glu152* in family 1, c.358C>T p.Gln120* in family 2) in the probands. Affected individuals were heterozygous for the mutation in each family. Segregation analysis within each family revealed individuals with incomplete penetrance or extremely mild enamel phenotype, in spite of having the same mutation with the other affected individuals. We believe that these findings will broaden our understanding of the clinical phenotype of AI caused by ENAM mutations. PMID:25143514

  20. Diagnosis and treatment of molar incisor hypomineralization.

    PubMed

    Mathu-Muju, Kavita; Wright, J Timothy

    2006-11-01

    Molar incisor hypomineralization (MIH) is a relatively common condition that varies in clinical severity and can result in early loss of the permanent 6-year molars. The etiology of MIH remains unclear, and the diagnosis can be confused with more generalized enamel defects such as those that occur in amelogenesis imperfecta. The management of MIH depends largely on the severity of the enamel defect. Degrees of hypomineralization can range from mild enamel opacities to enamel that readily abrades from the tooth as it emerges into the oral cavity. Usually, severely affected molars are extremely hypersensitive, prone to rapid caries development, and can be difficult to manage in young patients. The purpose of this article is to review approaches to diagnosing and treating MIH.

  1. Molecular basis and consequences of a deletion in the amelogenin gene, analyzed by capture PCR

    SciTech Connect

    Lagerstroem-Fermer, M.; Pettersson, U.; Landegren, U. )

    1993-07-01

    A mutation that disrupts the gene for one of the major proteins in tooth enamel has been investigated. The mutation is located in the amelogenin gene and causes X-linked amelogenesis imperfecta, characterized by defective mineralization of tooth enamel. The authors have isolated the breakpoints of a 5-kb deletion in the amelogenin gene on the basis of nucleotide sequence information located upstream of the lesion, using a technique termed capture PCR. The deletion removes five of the seven exons, spanning from the second intron to the last exon. Only the first two codons for the mature protein remain, consistent with the relatively severe phenotype of affected individuals in the present family. The mutation appears to have arisen as an illegitimate recombination event since of 11 nucleotide positions immediately surrounding the two breakpoints, 9 are identical. 17 refs., 3 figs., 1 tab.

  2. A Novel Mutation in the ROGDI Gene in a Patient with Kohlschütter-Tönz Syndrome

    PubMed Central

    Huckert, Mathilde; Mecili, Helen; Laugel-Haushalter, Virginie; Stoetzel, Corinne; Muller, Jean; Flori, Elisabeth; Laugel, Vincent; Manière, Marie-Cécile; Dollfus, Hélène; Bloch-Zupan, Agnès

    2014-01-01

    Kohlschütter-Tönz Syndrome (KTZS) is an autosomal recessive disorder caused by mutations in the ROGDI gene. This syndrome is characterized by epilepsy, psychomotor regression and amelogenesis imperfecta. In this paper, we report a case of a 13-year-old Malian girl presenting with this rare disease. By genetic analysis, we identified a novel ROGDI homozygous mutation NM_024589.1: c.117+1G>T [Chr16 (GRCh37): g.4852382C>A] which confirmed the diagnosis of Kohlschütter-Tönz syndrome. The mutation abolishes the usual splice donor site of intron 2 which leads to the deletion of exon 2 and in-frame assembly of exon 3. Exon 2 encodes a highly conserved leucine-rich region that is essential for ROGDI protein function. Hence, this deletion may affect the function of the ROGDI protein. PMID:25565929

  3. Pathognomonic oral profile of Enamel Renal Syndrome (ERS) caused by recessive FAM20A mutations

    PubMed Central

    2014-01-01

    Amelogenesis imperfecta (AI) is a genetically and clinically heterogeneous group of inherited dental enamel defects. Commonly described as an isolated trait, it may be observed concomitantly with other orodental and/or systemic features such as nephrocalcinosis in Enamel Renal Syndrome (ERS, MIM#204690), or gingival hyperplasia in Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome (AIGFS, MIM#614253). Patients affected by ERS/AIGFS present a distinctive orodental phenotype consisting of generalized hypoplastic AI affecting both the primary and permanent dentition, delayed tooth eruption, pulp stones, hyperplastic dental follicles, and gingival hyperplasia with variable severity and calcified nodules. Renal exam reveals a nephrocalcinosis which is asymptomatic in children affected by ERS. FAM20A recessive mutations are responsible for both syndromes. We suggest that AIGFS and ERS are in fact descriptions of the same syndrome, but that the kidney phenotype has not always been investigated fully in AIGFS. The aim of this review is to highlight the distinctive and specific orodental features of patients with recessive mutations in FAM20A. We propose ERS to be the preferred term for all the phenotypes arising from recessive FAM20A mutations. A differential diagnosis has to be made with other forms of AI, isolated or syndromic, where only a subset of the clinical signs may be shared. When ERS is suspected, the patient should be assessed by a dentist, nephrologist and clinical geneticist. Confirmed cases require long-term follow-up. Management of the orodental aspects can be extremely challenging and requires the input of multi-disciplinary specialized dental team, especially when there are multiple unerupted teeth. PMID:24927635

  4. Basolateral Mg2+ Extrusion via CNNM4 Mediates Transcellular Mg2+ Transport across Epithelia: A Mouse Model

    PubMed Central

    Miura, Jiro; Sato, Sunao; Toyosawa, Satoru; Furutani, Kazuharu; Kurachi, Yoshihisa; Omori, Yoshihiro; Furukawa, Takahisa; Tsuda, Tetsuya; Kuwabata, Susumu; Mizukami, Shin; Kikuchi, Kazuya; Miki, Hiroaki

    2013-01-01

    Transcellular Mg2+ transport across epithelia, involving both apical entry and basolateral extrusion, is essential for magnesium homeostasis, but molecules involved in basolateral extrusion have not yet been identified. Here, we show that CNNM4 is the basolaterally located Mg2+ extrusion molecule. CNNM4 is strongly expressed in intestinal epithelia and localizes to their basolateral membrane. CNNM4-knockout mice showed hypomagnesemia due to the intestinal malabsorption of magnesium, suggesting its role in Mg2+ extrusion to the inner parts of body. Imaging analyses revealed that CNNM4 can extrude Mg2+ by exchanging intracellular Mg2+ with extracellular Na+. Furthermore, CNNM4 mutations cause Jalili syndrome, characterized by recessive amelogenesis imperfecta with cone-rod dystrophy. CNNM4-knockout mice showed defective amelogenesis, and CNNM4 again localizes to the basolateral membrane of ameloblasts, the enamel-forming epithelial cells. Missense point mutations associated with the disease abolish the Mg2+ extrusion activity. These results demonstrate the crucial importance of Mg2+ extrusion by CNNM4 in organismal and topical regulation of magnesium. PMID:24339795

  5. Stress response pathways in ameloblasts: implications for amelogenesis and dental fluorosis.

    PubMed

    Sierant, Megan L; Bartlett, John D

    2012-09-01

    Human enamel development of the permanent teeth takes place during childhood and stresses encountered during this period can have lasting effects on the appearance and structural integrity of the enamel. One of the most common examples of this is the development of dental fluorosis after childhood exposure to excess fluoride, an elemental agent used to increase enamel hardness and prevent dental caries. Currently the molecular mechanism responsible for dental fluorosis remains unknown; however, recent work suggests dental fluorosis may be the result of activated stress response pathways in ameloblasts during the development of permanent teeth. Using fluorosis as an example, the role of stress response pathways during enamel maturation is discussed.

  6. Ameloblast Modulation and Transport of Cl−, Na+, and K+ during Amelogenesis

    PubMed Central

    Bronckers, A.L.J.J.; Lyaruu, D.; Jalali, R.; Medina, J.F.; Zandieh-Doulabi, B.; DenBesten, P.K.

    2015-01-01

    Ameloblasts express transmembrane proteins for transport of mineral ions and regulation of pH in the enamel space. Two major transporters recently identified in ameloblasts are the Na+K+-dependent calcium transporter NCKX4 and the Na+-dependent HPO42– (Pi) cotransporter NaPi-2b. To regulate pH, ameloblasts express anion exchanger 2 (Ae2a,b), chloride channel Cftr, and amelogenins that can bind protons. Exposure to fluoride or null mutation of Cftr, Ae2a,b, or Amelx each results in formation of hypomineralized enamel. We hypothesized that enamel hypomineralization associated with disturbed pH regulation results from reduced ion transport by NCKX4 and NaPi-2b. This was tested by correlation analyses among the levels of Ca, Pi, Cl, Na, and K in forming enamel of mice with null mutation of Cftr, Ae2a,b, and Amelx, according to quantitative x-ray electron probe microanalysis. Immunohistochemistry, polymerase chain reaction analysis, and Western blotting confirmed the presence of apical NaPi-2b and Nckx4 in maturation-stage ameloblasts. In wild-type mice, K levels in enamel were negatively correlated with Ca and Cl but less negatively or even positively in fluorotic enamel. Na did not correlate with P or Ca in enamel of wild-type mice but showed strong positive correlation in fluorotic and nonfluorotic Ae2a,b- and Cftr-null enamel. In hypomineralizing enamel of all models tested, 1) Cl− was strongly reduced; 2) K+ and Na+ accumulated (Na+ not in Amelx-null enamel); and 3) modulation was delayed or blocked. These results suggest that a Na+K+-dependent calcium transporter (likely NCKX4) and a Na+-dependent Pi transporter (potentially NaPi-2b) located in ruffle-ended ameloblasts operate in a coordinated way with the pH-regulating machinery to transport Ca2+, Pi, and bicarbonate into maturation-stage enamel. Acidification and/or associated physicochemical/electrochemical changes in ion levels in enamel fluid near the apical ameloblast membrane may reduce the transport activity of mineral transporters, which results in hypomineralization. PMID:26403673

  7. Role of genes in oro-dental diseases.

    PubMed

    Kavitha, B; Priyadharshini, Vijayashree; Sivapathasundharam, B; Saraswathi, T R

    2010-01-01

    In oral cavity, the spectrum of diseases due to genetic alterations ranges from developmental disturbances of teeth to the pre-cancerous and cancerous lesions. Of late, significant progress has been made in the molecular analysis of tumors. With molecular genetic testing emerging as diagnostic, prognostic, and therapeutic approach, a review of genetic alterations ranging from the development of oro-facial structures to the tumors in the head and neck region are addressed in this article. The functional regulatory aspect of genes in relation to oro-facial structures are discussed separately, i.e., in relation to tooth genesis, tooth agenesis (non-syndromic, syndromic), tooth structural alterations, syndromic oro-facial defects, bone diseases, skin diseases (genodermatoses), and malignant tumors. In this literature, various genes involved in the development of the oro-facial structures and tooth in particular are discussed. The genetic basis of disorders in the tooth development (agenesis, hypodontia), tooth structural defects like amelogenesis imperfecta (AI), dentinogenesis imperfecta (DI), and oro-facial structural alterations (various syndromes) are explained.

  8. The clinical measurement of tooth colour and stain.

    PubMed

    Brook, A H; Smith, R N; Lath, D J

    2007-10-01

    There are many contributory factors to tooth colour and different techniques for its measurement. The aim of this paper is to evaluate methods of tooth colour and stain measurement, with an emphasis on recent advances in objective clinical measurement techniques. The overall colour effect of natural teeth is created by a combination of light which is reflected and scattered by tooth enamel and the underlying dentine. Developmental defects of the dentition can affect the intrinsic discolouration of teeth, for example, amelogenesis imperfecta and dentinogenesis imperfecta. Extrinsic discolouration is predominantly caused by stain build up on a tooth surface from bacteria, foodstuffs or metalic compounds. Tooth colour and stain measurement are currently assessed using a wide range of measurement methods divided into subjective (visual shade matching) and objective instrumental assessment such as by colourimetry, spectrophotometry and digital image analysis. The most popular method of assessing tooth colour clinically is visual shade matching, as this approach is quick and simple to use. However, variation in results can occur as a consequence of the subjective nature of this method. The instrumental approaches including quantitative light-induced fluorescence remove or significantly reduce the subjective component. Image analysis appears to be the most suitable method for tooth colour measurement and further work is being carried out to establish this approach.

  9. Prevalence and distribution of selected dental anomalies among saudi children in Abha, Saudi Arabia

    PubMed Central

    2016-01-01

    Background Dental anomalies are not an unusual finding in routine dental examination. The effect of dental anomalies can lead to functional, esthetic and occlusal problems. The Purpose of the study was to determine the prevalence and distribution of selected developmental dental anomalies in Saudi children. Material and Methods The study was based on clinical examination and Panoramic radiographs of children who visited the Pediatric dentistry clinics at King Khalid University College of Dentistry, Saudi Arabia. These patients were examined for dental anomalies in size, shape, number, structure and position. Data collected were entered and analyzed using statistical package for social sciences version. Results Of the 1252 children (638 Boys, 614 girls) examined, 318 subjects (25.39%) presented with selected dental anomalies. The distribution by gender was 175 boys (27.42%) and 143 girls (23.28%). On intergroup comparison, number anomalies was the most common anomaly with Hypodontia (9.7%) being the most common anomaly in Saudi children, followed by hyperdontia (3.5%). The Prevalence of size anomalies were Microdontia (2.6%) and Macrodontia (1.8%). The prevalence of Shape anomalies were Talon cusp (1.4%), Taurodontism (1.4%), Fusion (0.8%).The prevalence of Positional anomalies were Ectopic eruption (2.3%) and Rotation (0.4%). The prevalence of structural anomalies were Amelogenesis imperfecta (0.3%) Dentinogenesis imperfecta (0.1%). Conclusions A significant number of children had dental anomaly with Hypodontia being the most common anomaly and Dentinogenesis imperfecta being the rare anomaly in the study. Early detection and management of these anomalies can avoid potential orthodontic and esthetic problems in a child. Key words:Dental anomalies, children, Saudi Arabia. PMID:27957258

  10. A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement

    PubMed Central

    Prasad, Megana K; Geoffroy, Véronique; Vicaire, Serge; Jost, Bernard; Dumas, Michael; Le Gras, Stéphanie; Switala, Marzena; Gasse, Barbara; Laugel-Haushalter, Virginie; Paschaki, Marie; Leheup, Bruno; Droz, Dominique; Dalstein, Amelie; Loing, Adeline; Grollemund, Bruno; Muller-Bolla, Michèle; Lopez-Cazaux, Séréna; Minoux, Maryline; Jung, Sophie; Obry, Frédéric; Vogt, Vincent; Davideau, Jean-Luc; Davit-Beal, Tiphaine; Kaiser, Anne-Sophie; Moog, Ute; Richard, Béatrice; Morrier, Jean-Jacques; Duprez, Jean-Pierre; Odent, Sylvie; Bailleul-Forestier, Isabelle; Rousset, Monique Marie; Merametdijan, Laure; Toutain, Annick; Joseph, Clara; Giuliano, Fabienne; Dahlet, Jean-Christophe; Courval, Aymeric; El Alloussi, Mustapha; Laouina, Samir; Soskin, Sylvie; Guffon, Nathalie; Dieux, Anne; Doray, Bérénice; Feierabend, Stephanie; Ginglinger, Emmanuelle; Fournier, Benjamin; de la Dure Molla, Muriel; Alembik, Yves; Tardieu, Corinne; Clauss, François; Berdal, Ariane; Stoetzel, Corinne; Manière, Marie Cécile; Dollfus, Hélène; Bloch-Zupan, Agnès

    2016-01-01

    Background Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. Methods We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. Results We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. Conclusions We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. Trial registration numbers NCT01746121 and NCT02397824. PMID:26502894

  11. Aesthetic management of dental fluorosis.

    PubMed

    Khandelwal, Vishal; Nayak, Ullal Anand; Nayak, Prathibha Anand; Ninawe, Nupur

    2013-05-22

    Significant numbers of patients visiting the paediatric dental clinics have aesthetically objectionable brown stains and desire treatment for them. Intrinsic tooth discolouration can be a significant aesthetic, and in some instances, functional, problem. Dental fluorosis, tetracycline staining, localised and chronological hypoplasia, and both amelogenesis and dentinogenesis imperfecta can all produce a cosmetically unsatisfactory dentition. The aetiology of intrinsic discolouration of enamel may sometimes be deduced from the patient's history, and one factor long associated with the problem has been a high level of fluoride intake. Optimal use of topical fluorides leads to a decrease in the caries prevalence but may show an increase in the prevalence of fluorosis staining because of metabolic alterations in the ameloblasts, causing a defective matrix formation and improper calcification. A 12-year-old male patient was screened at the dental clinic for routine dental care. He wanted us to remove and/or minimise the noticeable brown/yellow staining of his teeth. He requested the least invasive and most cost-effective treatment to change his smile. Various treatment modalities are present for the treatment of fluorosis stains. This report discusses the microabrasion technique in the patient having dental fluorosis.

  12. Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability.

    PubMed

    Ansar, Muhammad; Jan, Abid; Santos-Cortez, Regie Lyn P; Wang, Xin; Suliman, Muhammad; Acharya, Anushree; Habib, Rabia; Abbe, Izoduwa; Ali, Ghazanfar; Lee, Kwanghyuk; Smith, Joshua D; Nickerson, Deborah A; Shendure, Jay; Bamshad, Michael J; Ahmad, Wasim; Leal, Suzanne M

    2016-08-01

    Alopecia with mental retardation (APMR) is a very rare disorder. In this study, we report on a consanguineous Pakistani family (AP91) with mild-to-moderate intellectual disability, adolescent alopecia and dentogingival abnormalities. Using homozygosity mapping, linkage analysis and exome sequencing, we identified a novel rare missense variant c.898G>A (p.(Glu300Lys)) in ITGB6, which co-segregates with the phenotype within the family and is predicted to be deleterious. Structural modeling shows that Glu300 lies in the β-propeller domain, and is surrounded by several residues that are important for heterodimerization with α integrin. Previous studies showed that ITGB6 variants can cause amelogenesis imperfecta in humans, but patients from family AP91 who are homozygous for the c.898G>A variant present with neurological and dermatological features, indicating a role for ITGB6 beyond enamel formation. Our study demonstrates that a rare deleterious variant within ITGB6 causes not only dentogingival anomalies but also intellectual disability and alopecia.

  13. Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6

    PubMed Central

    Ratbi, Ilham; Falkenberg, Kim D.; Sommen, Manou; Al-Sheqaih, Nada; Guaoua, Soukaina; Vandeweyer, Geert; Urquhart, Jill E.; Chandler, Kate E.; Williams, Simon G.; Roberts, Neil A.; El Alloussi, Mustapha; Black, Graeme C.; Ferdinandusse, Sacha; Ramdi, Hind; Heimler, Audrey; Fryer, Alan; Lynch, Sally-Ann; Cooper, Nicola; Ong, Kai Ren; Smith, Claire E.L.; Inglehearn, Christopher F.; Mighell, Alan J.; Elcock, Claire; Poulter, James A.; Tischkowitz, Marc; Davies, Sally J.; Sefiani, Abdelaziz; Mironov, Aleksandr A.; Newman, William G.; Waterham, Hans R.; Van Camp, Guy

    2015-01-01

    Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6. PMID:26387595

  14. Tooth Enamel Protein Amelogenin Binds to Ameloblast Cell Membrane-Mimicking Vesicles via its N-terminus

    PubMed Central

    LOKAPPA, SOWMYA BEKSHE; CHANDRABABU, KARTHIK BALAKRISHNA; MORADIAN-OLDAK, JANET

    2015-01-01

    We have recently reported that the extracellular enamel protein amelogenin has affinity to interact with phospholipids and proposed that such interactions may play key roles in enamel biomineralization as well as reported amelogenin signaling activities. Here, in order to identify the liposome-interacting domains of amelogenin we designed four different amelogenin mutants containing only a single tryptophan at positions 25, 45, 112 and 161. Circular dichroism studies of the mutants confirmed that they are structurally similar to the wild-type amelogenin. Utilizing the intrinsic fluorescence of single tryptophan residues and fluorescence resonance energy transfer FRET, we analyzed the accessibility and strength of their binding with an ameloblast cell membrane-mimicking model membrane (ACML) and a negatively charged liposome used as a membrane model. We found that amelogenin has membrane-binding ability mainly via its N-terminal, close to residues W25 and W45. Significant blue shift was also observed in the fluorescence of a N-terminal peptide following addition of liposomes. We suggest that, among other mechanisms, enamel malformation in cases of Amelogenesis Imperfecta (AI) with mutations at the N-terminal may be the result of defective amelogenin-cell interactions. PMID:26188506

  15. Dental Enamel Development: Proteinases and Their Enamel Matrix Substrates

    PubMed Central

    Bartlett, John D.

    2013-01-01

    This review focuses on recent discoveries and delves in detail about what is known about each of the proteins (amelogenin, ameloblastin, and enamelin) and proteinases (matrix metalloproteinase-20 and kallikrein-related peptidase-4) that are secreted into the enamel matrix. After an overview of enamel development, this review focuses on these enamel proteins by describing their nomenclature, tissue expression, functions, proteinase activation, and proteinase substrate specificity. These proteins and their respective null mice and human mutations are also evaluated to shed light on the mechanisms that cause nonsyndromic enamel malformations termed amelogenesis imperfecta. Pertinent controversies are addressed. For example, do any of these proteins have a critical function in addition to their role in enamel development? Does amelogenin initiate crystallite growth, does it inhibit crystallite growth in width and thickness, or does it do neither? Detailed examination of the null mouse literature provides unmistakable clues and/or answers to these questions, and this data is thoroughly analyzed. Striking conclusions from this analysis reveal that widely held paradigms of enamel formation are inadequate. The final section of this review weaves the recent data into a plausible new mechanism by which these enamel matrix proteins support and promote enamel development. PMID:24159389

  16. Aesthetic management of dental fluorosis

    PubMed Central

    Khandelwal, Vishal; Nayak, Ullal Anand; Nayak, Prathibha Anand; Ninawe, Nupur

    2013-01-01

    Significant numbers of patients visiting the paediatric dental clinics have aesthetically objectionable brown stains and desire treatment for them. Intrinsic tooth discolouration can be a significant aesthetic, and in some instances, functional, problem. Dental fluorosis, tetracycline staining, localised and chronological hypoplasia, and both amelogenesis and dentinogenesis imperfecta can all produce a cosmetically unsatisfactory dentition. The aetiology of intrinsic discolouration of enamel may sometimes be deduced from the patient's history, and one factor long associated with the problem has been a high level of fluoride intake. Optimal use of topical fluorides leads to a decrease in the caries prevalence but may show an increase in the prevalence of fluorosis staining because of metabolic alterations in the ameloblasts, causing a defective matrix formation and improper calcification. A 12-year-old male patient was screened at the dental clinic for routine dental care. He wanted us to remove and/or minimise the noticeable brown/yellow staining of his teeth. He requested the least invasive and most cost-effective treatment to change his smile. Various treatment modalities are present for the treatment of fluorosis stains. This report discusses the microabrasion technique in the patient having dental fluorosis. PMID:23704468

  17. [Phenotype analysis and the molecular mechanism of enamel hypoplasia].

    PubMed

    Lv, Ping; Gao, Xue-jun

    2009-02-18

    Enamel hypoplasia is a surface defect of the tooth crown caused by a disturbance of enamel matrix secretion. Enamel hypoplasia may be inherited, or result from illness, malnutrition, trauma, or high concentrations of fluorides or strontium in the drinking water or food. Different types of enamel hypoplasia have been distinguished, such as pit-type, plane-type, and linear enamel hypoplasia. Hypoplasia has been related to the intensity and duration of stress events, the number of affected ameloblasts, and their position along the forming tooth crown. Amelogenesis imperfecta (AI) is a heterogeneous group of inherited defects in dental enamel formation, most teeth are affected in both the primary and permanent dentition. The malformed enamel can be unusually thin, soft, rough and stained. The strict definition of AI includes only those cases where enamel defects occur in the absence of other symptoms. Currently, there are seven candidate genes for AI: amelogenin, enamelin, ameloblastin, tuftelin, distal-less homeobox 3, enamelysin, and kallikrein 4. Since the enamel is formed according to a strict chronological sequence, and once formed, undergoes no repair or regeneration. Then the analysis the phenotype of enamel hypoplasia can provide insights of the severity of inherited or environmental stress and the molecular mechanism during the period of enamel formation.

  18. Enamel Protein Regulation and Dental and Periodontal Physiopathology in Msx2 Mutant Mice

    PubMed Central

    Molla, Muriel; Descroix, Vianney; Aïoub, Muhanad; Simon, Stéphane; Castañeda, Beatriz; Hotton, Dominique; Bolaños, Alba; Simon, Yohann; Lezot, Frédéric; Goubin, Gérard; Berdal, Ariane

    2010-01-01

    Signaling pathways that underlie postnatal dental and periodontal physiopathology are less studied than those of early tooth development. Members of the muscle segment homeobox gene (Msx) family encode homeoproteins that show functional redundancy during development and are known to be involved in epithelial-mesenchymal interactions that lead to crown morphogenesis and ameloblast cell differentiation. This study analyzed the MSX2 protein during mouse postnatal growth as well as in the adult. The analysis focused on enamel and periodontal defects and enamel proteins in Msx2-null mutant mice. In the epithelial lifecycle, the levels of MSX2 expression and enamel protein secretion were inversely related. Msx2+/− mice showed increased amelogenin expression, enamel thickness, and rod size. Msx2−/− mice displayed compound phenotypic characteristics of enamel defects, related to both enamel-specific gene mutations (amelogenin and enamelin) in isolated amelogenesis imperfecta, and cell-cell junction elements (laminin 5 and cytokeratin 5) in other syndromes. These effects were also related to ameloblast disappearance, which differed between incisors and molars. In Msx2−/− roots, Malassez cells formed giant islands that overexpressed amelogenin and ameloblastin that grew over months. Aberrant expression of enamel proteins is proposed to underlie the regional osteopetrosis and hyperproduction of cellular cementum. These enamel and periodontal phenotypes of Msx2 mutants constitute the first case report of structural and signaling defects associated with enamel protein overexpression in a postnatal context. PMID:20934968

  19. A new mutation of the PCNT gene in a Colombian patient with microcephalic osteodysplastic primordial dwarfism type II: a case report

    PubMed Central

    2014-01-01

    Introduction Microcephalic osteodysplastic primordial dwarfism is a syndrome characterized by the presence of intrauterine growth restriction, post-natal growth deficiency and microcephaly. Microcephalic osteodysplastic primordial dwarfism type II is the most distinctive syndrome in this group of entities. Individuals affected by this disease present at an adult height of less than 100cm, a post-pubertal head circumference of 40cm or less, mild mental retardation, an outgoing personality and bone dysplasia. Case presentation We report the first case of a five-year-old Colombian boy of mixed race ancestry (mestizo), with clinical features of microcephaly, prominent and narrow nose, arched palate, amelogenesis imperfecta, short stature, tall and narrow pelvis, disproportionate shortening of fore-arms and legs, and mild coxa vara. Analysis of the PCNT gene by sequencing showed the presence of a nucleotide change in exon 10, c. 1468C>T, evidencing a new mutation not reported in the literature for microcephalic osteodysplastic primordial dwarfism. Conclusion The new mutation identified in this case could be associated with the severity of the phenotypic expression of the disease, resulting in the extreme short stature of the patient. Further studies are required to reach an explanation that can justify such findings, and it is vital to emphasize the importance of detection and follow-up by the epidemiological surveillance groups in birth defects and rare diseases. PMID:24928221

  20. The human enamel protein gene amelogenin is expressed from both the X and the Y chromosomes

    SciTech Connect

    Salido, E.C. ); Yen, P.H.; Koprivnikar, K.; Shapiro, L.J. ); Yu, Lohchung )

    1992-02-01

    Amelogenins, a family of extracellular matrix proteins of the dental enamel, are transiently but abundantly expressed by ameloblasts during tooth development. In this paper the authors report the characterization of the AMGX and AMGY genes on the short arms of the human X and Y chromosomes which encode the amelogenins. Their studies on the expression of the amelogenin genes in male developing tooth buds showed that both the AMGX and AMGY genes are transcriptionally active and encode potentially functional proteins. They have isolated genomic and cDNA clones form both the AMGX and AMGY loci and have studied the sequence organization of these two genes. Reverse transcriptase (RT)PCR amplification of the 5[prime] portion of the amelogenin transcripts revealed several alternatively spliced products. This information will be useful for studying the molecular basis of X-linked amelogenesis imperfecta, for understanding the evolution and regulation of gene expression on the mammalian sex chromosomes, and for investigating the role of amelogenin genes during tooth development.

  1. Amelogenin processing by MMP-20 prevents protein occlusion inside calcite crystals

    PubMed Central

    Bromley, Keith M.; Lakshminarayanan, Rajamani; Thompson, Mitchell; Lokappa, Sowmya B.; Gallon, Victoria A.; Cho, Kang R.; Qiu, S. Roger; Moradian-Oldak, Janet

    2012-01-01

    Calcite crystals were grown in the presence of full-length amelogenin and during its proteolysis by recombinant human matrix metalloproteinase 20 (rhMMP-20). Recombinant porcine amelogenin (rP172) altered the shape of calcite crystals by inhibiting the growth of steps on the {104} faces and became occluded inside the crystals. Upon co-addition of rhMMP-20, the majority of the protein was digested resulting in a truncated amelogenin lacking the C-terminal segment. In rP172-rhMMP-20 samples, the occlusion of amelogenin into the calcite crystals was drastically decreased. Truncated amelogenin (rP147) and the 25-residue C-terminal domain produced crystals with regular shape and less occluded organic material. Removal of the C-terminal diminished the affinity of amelogenin to the crystals and therefore prevented occlusion. We hypothesize that HAP and calcite interact with amelogenin in a similar manner. In the case of each material, full-length amelogenin binds most strongly, truncated amelogenin binds weakly and the C-terminus alone has the weakest interaction. Regarding enamel crystal growth, the prevention of occlusion into maturing enamel crystals might be a major benefit resulting from the selective cleavage of amelogenin at the C-terminus by MMP-20. Our data have important implications for understanding the hypomineralized enamel phenotype in cases of amelogenesis imperfecta resulting from MMP-20 mutations and will contribute to the design of enamel inspired biomaterials. PMID:23226976

  2. FAM20A binds to and regulates FAM20C localization

    PubMed Central

    Ohyama, Yoshio; Lin, Ju-Hsien; Govitvattana, Nattanan; Lin, I-Ping; Venkitapathi, Sundharamani; Alamoudi, Ahmed; Husein, Dina; An, Chunying; Hotta, Hak; Kaku, Masaru; Mochida, Yoshiyuki

    2016-01-01

    Mutations in the Family with sequence similarity (FAM) 20 gene family are associated with mineralized tissue phenotypes in humans. Among these genes, FAM20A mutations are associated with Amelogenesis Imperfecta (AI) with gingival hyperplasia and nephrocalcinosis, while FAM20C mutations cause Raine syndrome, exhibiting bone and craniofacial/dental abnormalities. Although it has been demonstrated that Raine syndrome associated-FAM20C mutants prevented FAM20C kinase activity and secretion, overexpression of the catalytically inactive D478A FAM20C mutant was detected in both cell extracts and the media. This suggests that FAM20C secretion doesn’t require its kinase activity, and that another molecule(s) may control the secretion. In this study, we found that extracellular FAM20C localization was increased when wild-type (WT), but not AI-forms of FAM20A was co-transfected. On the other hand, extracellular FAM20C was absent in the conditioned media of mouse embryonic fibroblasts (MEFs) derived from Fam20a knock-out (KO) mouse, while it was detected in the media from WT MEFs. We also showed that cells with the conditioned media of Fam20a WT MEFs mineralized, but those with the conditioned media of KO MEFs failed to mineralize in vitro. Our data thus demonstrate that FAM20A controls FAM20C localization that may assist in the extracellular function of FAM20C in mineralized tissues. PMID:27292199

  3. FAM83H and casein kinase I regulate the organization of the keratin cytoskeleton and formation of desmosomes

    PubMed Central

    Kuga, Takahisa; Sasaki, Mitsuho; Mikami, Toshinari; Miake, Yasuo; Adachi, Jun; Shimizu, Maiko; Saito, Youhei; Koura, Minako; Takeda, Yasunori; Matsuda, Junichiro; Tomonaga, Takeshi; Nakayama, Yuji

    2016-01-01

    FAM83H is essential for the formation of dental enamel because a mutation in the FAM83H gene causes amelogenesis imperfecta (AI). We previously reported that the overexpression of FAM83H often occurs and disorganizes the keratin cytoskeleton in colorectal cancer cells. We herein show that FAM83H regulates the organization of the keratin cytoskeleton and maintains the formation of desmosomes in ameloblastoma cells. FAM83H is expressed and localized on keratin filaments in human ameloblastoma cell lines and in mouse ameloblasts and epidermal germinative cells in vivo. FAM83H shows preferential localization to keratin filaments around the nucleus that often extend to cell-cell junctions. Alterations in the function of FAM83H by its overexpression, knockdown, or an AI-causing truncated mutant prevent the proper organization of the keratin cytoskeleton in ameloblastoma cells. Furthermore, the AI-causing mutant prevents desmosomal proteins from being localized to cell-cell junctions. The effects of the AI-causing mutant depend on its binding to and possible inhibition of casein kinase I (CK-1). The suppression of CK-1 by its inhibitor, D4476, disorganizes the keratin cytoskeleton. Our results suggest that AI caused by the FAM83H mutation is mediated by the disorganization of the keratin cytoskeleton and subsequent disruption of desmosomes in ameloblasts. PMID:27222304

  4. Diseases of the tooth: the genetic and molecular basis of inherited anomalies affecting the dentition.

    PubMed

    Cobourne, Martyn T; Sharpe, Paul T

    2013-01-01

    In humans, inherited variation in the number, size, and shape of teeth within the dentitions are relatively common, while rarer defects of hard tissue formation, including amelogenesis and dentinogenesis imperfecta, and problems associated with tooth eruption are also seen. In many cases, these anomalies occur in isolation, but they can also present as a feature of numerous well-characterized developmental syndromes. Complex reiterative signaling between the epithelium and mesenchyme is a feature of normal tooth development in the embryo, occurring from early patterning through morphogenesis, hard tissue formation and during root development. Significant events also occur during postnatal development of the dentition, including hard tissue maturation and tooth eruption. In the last decade, advances in human and mouse genetics have meant that in many cases candidate genes have been identified for these anomalies. These genes have provided a useful platform for developmental biologists, allowing them to begin elucidating how these signals interact to generate a functional dentition and understand the mechanisms underlying many of the anomalies that are seen in human populations. In this article, we review current concepts relating to the developmental biology of tooth number, size, and shape, formation of the dental hard tissues and eruption of the tooth into the oral cavity. We will focus on the molecular mechanisms underlying these processes in both health and disease.

  5. Dental and maxillofacial abnormalities in long-term survivors of childhood cancer: effects of treatment with chemotherapy and radiation to the head and neck

    SciTech Connect

    Jaffe, N.; Toth, B.B.; Hoar, R.E.; Ried, H.L.; Sullivan, M.P.; McNeese, M.D.

    1984-06-01

    Sixty-eight long-term survivors of childhood cancer were evaluated for dental and maxillofacial abnormalities. Forty-five patients had received maxillofacial radiation for lymphoma, leukemia, rhabdomyosarcoma, and miscellaneous tumors. Forty-three of the 45 patients and the remaining 23 who had not received maxillofacial radiation also received chemotherapy. Dental and maxillofacial abnormalities were detected in 37 of the 45 (82%) radiated patients. Dental abnormalities comprised foreshortening and blunting of roots, incomplete calcification, premature closure of apices, delayed or arrested tooth development, and caries. Maxillofacial abnormalities comprised trismus, abnormal occlusal relationships, and facial deformities. The abnormalities were more severe in those patients who received radiation at an earlier age and at higher dosages. Possible chemotherapeutic effects in five of 23 patients who received treatment for tumors located outside the head and neck region comprised acquired amelogenesis imperfecta, microdontia of bicuspid teeth, and a tendency toward thinning of roots with an enlarged pulp chamber. Dental and maxillofacial abnormalities should be recognized as a major consequence of maxillofacial radiation in long-term survivors of childhood cancer, and attempts to minimize or eliminate such sequelae should involve an effective interaction between radiation therapists, and medical and dental oncologists.

  6. Evolutionary analysis suggests that AMTN is enamel-specific and a candidate for AI.

    PubMed

    Gasse, B; Silvent, J; Sire, J-Y

    2012-11-01

    Molecular evolutionary analysis is an efficient method to predict and/or validate amino acid substitutions that could lead to a genetic disease and to highlight residues and motifs that could play an important role in the protein structure and/or function. We have applied such analysis to amelotin (AMTN), a recently identified enamel protein in the rat, mouse, and humans. An in silico search for AMTN provided 42 new mammalian sequences that were added to the 3 published sequences with which we performed the analysis using a dataset representative of all lineages (circa 220 million years of evolution), including 2 enamel-less species, sloth and armadillo. During evolution, of the 209 residues of human AMTN, 17 were unchanged and 34 had conserved their chemical properties. Substituting these important residues could lead to amelogenesis imperfecta (AI). Also, AMTN possesses a well-conserved signal peptide, 2 conserved motifs whose function is certainly important but unknown, and a putative phosphorylation site (SXE). In addition, the sequences of the 2 enamel-less species display mutations revealing that AMTN underwent pseudogenization, which suggests that AMTN is an enamel-specific protein.

  7. Clinical Performance of a New Biomimetic Double Network Material

    PubMed Central

    Dirxen, Christine; Blunck, Uwe; Preissner, Saskia

    2013-01-01

    Background: The development of ceramics during the last years was overwhelming. However, the focus was laid on the hardness and the strength of the restorative materials, resulting in high antagonistic tooth wear. This is critical for patients with bruxism. Objectives: The purpose of this study was to evaluate the clinical performance of the new double hybrid material for non-invasive treatment approaches. Material and Methods: The new approach of the material tested, was to modify ceramics to create a biomimetic material that has similar physical properties like dentin and enamel and is still as strong as conventional ceramics. Results: The produced crowns had a thickness ranging from 0.5 to 1.5 mm. To evaluate the clinical performance and durability of the crowns, the patient was examined half a year later. The crowns were still intact and soft tissues appeared healthy and this was achieved without any loss of tooth structure. Conclusions: The material can be milled to thin layers, but is still strong enough to prevent cracks which are stopped by the interpenetrating polymer within the network. Depending on the clinical situation, minimally- up to non-invasive restorations can be milled. Clinical Relevance: Dentistry aims in preservation of tooth structure. Patients suffering from loss of tooth structure (dental erosion, Amelogenesis imperfecta) or even young patients could benefit from minimally-invasive crowns. Due to a Vickers hardness between dentin and enamel, antagonistic tooth wear is very low. This might be interesting for treating patients with bruxism. PMID:24167534

  8. Enamel microabrasion: An overview of clinical and scientific considerations

    PubMed Central

    Pini, Núbia Inocencya Pavesi; Sundfeld-Neto, Daniel; Aguiar, Flavio Henrique Baggio; Sundfeld, Renato Herman; Martins, Luis Roberto Marcondes; Lovadino, José Roberto; Lima, Débora Alves Nunes Leite

    2015-01-01

    Superficial stains and irregularities of the enamel are generally what prompt patients to seek dental intervention to improve their smile. These stains or defects may be due to hypoplasia, amelogenesis imperfecta, mineralized white spots, or fluorosis, for which enamel microabrasion is primarily indicated. Enamel microabrasion involves the use of acidic and abrasive agents, such as with 37% phosphoric acid and pumice or 6% hydrochloric acid and silica, applied to the altered enamel surface with mechanical pressure from a rubber cup coupled to a rotatory mandrel of a low-rotation micromotor. If necessary, this treatment can be safely combined with bleaching for better esthetic results. Recent studies show that microabrasion is a conservative treatment when the enamel wear is minimal and clinically imperceptible. The most important factor contributing to the success of enamel microabrasion is the depth of the defect, as deeper, opaque stains, such as those resulting from hypoplasia, cannot be resolved with microabrasion, and require a restorative approach. Surface enamel alterations that result from microabrasion, such as roughness and microhardness, are easily restored by saliva. Clinical studies support the efficacy and longevity of this safe and minimally invasive treatment. The present article presents the clinical and scientific aspects concerning the microabrasion technique, and discusses the indications for and effects of the treatment, including recent works describing microscopic and clinical evaluations. PMID:25610848

  9. Impacted Maxillary Canine Prevalence and Its Association with Other Dental Anomalies in a Mexican Population

    PubMed Central

    Agüayo-de-Pau, María del Rosario; Escoffié-Ramírez, Mauricio; Aguilar-Ayala, Fernando Javier; Carrillo-Ávila, Bertha Arelly; Rejón-Peraza, Marina Eduviges

    2017-01-01

    Objective. We quantified the prevalence of impacted maxillary canines (IMC) and their association with other dental anomalies (DAs). Materials and Methods. A retrospective study was done with 860 patients 12 to 39 years of age. The prevalence of IMC was calculated and compared by sex. The sample was divided into a control group and an impaction group, and the prevalence was calculated in both for a series of anomalies: agenesis, supernumerary teeth, shape anomalies of the upper laterals (microdontia, peg and barrel shape, and talon cusp), fusion, gemination, other impacted teeth, transposition, and amelogenesis imperfecta. The prevalence values for both groups were compared (Pearson's χ2 test, p ≤ 0.05). Results. IMC were present in 6.04% of the sample with no difference by sex (p = 0.540). Other DAs occurred in 51.92% of the IMC group and in 20.17% of the controls (p < 0.05). Significant associations (p < 0.05) were identified between IMC and four other DAs: microdontia, barrel shape, other impacted teeth, and transposition. The prevalence of all anomalies was lower in the control group. Conclusion. IMC were seen in 6.04% of patients. Patients with this condition also had a higher prevalence of other DAs. These other anomalies should be used as risk indicators for early diagnosis. PMID:28326102

  10. Hyperimmunoglobulin E Syndrome Presenting as Osteogenesis Imperfecta in a 3 Year Old Child

    PubMed Central

    Gorgas, Stephen; Abuhammour, Walid; Blackwood, R. Alexander

    2013-01-01

    We present a case of hyperimmunoglobulin E (hyper-IgE) syndrome in a three year old boy. There are many pitfalls in diagnosing this disease in the very young population, mainly due to the ambiguity of some diagnostic criteria in this population. Recognizing this syndrome early in life can potentially be very beneficial to the patients involved and the medical system as a whole. Early diagnosis can lead to fewer diagnostic tests, fewer referrals, and more focused exams, thus potentially reducing medical cost while also reducing the number of serious infections later in life, including those which are potentially fatal. Additionally, a wellknown association between lymphoma and hyper-IgE syndrome has been established; while no recommendations are currently in place for screening, early diagnosis could help medical providers have a higher threshold for diagnosis of this disease. PMID:24470957

  11. OI Issues: Type I - Understanding the Mildest Form of Osteogenesis Imperfecta

    MedlinePlus

    ... develop bone and muscle strength, and maintain a healthy weight. Water therapy and swimming are particularly good exercises for children with OI, as the gravity-free environment reduces fracture risk. Many children with Type I ...

  12. Study in Mice Links Key Signaling Molecule to Underlying Cause of Osteogenesis Imperfecta

    MedlinePlus

    ... levels (lower panel). Credit: Brendan Lee, M.D., Ph.D., Baylor College of Medicine. The most common ... disturbance in bone remodeling, Brendan Lee, M.D., Ph.D., of the Baylor College of Medicine, turned ...

  13. Folding, Assembly, and Aggregation of Recombinant Murine Amelogenins with T21I and P41T Point Mutations

    PubMed Central

    Bromley, Keith M.; Lakshminarayanan, Rajamani; Lei, Ya-Ping; Snead, Malcolm L.; Moradian-Oldak, Janet

    2011-01-01

    Two point mutations (T21I and P40T) within amelogenin have been identified from human DNA sequences in 2 instances of amelogenesis imperfecta. We studied the folding and self-assembly of recombinant amelogenin (rM180) compared to the T21I and P40T mutants analogs. At pH 5.8 and 25°C, rM180 and the P41T mutant existed as monomers, whereas the T21I mutant formed small oligomers. At pH 8 and 25°C, all of the amelogenin samples formed nanospheres with hydrodynamic radii (RH) of around 15–16 nm. Upon heating to 37°C, particles of P41T increased in size (RH = 18 nm). During thermal denaturation at pH 5.8, both of the mutant proteins refolded more slowly than the wild-type (WT) rM180. Variable temperature tryptophan fluorescence and dynamic light scattering studies showed that the WT transformed to a partially folded conformation upon heating and remained stable. Thermal denaturation and refolding studies indicated that the mutants were less stable and exhibit a greater ability to prematurely aggregate compared to the WT. Our data suggest that in the case of P41T, alterations in the self-assembly of amelogenin are a consequence of destabilization of the secondary structure, while in the case of T21I they are a consequence of change in the overall hydrophobicity at the N-terminal region. We propose that alterations in the assembly (i.e. premature aggregation) of mutant amelogenins may have a profound effect on intra- and extracellular processes such as amelogenin secretion, proteolysis, and its interactions with nonamelogenins as well as with the forming mineral. PMID:21540557

  14. Enamel defects and ameloblast-specific expression in Enam knock-out/lacz knock-in mice.

    PubMed

    Hu, Jan C-C; Hu, Yuanyuan; Smith, Charles E; McKee, Marc D; Wright, J Timothy; Yamakoshi, Yasuo; Papagerakis, Petros; Hunter, Graeme K; Feng, Jerry Q; Yamakoshi, Fumiko; Simmer, James P

    2008-04-18

    Enamelin is critical for proper dental enamel formation, and defects in the human enamelin gene cause autosomal dominant amelogenesis imperfecta. We used gene targeting to generate a knock-in mouse carrying a null allele of enamelin (Enam) that has a lacZ reporter gene replacing the Enam translation initiation site and gene sequences through exon 7. Correct targeting of the transgene was confirmed by Southern blotting and PCR analyses. No enamelin protein could be detected by Western blotting in the Enam-null mice. Histochemical 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside (X-gal) staining demonstrated ameloblast-specific expression of enamelin. The enamel of the Enam(+/-) mice was nearly normal in the maxillary incisors, but the mandibular incisors were discolored and tended to wear rapidly where they contacted the maxillary incisors. The Enam(-/-) mice showed no true enamel. Radiography, microcomputed tomography, and light and scanning electron microscopy were used to document changes in the enamel of Enam(-/-) mice but did not discern any perturbations of bone, dentin, or any other tissue besides the enamel layer. Although a thick layer of enamel proteins covered normal-appearing dentin of unerupted teeth, von Kossa staining revealed almost a complete absence of mineral formation in this protein layer. However, a thin, highly irregular, mineralized crust covered the dentin on erupted teeth, apparently arising from the formation and fusion of small mineralization foci (calcospherites) in the deeper part of the accumulated enamel protein layer. These results demonstrate ameloblast-specific expression of enamelin and reveal that enamelin is essential for proper enamel matrix organization and mineralization.

  15. Spectrum of PEX1 and PEX6 variants in Heimler syndrome

    PubMed Central

    Smith, Claire E L; Poulter, James A; Levin, Alex V; Capasso, Jenina E; Price, Susan; Ben-Yosef, Tamar; Sharony, Reuven; Newman, William G; Shore, Roger C; Brookes, Steven J; Mighell, Alan J; Inglehearn, Chris F

    2016-01-01

    Heimler syndrome (HS) consists of recessively inherited sensorineural hearing loss, amelogenesis imperfecta (AI) and nail abnormalities, with or without visual defects. Recently HS was shown to result from hypomorphic mutations in PEX1 or PEX6, both previously implicated in Zellweger Syndrome Spectrum Disorders (ZSSD). ZSSD are a group of conditions consisting of craniofacial and neurological abnormalities, sensory defects and multi-organ dysfunction. The finding of HS-causing mutations in PEX1 and PEX6 shows that HS represents the mild end of the ZSSD spectrum, though these conditions were previously thought to be distinct nosological entities. Here, we present six further HS families, five with PEX6 variants and one with PEX1 variants, and show the patterns of Pex1, Pex14 and Pex6 immunoreactivity in the mouse retina. While Ratbi et al. found more HS-causing mutations in PEX1 than in PEX6, as is the case for ZSSD, in this cohort PEX6 variants predominate, suggesting both genes play a significant role in HS. The PEX6 variant c.1802G>A, p.(R601Q), reported previously in compound heterozygous state in one HS and three ZSSD cases, was found in compound heterozygous state in three HS families. Haplotype analysis suggests a common founder variant. All families segregated at least one missense variant, consistent with the hypothesis that HS results from genotypes including milder hypomorphic alleles. The clinical overlap of HS with the more common Usher syndrome and lack of peroxisomal abnormalities on plasma screening suggest that HS may be under-diagnosed. Recognition of AI is key to the accurate diagnosis of HS. PMID:27302843

  16. Achondrogenesis-hypochondrogenesis: the spectrum of chondrogenesis imperfecta. A radiological, ultrasonographic, and histopathologic study of 23 cases.

    PubMed

    van der Harten, H J; Brons, J T; Dijkstra, P F; Niermeyer, M F; Meijer, C J; van Giejn, H P; Arts, N F

    1988-01-01

    In the classification of lethal osteochondrodysplasias, achondrogenesis and hypochondrogenesis have recently received special attention. We describe 23 cases representing the different subtypes. Within the classical type I (Parenti-Fraccaro) two distinct disorders can be recognized: type IA (Houston-Harris) and type IB (Fraccaro). The classical type II (Langer-Saldino) and hypochondrogenesis represent phenotypic variants of one disorder in which type II is the most severe form and hypochondrogenesis the mildest form, while transitional forms exist. It is likely that a basic defect in cellular function of the chondrocyte results in a deficient cartilage matrix and in disorganized enchondral ossification.

  17. Nuclear sequestration of COL1A1 mRNA transcript associated with type I osteogenesis imperfecta (OI)

    SciTech Connect

    Primorac, D.; Stover, M.L.; McKinstry, M.B.

    1994-09-01

    Previously we identified an OI type I patient with a splice donor mutation that resulted in intron 26 retention instead of exon skipping and sequestration of normal levels of the mutant transcript in the nuclear compartment. Intron retention was consistent with the exon definition hypothesis for splice site selection since the size of the exon-intron-exon unit was less than 300 bp. Furthermore, the retained intron contained in-frame stop codons which is thought to cause the mutant RNA to remain within the nucleus rather than appearing in the cytoplasm. To test these hypotheses, genomic fragments containing the normal sequence or the donor mutation were cloned into a collagen minigene and expressed in stably tansfected NIH 3T3 cells. None of the modifications to the normal intron altered the level of RNA that accumulated in the cytoplasm, as expected. However none of the modifications to the mutant intron allowed accumulation of normal levels of mRNA in the cytoplasm. Moreover, in contrast to our findings in the patient`s cells only low levels of mutant transcript were found in the nucleus; a fraction of the transcript did appear in the cytoplasm which had spliced the mutant donor site correctly. Nuclear run-on experiments demonstrated equal levels of transcription from each transgene. Expression of another donor mutation known to cause in-frame exon skipping in OI type IV was accurately reproduced in the minigene in transfected 3T3 cells. Our experience suggests that either mechanism can lead to formation of a null allele possibly related to the type of splicing events surrounding the potential stop codons. Understanding the rules governing inactivation of a collagen RNA transcript may be important in designing a strategy to inactivate a dominate negative mutation associated with the more severe forms of OI.

  18. Preventing and Treating Compression Fractures of the Spine

    MedlinePlus

    ... Treating Compression Fractures of the Spine 804 W. Diamond Ave., Ste. 210 Gaithersburg, MD 20878 (800) 981- ... osteogenesis imperfecta contact : Osteogenesis Imperfecta Foundation 804 W. Diamond Avenue, Suite 210, Gaithersburg, MD 20878 Tel: 800- ...

  19. Understanding the Structure of Bones

    MedlinePlus

    ... bad collagen fibers. Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ... publication. Revised 2006 Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ...

  20. Respiratory Issues in OI

    MedlinePlus

    ... right heart failure) Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ... CO. 2008; 2015 Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ...

  1. Nutrition and OI

    MedlinePlus

    ... increasing physically activity. Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ... 2007, December 2016 Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ...

  2. OI Issues: Hearing Loss

    MedlinePlus

    ... in noisy surroundings. Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ... implanted behind the Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ...

  3. Surgery Considerations for Adults and Children

    MedlinePlus

    ... recovery and rehabilitation. Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ... products contain a Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ...

  4. Infant Care Suggestions for Parents

    MedlinePlus

    ... the baby at Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ... below. Revised 2016 Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ...

  5. Rodding Surgery

    MedlinePlus

    ... has ceased growing. Osteogenesis Imperfecta Foundation* 804 W. Diamond Ave, Suite 210 Gaithersburg, MD 20878 www.oif. ... Infection, and  Bleeding. Osteogenesis Imperfecta Foundation* 804 W. Diamond Ave, Suite 210 Gaithersburg, MD 20878 www.oif. ...

  6. Vertebral Compression Fractures

    MedlinePlus

    ... OI: Information on Vertebral Compression Fractures 804 W. Diamond Ave., Ste. 210 Gaithersburg, MD 20878 (800) 981- ... osteogenesis imperfecta contact : Osteogenesis Imperfecta Foundation 804 W. Diamond Avenue, Suite 210, Gaithersburg, MD 20878 Tel: 800- ...

  7. Transition from Pediatric to Adult OI Care

    MedlinePlus

    ... for a list. ____________________________________________________________________________________ Osteogenesis Imperfecta Foundation • 804 W. Diamond Ave, Suite 210 • Gaithersburg, MD 20878 www.oif. ...

  8. MMP20, KLK4, and MMP20/KLK4 double null mice define roles for matrix proteases during dental enamel formation.

    PubMed

    Hu, Yuanyuan; Smith, Charles E; Richardson, Amelia S; Bartlett, John D; Hu, Jan C C; Simmer, James P

    2016-03-01

    Matrix metalloproteinase 20 (MMP20) and kallikrein-related peptidase 4 (KLK4) are secreted proteinases that are essential for proper dental enamel formation. We characterized and compared enamel formed in wild-type, Mmp20 (-/-), Klk4 (-/-), Mmp20 (+/-) Klk4 (+/-), and Mmp20 (-/-) Klk4 (-/-) mice using dissecting and light microscopy, backscattered scanning electron microscopy (bSEM), SEM, microcomputed tomography (μCT), and energy-dispersive X-ray analysis (EDX). Following eruption, fractures were observed on Mmp20 (-/-), Klk4 (-/-), Mmp20 (+/-) Klk4 (+/-), and Mmp20 (-/-) Klk4 (-/-) molars. Failure of the enamel in the Mmp20 (+/-) Klk4 (+/-) molars was unexpected and suggested that digenic effects could contribute to the etiology of amelogenesis imperfecta in humans. Micro-CT analyses of hemimandibles demonstrated significantly reduced high-density enamel volume in the Mmp20 (-/-) and Klk4 (-/-) mice relative to the wild-type, which was further reduced in Mmp20 (-/-) Klk4 (-/-) mice. bSEM images of 7-week Mmp20 (-/-) and Mmp20 (-/-) Klk4 (-/-) mandibular incisors showed rough, pitted enamel surfaces with numerous indentations and protruding nodules. The Mmp20 (+/-) and Mmp20 (+/-) Klk4 (+/-) incisors showed prominent, evenly spaced, horizontal ridges that were more distinct in Mmp20 (+/-) Klk4 (+/-) incisors relative to Mmp20 (+/-) incisors due to the darkening of the valleys between the ridges. In cross sections, the Mmp20 (-/-) and Mmp20 (-/-) Klk4 (-/-) exhibited three distinct layers. The outer layer exhibited a disturbed elemental composition and an irregular enamel surface covered with nodules. The Mmp20 null enamel was apparently unable to withstand the sheer forces associated with eruption and separated from dentin during development. Cells invaded the cracks and interposed between the dentin and enamel layers. MMP20 and KLK4 serve overlapping and complementary functions to harden enamel by removing protein, but MMP20 potentially serves multiple

  9. Inactivation of C4orf26 in toothless placental mammals.

    PubMed

    Springer, Mark S; Starrett, James; Morin, Phillip A; Lanzetti, Agnese; Hayashi, Cheryl; Gatesy, John

    2016-02-01

    Previous studies have reported inactivated copies of six enamel-related genes (AMBN, AMEL, AMTN, ENAM, KLK4, MMP20) and one dentin-related gene (DSPP) in one or more toothless vertebrates and/or vertebrates with enamelless teeth, thereby providing evidence that these genes are enamel or tooth-specific with respect to their critical functions that are maintained by natural selection. Here, we employ available genome sequences for edentulous and enamelless mammals to evaluate the enamel specificity of four genes (WDR72, SLC24A4, FAM83H, C4orf26) that have been implicated in amelogenesis imperfecta, a condition in which proper enamel formation is abrogated during tooth development. Coding sequences for WDR72, SCL24A4, and FAM83H are intact in four edentulous taxa (Chinese pangolin, three baleen whales) and three taxa (aardvark, nine-banded armadillo, Hoffmann's two-toed sloth) with enamelless teeth, suggesting that these genes have critical functions beyond their involvement in tooth development. By contrast, genomic data for C4orf26 reveal inactivating mutations in pangolin and bowhead whale as well as evidence for deletion of this gene in two minke whale species. Hybridization capture of exonic regions and PCR screens provide evidence for inactivation of C4orf26 in eight additional baleen whale species. However, C4orf26 is intact in all three species with enamelless teeth that were surveyed, as well as in 95 additional mammalian species with enamel-capped teeth. Estimates of selection intensity suggest that dN/dS ratios on branches leading to taxa with enamelless teeth are similar to the dN/dS ratio on branches leading to taxa with enamel-capped teeth. Based on these results, we conclude that C4orf26 is tooth-specific, but not enamel-specific, with respect to its essential functions that are maintained by natural selection. A caveat is that an alternative splice site variant, which translates exon 3 in a different reading frame, is putatively functional in

  10. Fontanelles - enlarged

    MedlinePlus

    Soft spot - large; Newborn care - enlarged fontanelle; Neonatal care - enlarged fontanelle ... causes: Achondroplasia Apert syndrome Cleidocranial dysostosis Congenital rubella Neonatal hypothyroidism Osteogenesis imperfecta Rickets

  11. U.S. Army Medical Department Journal (May-June 1998)

    DTIC Science & Technology

    1998-06-01

    burned patients. "Dental Management of a Patient with Osteogenesis Imperfecta " is a case report on the dental management of molar extraction in a...patient with the bone-forming disease osteogenesis imperfecta . Through a continual process of evaluation and improvement in training, the AMEDD’s combat medics will continue to conserve the fighting strength.

  12. Intermolecular Slip Mechanism in Tropocollagen Nanofibrils

    DTIC Science & Technology

    2009-01-01

    Imperfecta or Ehlers - Danlos Syndrome. REPORT DOCUMENTATION PAGE (SF298) (Continuation Sheet) Continuation for Block 13 ARO Report Number Intermolecular slip...our studies could advance our knowledge of mechan- isms underlying important collagen-related diseases like Osteogenesis Imperfecta or Ehlers - Danlos

  13. Children with Brittle Bones.

    ERIC Educational Resources Information Center

    Alston, Jean

    1982-01-01

    Special help given to children with Osteogenesis Imperfecta (brittle bone disease) is described, including adapted equipment to allow for writing and use of a classroom assistant to aid participation in a regular classroom. (CL)

  14. Get in the Swim: Gaining Access to Recreational Facilities.

    ERIC Educational Resources Information Center

    Richard, Jean-Paul

    1980-01-01

    The father of a child with osteogenesis imperfecta, an orthopedic condition, recounts his struggles to convince local agencies to operate a swimming program for disabled students. He offers eight guidelines for advocating such programs in other areas. (CL)

  15. [The genetics of collagen diseases].

    PubMed

    Kaplan, J; Maroteaux, P; Frezal, J

    1986-01-01

    Heritable disorders of collagen include Ehler-Danlos syndromes (11 types are actually known), Larsen syndrome and osteogenesis imperfecta. Their clinical, genetic and biochemical features are reviewed. Marfan syndrome is closely related to heritable disorders of collagen.

  16. Analysis of developmental processes possibly related to human dental sexual dimorphism in permanent and deciduous canines.

    PubMed

    Moss, M L; Moss-Salentijn, L

    1977-05-01

    Analysis of published odontometric data on human dental sexual dimorphism indicates that this characteristic is most clearly expressed by the canine teeth. Review of the several processes involved in coronal odontogenesis suggests that such dimorphism is related to an absolutely longer period of amelogenesis for both deciduous and permanent dentitions.

  17. Histomorphometric and microchemical characterization of maturing dental enamel in rats fed a boron-deficient diet

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Few reports are available in the literature on enamel formation under nutritional deficiencies. Continuously erupting rodent incisors have considerable potential to serve as a model system for amelogenesis. Thus, we performed a study to determine the effects of boron (B) deficiency on the maturing d...

  18. Design and validation of bending test method for characterization of miniature pediatric cortical bone specimens.

    PubMed

    Albert, Carolyne I; Jameson, John; Harris, Gerald

    2013-02-01

    Osteogenesis imperfecta is a genetic disorder of bone fragility; however, the effects of this disorder on bone material properties are not well understood. No study has yet measured bone material strength in humans with osteogenesis imperfecta. Small bone specimens are often extracted during routine fracture surgeries in children with osteogenesis imperfecta. These specimens could provide valuable insight into the effects of osteogenesis imperfecta on bone material strength; however, their small size poses a challenge to their mechanical characterization. In this study, a validated miniature three-point bending test is described that enables measurement of the flexural material properties of pediatric cortical osteotomy specimens as small as 5 mm in length. This method was validated extensively using bovine bone, and the effect of span/depth aspect ratio (5 vs 6) on the measured flexural properties was examined. The method provided reasonable results for both Young's modulus and flexural strength in bovine bone. With a span/depth ratio of 6, the median longitudinal modulus and flexural strength results were 16.1 (range: 14.4-19.3)GPa and 251 (range: 219-293)MPa, respectively. Finally, the pilot results from two osteotomy specimens from children with osteogenesis imperfecta are presented. These results provide the first measures of bone material strength in this patient population.

  19. [Clinical condition and therapy of bone diseases].

    PubMed

    Miura, Kohji; Oznono, Keiichi

    2013-12-01

    Skeletal dysplasia is the term which represents disorders including growth and differentiation of bone, cartilage and ligament. A lot of diseases are included, and new disorders have been added. However, the therapy of most bone diseases is less well-established. Achondroplasia, hypochondroplasia, and osteogenesis imperfecta are most frequent bone diseases. There is no curative treatment for these diseases, however, supportive therapies are available ; for example, growth-hormone therapy for achondroplasia and hypochondroplasia, and bisphosphonate therapy for osteogenesis imperfecta. In addition, enzyme replacement therapy for hypophosphatasia is now on clinical trial.

  20. Enamel Defects Reflect Perinatal Exposure to Bisphenol A

    PubMed Central

    Jedeon, Katia; De la Dure-Molla, Muriel; Brookes, Steven J.; Loiodice, Sophia; Marciano, Clémence; Kirkham, Jennifer; Canivenc-Lavier, Marie-Chantal; Boudalia, Sofiane; Bergès, Raymond; Harada, Hidemitsu; Berdal, Ariane; Babajko, Sylvie

    2014-01-01

    Endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), are environmental ubiquitous pollutants and associated with a growing health concern. Anecdotally, molar incisor hypomineralization (MIH) is increasing concurrently with EDC-related conditions, which has led us to investigate the effect of BPA on amelogenesis. Rats were exposed daily to BPA from conception until day 30 or 100. At day 30, BPA-affected enamel exhibited hypomineralization similar to human MIH. Scanning electron microscopy and elemental analysis revealed an abnormal accumulation of organic material in erupted enamel. BPA-affected enamel had an abnormal accumulation of exogenous albumin in the maturation stage. Quantitative real-timePCR, Western blotting, and luciferase reporter assays revealed increased expression of enamelin but decreased expression of kallikrein 4 (protease essential for removing enamel proteins) via transcriptional regulation. Data suggest that BPA exerts its effects on amelogenesis by disrupting normal protein removal from the enamel matrix. Interestingly, in 100-day-old rats, erupting incisor enamel was normal, suggesting amelogenesis is only sensitive to MIH-causing agents during a specific time window during development (as reported for human MIH). The present work documents the first experimental model that replicates MIH and presents BPA as a potential causative agent of MIH. Because human enamel defects are irreversible, MIH may provide an easily accessible marker for reporting early EDC exposure in humans. PMID:23764278

  1. Johanna and Tommy: Two Preschoolers in Sweden with Brittle Bones.

    ERIC Educational Resources Information Center

    Millde, Kristina; Brodin, Jane

    Information is presented for caregivers of Swedish children with osteogenesis imperfecta (brittle bones) and their families. Approximately five children with brittle bones are born in Sweden annually. Two main types of brittle bone disease have been identified: congenita and tarda. Typical symptoms include numerous and unexpected fractures, bluish…

  2. Children with Brittle Bones: An Examination of Their Educational Needs and Progress.

    ERIC Educational Resources Information Center

    Alston, Jean

    1983-01-01

    A study of the educational achievements of 40 children (5-16 years old) with osteogenesis imperfecta, brittle bone disease, revealed no differences between Ss and control Ss without the condition in terms of nonverbal intelligence. Differences were found, however, in writing speed. Inteviews with children, teachers, and parents revealed…

  3. What Happens After School? A Study of Disabled Women and Education.

    ERIC Educational Resources Information Center

    O'Toole, J. Corbett; Weeks, CeCe

    The report, over half of which consists of appendixes and lists of resources, discusses the educational and related life experiences of six disabled women. Focus is on their early experiences with school and family, their high school years, their college years, and their work. Their disabilities include blindness, osteogenesis imperfecta (fragile…

  4. Mesenchymal Stem Cell as Targeted-Delivery Vehicle in Breast Cancer

    DTIC Science & Technology

    2008-06-01

    Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta . Nat Med. 1999;5:309-13. 3. Le...relevant because the beneficial effects of MSCs are being tested clinically in attempts to improve hematopoietic engraftment [1], to treat osteogenesis

  5. National Institutes of Health Osteoporosis and Related Bone Diseases~National Resource Center

    MedlinePlus

    ... Language Publications (en español) | Asian-Language Publications NIH Osteoporosis and Related Bone Diseases ~ NIH National Resource Center ... Font Size | S S M M L L Bone Basics Osteoporosis Osteogenesis Imperfecta Paget’s Disease of Bone Related Topics ...

  6. OI Positive: A Look at Unbreakable Spirits

    ERIC Educational Resources Information Center

    Carlson, Priscilla

    2007-01-01

    In this article, the author reflects on the positive outlook of parents and children with OI (Osteogenesis Imperfecta or simply, brittle bones), who attended the 15th Biennial National OI Conference. The author believes that the attendees positive attitudes comes from the positive influences they have had from the beginning. One example of an…

  7. Prospects and Pits on the Path of Biomimetics: The case of tooth enamel

    PubMed Central

    Uskoković, Vuk

    2013-01-01

    This review presents a discourse on challenges in understanding and imitating the process of amelogenesis in vitro on the molecular scale. In light of the analysis of imitation of the growth of dental enamel, it also impends on the prospects and potential drawbacks of the biomimetic approach in general. As the formation of enamel proceeds with the protein matrix guiding the crystal growth, while at the same time conducting its own degradation and removal, it is argued that three aspects of amelogenesis need to be induced in parallel: a) crystal growth; b) protein assembly; c) proteolytic degradation. A particular emphasis is therefore placed on ensuring conditions for proteolysis-coupled protein-guided crystallization to occur. Discussed are structural and functional properties of the protein species involved in amelogenesis, mainly amelogenin and enamelysin, the main protein and the protease of the developing enamel matrix, respectively. A model of enamel growth based on controlled delivery of constituent ions or crystalline or amorphous building blocks by means of amelogenin is proposed. The importance of high viscosity of the enamel matrix and a more intricate role that water may play in such a gelatinous medium are also touched upon. The tendency of amelogenin to self-assemble into fibrous and rod-shaped morphologies is considered as potentially important in explaining the formation of elongated apatite crystals. The idea that a preassembling protein matrix serves as a template for the uniaxial growth of apatite crystals in enamel is finally challenged with the one based on co-assembly of the protein and the mineral phases. PMID:26877723

  8. Expression of the Sodium/Calcium/Potassium Exchanger, NCKX4, in Ameloblasts

    PubMed Central

    Hu, Ping; Lacruz, Rodrigo S.; Smith, Charles E.; Smith, Susan M.; Kurtz, Ira; Paine, Michael L.

    2012-01-01

    Transcellular calcium transport is an essential activity in mineralized tissue formation, including dental hard tissues. In many organ systems, this activity is regulated by membrane-bound sodium/calcium (Na+/Ca2+) exchangers, which include the NCX and NCKX [sodium/calcium-potassium (Na+/Ca2+-K+ ) exchanger] proteins. During enamel maturation, when crystals expand in thickness, Ca2+ requirements vastly increase but exactly how Ca2+ traffics through ameloblasts remains uncertain. Previous studies have shown that several NCX proteins are expressed in ameloblasts, although no significant shifts in expression were observed during maturation which pointed to the possible identification of other Ca2+ membrane transporters. NCKX proteins are encoded by members of the solute carrier gene family, Slc24a, which include 6 different proteins (NCKX1–6). NCKX are bidirectional electrogenic transporters regulating Ca2+ transport in and out of cells dependent on the transmembrane ion gradient. In this study we show that all NCKX mRNAs are expressed in dental tissues. Real-time PCR indicates that of all the members of the NCKX group, NCKX4 is the most highly expressed gene transcript during the late stages of amelogenesis. In situ hybridization and immunolocalization analyses clearly establish that in the enamel organ, NCKX4 is expressed primarily by ameloblasts during the maturation stage. Further, during the mid-late maturation stages of amelogenesis, the expression of NCKX4 in ameloblasts is most prominent at the apical poles and at the lateral membranes proximal to the apical ends. These data suggest that NCKX4 might be an important regulator of Ca2+ transport during amelogenesis. PMID:22677781

  9. Inverse methods for estimating primary input signals from time-averaged isotope profiles

    NASA Astrophysics Data System (ADS)

    Passey, Benjamin H.; Cerling, Thure E.; Schuster, Gerard T.; Robinson, Todd F.; Roeder, Beverly L.; Krueger, Stephen K.

    2005-08-01

    Mammalian teeth are invaluable archives of ancient seasonality because they record along their growth axes an isotopic record of temporal change in environment, plant diet, and animal behavior. A major problem with the intra-tooth method is that intra-tooth isotope profiles can be extremely time-averaged compared to the actual pattern of isotopic variation experienced by the animal during tooth formation. This time-averaging is a result of the temporal and spatial characteristics of amelogenesis (tooth enamel formation), and also results from laboratory sampling. This paper develops and evaluates an inverse method for reconstructing original input signals from time-averaged intra-tooth isotope profiles. The method requires that the temporal and spatial patterns of amelogenesis are known for the specific tooth and uses a minimum length solution of the linear system Am = d, where d is the measured isotopic profile, A is a matrix describing temporal and spatial averaging during amelogenesis and sampling, and m is the input vector that is sought. Accuracy is dependent on several factors, including the total measurement error and the isotopic structure of the measured profile. The method is shown to accurately reconstruct known input signals for synthetic tooth enamel profiles and the known input signal for a rabbit that underwent controlled dietary changes. Application to carbon isotope profiles of modern hippopotamus canines reveals detailed dietary histories that are not apparent from the measured data alone. Inverse methods show promise as an effective means of dealing with the time-averaging problem in studies of intra-tooth isotopic variation.

  10. Simulating certain aspects of hypogravity: Effects on the mandibular incisors of suspended rats (PULEH model)

    NASA Technical Reports Server (NTRS)

    Simmons, D. J.; Winter, F.; Morey-Holton, E. R.

    1984-01-01

    The effect of a hypogravity simulating model on the rate of mandibular incisor formation, dentinogenesis and, amelogenesis in laboratory rats was studied. The model is the partial unloading by elevating the hindquarters. In this system, rat hindquarters are elevated 30 to 40 deg from the cage floors to completely unload the hindlimbs, but the animals are free to move about using their forelimbs. This model replicates the fluid sift changes which occur during the weightlessness of spaceflight and produces an osteopenia in the weight bearing skeletons. The histogenesis and/or mineralization rates of the mandibular incisor during the first 19d of PULEH in young growing rats are recorded.

  11. V-type ATPase proton pump expression during enamel formation.

    PubMed

    Sarkar, Juni; Wen, Xin; Simanian, Emil J; Paine, Michael L

    2016-01-01

    Several diseases such as proximal and distal renal tubular acidosis and osteoporosis are related to intracellular pH dysregulation resulting from mutations in genes coding for ion channels, including proteins comprising the proton-pumping V-type ATPase. V-type ATPase is a multi-subunit protein complex expressed in enamel forming cells. V-type ATPase plays a key role in enamel development, specifically lysosomal acidification, yet our understanding of the relationship between the endocytotic activities and dental health and disease is limited. The objective of this study is to better understand the ameloblast-associated pH regulatory networks essential for amelogenesis. Quantitative RT-PCR was performed on tissues from secretory-stage and maturation-stage enamel organs to determine which of the V-type ATPase subunits are most highly upregulated during maturation-stage amelogenesis: a time when ameloblast endocytotic activity is highest. Western blot analyses, using specific antibodies to four of the V-type ATPase subunits (Atp6v0d2, Atp6v1b2, Atp6v1c1 and Atp6v1e1), were then applied to validate much of the qPCR data. Immunohistochemistry using these same four antibodies was also performed to identify the spatiotemporal expression profiles of individual V-type ATPase subunits. Our data show that cytoplasmic V-type ATPase is significantly upregulated in enamel organ cells during maturation-stage when compared to secretory-stage. These data likely relate to the higher endocytotic activities, and the greater need for lysosomal acidification, during maturation-stage amelogenesis. It is also apparent from our immunolocalization data, using antibodies against two of the V-type ATPase subunits (Atp6v1c1 and Atp6v1e1), that significant expression is seen at the apical membrane of maturation-stage ameloblasts. Others have also identified this V-type ATPase expression profile at the apical membrane of maturation ameloblasts. Collectively, these data better define the

  12. Tooth enamel hypoplasia in PHACE syndrome.

    PubMed

    Chiu, Yvonne E; Siegel, Dawn H; Drolet, Beth A; Hodgson, Brian D

    2014-01-01

    Individuals with PHACE syndrome (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, eye abnormalities, sternal cleft, and supraumbilical raphe syndrome) have reported dental abnormalities to their healthcare providers and in online forums, but dental involvement has not been comprehensively studied. A study was conducted at the third PHACE Family Conference, held in Milwaukee, Wisconsin, in July 2012. A pediatric dentist examined subjects at enrollment. Eighteen subjects were enrolled. The median age was 4.2 years (range 9 mos-9 yrs; 14 girls, 4 boys). Eleven of 18 patients had intraoral hemangiomas and five of these (50%) had hypomature enamel hypoplasia. None of the seven patients without intraoral hemangiomas had enamel hypoplasia. No other dental abnormalities were seen. Enamel hypoplasia may be a feature of PHACE syndrome when an intraoral hemangioma is present. Enamel hypoplasia increases the risk of caries, and clinicians should refer children with PHACE syndrome to a pediatric dentist by 1 year of age.

  13. First Record of Anisoptera (Insecta: Odonata) from mid-Cretaceous Burmese Amber.

    PubMed

    Schädel, Mario; Bechly, Günter

    2016-04-18

    The fossil dragonfly Burmalindenia imperfecta gen. et sp. nov. is described from mid-Cretaceous Burmese amber as the first record of the odonate suborder Anisoptera for this locality and one of the few records from amber in general. The inclusion comprises two fragments of the two hind wings of a dragonfly. The fossil can be attributed to a new genus and species of the family Gomphidae, presumably in the subfamily Lindeniinae, and features a strange teratological phenomenon in its wing venation.

  14. TGF-ß Regulates Enamel Mineralization and Maturation through KLK4 Expression

    PubMed Central

    Cho, Andrew; Haruyama, Naoto; Hall, Bradford; Danton, Mary Jo S.; Zhang, Lu; Arany, Praveen; Mooney, David J.; Harichane, Yassine; Goldberg, Michel; Gibson, Carolyn W.; Kulkarni, Ashok B.

    2013-01-01

    Transforming growth factor-ß (TGF-ß) signaling plays an important role in regulating crucial biological processes such as cell proliferation, differentiation, apoptosis, and extracellular matrix remodeling. Many of these processes are also an integral part of amelogenesis. In order to delineate a precise role of TGF-ß signaling during amelogenesis, we developed a transgenic mouse line that harbors bovine amelogenin promoter-driven Cre recombinase, and bred this line with TGF-ß receptor II floxed mice to generate ameloblast-specific TGF-ß receptor II conditional knockout (cKO) mice. Histological analysis of the teeth at postnatal day 7 (P7) showed altered enamel matrix composition in the cKO mice as compared to the floxed mice that had enamel similar to the wild-type mice. The µCT and SEM analyses revealed decreased mineral content in the cKO enamel concomitant with increased attrition and thinner enamel crystallites. Although the mRNA levels remained unaltered, immunostaining revealed increased amelogenin, ameloblastin, and enamelin localization in the cKO enamel at the maturation stage. Interestingly, KLK4 mRNA levels were significantly reduced in the cKO teeth along with a slight increase in MMP-20 levels, suggesting that normal enamel maturation is regulated by TGF-ß signaling through the expression of KLK4. Thus, our study indicates that TGF-ß signaling plays an important role in ameloblast functions and enamel maturation. PMID:24278477

  15. TGF-β1 autocrine signalling and enamel matrix components

    PubMed Central

    Kobayashi-Kinoshita, Saeko; Yamakoshi, Yasuo; Onuma, Kazuo; Yamamoto, Ryuji; Asada, Yoshinobu

    2016-01-01

    Transforming growth factor-β1 (TGF-β1) is present in porcine enamel extracts and is critical for proper mineralization of tooth enamel. Here, we show that the mRNA of latent TGF-β1 is expressed throughout amelogenesis. Latent TGF-β1 is activated by matrix metalloproteinase 20 (MMP20), coinciding with amelogenin processing by the same proteinase. Activated TGF-β1 binds to the major amelogenin cleavage products, particularly the neutral-soluble P103 amelogenin, to maintain its activity. The P103 amelogenin-TGF-β1 complex binds to TGFBR1 to induce TGF-β1 signalling. The P103 amelogenin-TGF-β1 complex is slowly cleaved by kallikrein 4 (KLK4), which is secreted into the transition- and maturation-stage enamel matrix, thereby reducing TGF-β1 activity. To exert the multiple biological functions of TGF-β1 for amelogenesis, we propose that TGF-β1 is activated or inactivated by MMP20 or KLK4 and that the amelogenin cleavage product is necessary for the in-solution mobility of TGF-β1, which is necessary for binding to its receptor on ameloblasts and retention of its activity. PMID:27633089

  16. Tooth enamel mineralization in ungulates: implications for recovering a primary isotopic time-series

    NASA Astrophysics Data System (ADS)

    Passey, Benjamin H.; Cerling, Thure E.

    2002-09-01

    Temporal changes in the carbon and oxygen isotopic composition of an animal are an environmental and behavioral input signal that is recorded into the enamel of developing teeth. In this paper, we evaluate changes in phosphorus content and density along the axial lengths of three developing ungulate teeth to illustrate the protracted nature of mineral accumulation in a volume of developing enamel. The least mature enamel in these teeth contains by volume about 25% of the mineral mass of mature enamel, and the remaining 75% of the mineral accumulates during maturation. Using data from one of these teeth (a Hippopotamus amphibius canine), we develop a model for teeth growing at constant rate that describes how an input signal is recorded into tooth enamel. The model accounts for both the temporal and spatial patterns of amelogenesis (enamel formation) and the sampling geometry. The model shows that input signal attenuation occurs as a result of time-averaging during amelogenesis when the maturation interval is long compared to the duration of features in the input signal. Sampling does not induce significant attenuation, provided that the sampling interval is several times shorter than the maturation interval. We present a detailed δ 13C and δ 18O record for the H. amphibius canine and suggest possible input isotope signals that may have given rise to the measured isotope signal.

  17. Use of CT in the evaluation of cochlear otosclerosis

    SciTech Connect

    Mafee, M.F.; Valvassori, G.E.; Deitch, R.L.; Norouzi, P.; Henrikson, G.C.; Capek, V.; Applebaum, E.L.

    1985-09-01

    Otosclerosis (otospongiosis) occurs when the hard endochondral bone of the otic capsule is replaced by spongy vascular foci of haversian bone. Using computed tomography (CT), the authors studied the ears of 32 selected patients with mixed or sensorineural hearing loss; 24 were suspected of having otosclerosis. CT proved valuable in detecting cochlear otosclerosis, foci of demineralization, and changes in bony texture and enables the easy recognition of subtle radiographic findings. This paper also reports the CT findings of temporal bones in osteogenesis imperfecta and Paget disease.

  18. Dural ectasia

    PubMed Central

    Gupta, Neha; Gupta, Veena; Kumar, Abhishake; Kumar, Gaurav

    2014-01-01

    Dural ectasia is one of the likely causes of incomplete or failed spinal anaesthesia. Its association with diseases like Marfans syndrome, neurofibromatosis, osteogenesis imperfecta, vertebral fracture, postopertative adhesions, trauma etc., is often overlooked as a reason for inadequate spinal anaesthesia. Greater than normal volume of cerebrospinal fluid in the lumber theca in dural ectasia is postulated to restrict the spread of intrathecally injected Local anaesthetic. Here, we report a case of failed spinal anaesthesia but successful epidural anaesthesia in later setting in a patient with dural ectasia. PMID:24963189

  19. [Enamel: a unique self-assembling in mineral world].

    PubMed

    Lignon, Guilhem; de la Dure-Molla, Muriel; Dessombz, Arnaud; Berdal, Ariane; Babajko, Sylvie

    2015-05-01

    Enamel is a unique tissue in vertebrates, acellular, formed on a labile scaffolding matrix and hypermineralized. The ameloblasts are epithelial cells in charge of amelogenesis. They secrete a number of matrix proteins degraded by enzymes during enamel mineralization. This ordered cellular and extracellular events imply that any genetic or environmental perturbation will produce indelible and recognizable defects. The specificity of defects will indicate the affected cellular process. Thus, depending on the specificity of alterations, the teratogenic event can be retrospectively established. Advances in the field allow to use enamel defects as diagnostic tools for molecular disorders. The multifunctionality of enamel peptides is presently identified from their chemical roles in mineralization to cell signaling, constituting a source of concrete innovations in regenerative medicine.

  20. Mapping residual organics and carbonate at grain boundaries and the amorphous interphase in mouse incisor enamel

    PubMed Central

    Gordon, Lyle M.; Joester, Derk

    2015-01-01

    Dental enamel has evolved to resist the most grueling conditions of mechanical stress, fatigue, and wear. Adding insult to injury, it is exposed to the frequently corrosive environment of the oral cavity. While its hierarchical structure is unrivaled in its mechanical resilience, heterogeneity in the distribution of magnesium ions and the presence of Mg-substituted amorphous calcium phosphate (Mg-ACP) as an intergranular phase have recently been shown to increase the susceptibility of mouse enamel to acid attack. Herein we investigate the distribution of two important constituents of enamel, residual organic matter and inorganic carbonate. We find that organics, carbonate, and possibly water show distinct distribution patterns in the mouse enamel crystallites, at simple grain boundaries, and in the amorphous interphase at multiple grain boundaries. This has implications for the resistance to acid corrosion, mechanical properties, and the mechanism by which enamel crystals grow during amelogenesis. PMID:25852562

  1. Evaluation of the Esthetic Properties of Developmental Defects of Enamel: A Spectrophotometric Clinical Study

    PubMed Central

    Guerra, Fabrizio; Mazur, Marta; Corridore, Denise; Pasqualotto, Debora; Nardi, Gianna Maria; Ottolenghi, Livia

    2015-01-01

    Objectives. Detailed clinical quantification of optical properties of developmental defect of enamel is possible with spectrophotometric evaluation. Developmental defects of enamel (DDE) are daily encountered in clinical practice. DDE are an alteration in quality and quantity of the enamel, caused by disruption and/or damage to the enamel organ during amelogenesis. Methods. Several clinical indices have been developed to categorize enamel defects based on their nature, appearance, microscopic features, or cause. A sample of 39 permanent teeth presenting DDE on labial surface was examined using the DDE Modified Index and SpectroShade evaluation. The spectrophotometric approach quantifies L* (luminosity), a* (quantity of green-red), and b* (quantity of blue-yellow) of different DDE. Conclusions. SpectroShade evaluation of the optical properties of the enamel defect enhances clinical understanding of severity and extent of the defect and characterizes the enamel alteration in terms of color discrepancy and surface characterization. PMID:25874260

  2. Amoxicillin may cause molar incisor hypomineralization.

    PubMed

    Laisi, S; Ess, A; Sahlberg, C; Arvio, P; Lukinmaa, P-L; Alaluusua, S

    2009-02-01

    The etiology of molar incisor hypomineralization (MIH) is unclear. Our hypothesis was that certain antibiotics cause MIH. We examined 141 schoolchildren for MIH and, from their medical files, recorded the use of antibiotics under the age of 4 yrs. MIH was found in 16.3% of children. MIH was more common among those children who had taken, during the first year of life, amoxicillin (OR=2.06; 95% CI, 1.01-4.17) or the rarely prescribed erythromycin (OR=4.14; 95% CI, 1.05-16.4), compared with children who had not received treatment. Mouse E18 teeth were cultured for 10 days with/without amoxicillin at concentrations of 100 microg/mL-4 mg/mL. Amoxicillin increased enamel but not dentin thickness. An altered pattern of amelogenesis may have interfered with mineralization. We conclude that the early use of amoxicillin is among the causative factors of MIH.

  3. Dental development in children with severe molar-incisor hypomineralization in Samsun, Turkey.

    PubMed

    Tunc, Emine S; Ulusoy, Ayca T; Bayrak, Sule; Cankaya, Soner

    2013-09-01

    Anomalies in amelogenesis may be due to developmental defects or abnormalities in different components of developing teeth and can affect dental development. We compared dental development in a group of children with molar-incisor hypomineralization (MIH) with that in age- and sex-matched controls. Dental age was determined using panoramic radiographs of 105 children (59 girls, 46 boys) aged 7-11 years with severe MIH, and the findings were compared with those from 105 healthy age- and sex-matched controls. Although accelerated dental development was noted in the MIH group, the difference between the MIH and control groups was not statistically significant (P < 0.05). Furthermore, no relationship was found between number of affected teeth and the difference between dental and chronological age. In conclusion, children with severe MIH had slightly accelerated dental development as compared with controls.

  4. Development of the permanent mandibular cheek teeth in fallow deer (Dama dama).

    PubMed

    Kierdorf, H; Hommelsheim, S; Kierdorf, U

    2012-12-01

    The study describes crown and root formation of the permanent mandibular cheek teeth of fallow deer from a gestational age of 22-23 weeks up to a post-natal age of 33 months. Tooth development was recorded using a scoring scheme based on morphological criteria ranging from crypt formation to completion of root growth. The morphological appearance of the enamel surface during three different stages (secretory-stage enamel, maturation-stage enamel and mature enamel) was described, and the approximate age at termination of the secretory stage of amelogenesis in the deciduous and permanent mandibular cheek teeth was determined. The data enable an age estimation of fallow deer up to 3 years of age and provide a basis for assessing the timing of stress episodes that affect tooth crown formation. This information is useful for the management of the species as well as in bioarchaeological and bioindication studies.

  5. Protein- mediated enamel mineralization

    PubMed Central

    Moradian-Oldak, Janet

    2012-01-01

    Enamel is a hard nanocomposite bioceramic with significant resilience that protects the mammalian tooth from external physical and chemical damages. The remarkable mechanical properties of enamel are associated with its hierarchical structural organization and its thorough connection with underlying dentin. This dynamic mineralizing system offers scientists a wealth of information that allows the study of basic principals of organic matrix-mediated biomineralization and can potentially be utilized in the fields of material science and engineering for development and design of biomimetic materials. This chapter will provide a brief overview of enamel hierarchical structure and properties as well as the process and stages of amelogenesis. Particular emphasis is given to current knowledge of extracellular matrix protein and proteinases, and the structural chemistry of the matrix components and their putative functions. The chapter will conclude by discussing the potential of enamel for regrowth. PMID:22652761

  6. Summary of the IADR Cariology Research, Craniofacial Biology, and Mineralized Tissue Groups Symposium, Iguaçu Falls, Brazil, June 2012

    PubMed Central

    Modesto, Adriana; Klein, Ophir; Tenuta, Livia M.A.; Gerlach, Raquel F.; Vieira, Alexandre R.

    2014-01-01

    Characteristics of enamel may influence or modulate individual susceptibility to caries and erosion. These characteristics are defined during development, which is under strict genetic control, but can easily be modified in many ways by environmental factors. In the symposium, translational aspects of embryology, biochemistry, and genetics of amelogenesis were presented. The symposium provided unique insight into how basic sciences integrate with clinically relevant problems. The need for improved understanding of risks at the individual level, taking into consideration both environmental exposures and genetic background, was presented. The symposium was divided into four stepwise and interconnected topics as follows: 1) The Many Faces of Enamel Development; 2) Enamel Pathogenesis: Biochemistry Lessons; 3) Environmental Factors on Enamel Formation; and, 4) Genetic Variation in Enamel Formation Genes. PMID:25392764

  7. Matrix metalloproteinase-20 mediates dental enamel biomineralization by preventing protein occlusion inside apatite crystals.

    PubMed

    Prajapati, Saumya; Tao, Jinhui; Ruan, Qichao; De Yoreo, James J; Moradian-Oldak, Janet

    2016-01-01

    Reconstruction of enamel-like materials is a central topic of research in dentistry and material sciences. The importance of precise proteolytic mechanisms in amelogenesis to form a hard tissue with more than 95% mineral content has already been reported. A mutation in the Matrix Metalloproteinase-20 (MMP-20) gene results in hypomineralized enamel that is thin, disorganized and breaks from the underlying dentin. We hypothesized that the absence of MMP-20 during amelogenesis results in the occlusion of amelogenin in the enamel hydroxyapatite crystals. We used spectroscopy and electron microscopy techniques to qualitatively and quantitatively analyze occluded proteins within the isolated enamel crystals from MMP-20 null and Wild type (WT) mice. Our results showed that the isolated enamel crystals of MMP-20 null mice had more organic macromolecules occluded inside them than enamel crystals from the WT. The crystal lattice arrangements of MMP-20 null enamel crystals analyzed by High Resolution Transmission Electron Microscopy (HRTEM) were found to be significantly different from those of the WT. Raman studies indicated that the crystallinity of the MMP-20 null enamel crystals was lower than that of the WT. In conclusion, we present a novel functional mechanism of MMP-20, specifically prevention of unwanted organic material entrapped in the forming enamel crystals, which occurs as the result of precise amelogenin cleavage. MMP-20 action guides the growth morphology of the forming hydroxyapatite crystals and enhances their crystallinity. Elucidating such molecular mechanisms can be applied in the design of novel biomaterials for future clinical applications in dental restoration or repair.

  8. Amelotin Gene Structure and Expression during Enamel Formation in the Opossum Monodelphis domestica

    PubMed Central

    Gasse, Barbara; Liu, Xi; Corre, Erwan; Sire, Jean-Yves

    2015-01-01

    Amelotin (AMTN) is an ameloblast-secreted protein that belongs to the secretory calcium-binding phosphoprotein family, which also includes the enamel matrix proteins amelogenin, ameloblastin and enamelin. Although AMTN is supposed to play an important role in enamel formation, data were long limited to the rodents, in which it is expressed during the maturation stage. Recent comparative studies in sauropsids and amphibians revealed that (i) AMTN was expressed earlier, i.e. as soon as ameloblasts are depositing the enamel matrix, and (ii) AMTN structure was different, a change which mostly resulted from an intraexonic splicing in the large exon 8 of an ancestral mammal. The present study was performed to know whether the differences in AMTN structure and expression in rodents compared to non-mammalian tetrapods dated back to an early ancestral mammal or were acquired later in mammalian evolution. We sequenced, assembled and screened the jaw transcriptome of a neonate opossum Monodelphis domestica, a marsupial. We found two AMTN transcripts. Variant 1, representing 70.8% of AMTN transcripts, displayed the structure known in rodents, whereas variant 2 (29.2%) exhibited the nonmammalian tetrapod structure. Then, we studied AMTN expression during amelogenesis in a neonate specimen. We obtained similar data as those reported in rodents. These findings indicate that more than 180 million years ago, before the divergence of marsupials and placentals, changes occurred in AMTN function and structure. The spatiotemporal expression was delayed to the maturation stage of amelogenesis and the intraexonic splicing gave rise to isoform 1, encoded by variant 1 and lacking the RGD motif. The ancestral isoform 2, housing the RGD, was initially conserved, as demonstrated here in a marsupial, then secondarily lost in the placental lineages. These findings bring new elements towards our understanding of the non-prismatic to prismatic enamel transition that occurred at the onset of

  9. Amelotin Gene Structure and Expression during Enamel Formation in the Opossum Monodelphis domestica.

    PubMed

    Gasse, Barbara; Liu, Xi; Corre, Erwan; Sire, Jean-Yves

    2015-01-01

    Amelotin (AMTN) is an ameloblast-secreted protein that belongs to the secretory calcium-binding phosphoprotein family, which also includes the enamel matrix proteins amelogenin, ameloblastin and enamelin. Although AMTN is supposed to play an important role in enamel formation, data were long limited to the rodents, in which it is expressed during the maturation stage. Recent comparative studies in sauropsids and amphibians revealed that (i) AMTN was expressed earlier, i.e. as soon as ameloblasts are depositing the enamel matrix, and (ii) AMTN structure was different, a change which mostly resulted from an intraexonic splicing in the large exon 8 of an ancestral mammal. The present study was performed to know whether the differences in AMTN structure and expression in rodents compared to non-mammalian tetrapods dated back to an early ancestral mammal or were acquired later in mammalian evolution. We sequenced, assembled and screened the jaw transcriptome of a neonate opossum Monodelphis domestica, a marsupial. We found two AMTN transcripts. Variant 1, representing 70.8% of AMTN transcripts, displayed the structure known in rodents, whereas variant 2 (29.2%) exhibited the nonmammalian tetrapod structure. Then, we studied AMTN expression during amelogenesis in a neonate specimen. We obtained similar data as those reported in rodents. These findings indicate that more than 180 million years ago, before the divergence of marsupials and placentals, changes occurred in AMTN function and structure. The spatiotemporal expression was delayed to the maturation stage of amelogenesis and the intraexonic splicing gave rise to isoform 1, encoded by variant 1 and lacking the RGD motif. The ancestral isoform 2, housing the RGD, was initially conserved, as demonstrated here in a marsupial, then secondarily lost in the placental lineages. These findings bring new elements towards our understanding of the non-prismatic to prismatic enamel transition that occurred at the onset of

  10. Amelogenin in Enamel Tissue Engineering

    PubMed Central

    2016-01-01

    In this chapter the basic premises, the recent findings and the future challenges in the use of amelogenin for enamel tissue engineering are being discoursed on. Results emerging from the experiments performed to assess the fundamental physicochemical mechanisms of the interaction of amelogenin, the main protein of the enamel matrix, and the growing crystals of apatite, are mentioned, alongside a moderately comprehensive literature review of the subject at hand. The clinical importance of understanding this protein/mineral interaction at the nanoscale are highlighted as well as the potential for tooth enamel to act as an excellent model system for studying some of the essential aspects of biomineralization processes in general. The dominant paradigm stating that amelogenin directs the uniaxial growth of apatite crystals in enamel by slowing down the growth of (hk0) faces on which it adheres is being questioned based on the results demonstrating the ability of amelogenin to promote the nucleation and crystal growth of apatite under constant titration conditions designed to mimic those present in the developing enamel matrix. The role of numerous minor components of the enamel matrix is being highlighted as essential and impossible to compensate for by utilizing its more abundant ingredients only. It is concluded that the three major aspects of amelogenesis outlined hereby – (1) the assembly of amelogenin and other enamel matrix proteins, (2) the proteolytic activity, and (3) crystallization – need to be in precise synergy with each other in order for the grounds for the proper imitation of amelogenesis in the lab to be created. PMID:26545753

  11. Matrix metalloproteinase-20 mediates dental enamel biomineralization by preventing protein occlusion inside apatite crystals

    PubMed Central

    Prajapati, Saumya; Tao, Jinhui; Ruan, Qichao; De Yoreo, James J.; Moradian-Oldak, Janet

    2015-01-01

    Reconstruction of enamel-like materials is a central topic of research in dentistry and material sciences. The importance of precise proteolytic mechanisms in amelogenesis to form a hard tissue with more than 95% mineral content has already been reported. A mutation in the Matrix Metalloproteinase-20 (MMP-20) gene results in hypomineralized enamel that is thin, disorganized and breaks from the underlying dentin. We hypothesized that the absence of MMP-20 during amelogenesis results in the occlusion of amelogenin in the enamel hydroxyapatite crystals. We used spectroscopy and electron microscopy techniques to qualitatively and quantitatively analyze occluded proteins within the isolated enamel crystals from MMP-20 null and Wild type (WT) mice. Our results showed that the isolated enamel crystals of MMP-20 null mice had more organic macromolecules occluded inside them than enamel crystals from the WT. The crystal lattice arrangements of MMP-20 null enamel crystals analyzed by High Resolution Transmission Electron Microscopy (HRTEM) were found to be significantly different from those of the WT. Raman studies indicated that the crystallinity of the MMP-20 null enamel crystals was lower than that of the WT. In conclusion, we present a novel functional mechanism of MMP-20, specifically prevention of unwanted organic material entrapped in the forming enamel crystals, which occurs as the result of precise amelogenin cleavage. MMP-20 action guides the growth morphology of the forming hydroxyapatite crystals and enhances their crystallinity. Elucidating such molecular mechanisms can be applied in the design of novel biomaterials for future clinical applications in dental restoration or repair. PMID:26513418

  12. FATE OF FLUORIDE-INDUCED SUBAMELOBLASTIC CYSTS IN DEVELOPING HAMSTER MOLAR TOOTH GERMS

    PubMed Central

    Lyaruu, DM; Alberga, JMR; Kwee, NCH; Bervoets, TJM; Bronckers, ALJJ; DenBesten, PK

    2016-01-01

    White opacities and pits are developmental defects in enamel caused by high intake of fluoride (F) during amelogenesis. We tested the hypothesis that these enamel pits develop at locations where F induces the formation of sub-ameloblastic cysts. We followed the fate of these cysts during molar development over time. Mandibles from hamster pups injected with 20 mg NaF/kg at postnatal day 4 were excised from 1 h after injection till shortly after tooth eruption, 8 days later. Tissues were histologically processed and cysts located and measured. Cysts were formed at early secretory stage and transitional stage of amelogenesis and detected as early 1 h after injection. The number of cysts increased from 1 to almost 4 per molar during the first 16 h post-injection. The size of the cysts was about the same, i.e., 0.46±0.29 ×106 μm3 at 2hr and 0.50±0.35×106 μm3 at 16 h post-injection. By detachment of the ameloblasts the forming enamel surface below the cyst was cell-free the first 16 h post-injection. With time new ameloblasts repopulated and covered the enamel surface in the cystic area. Three days after injection all cysts had disappeared and the integrity of the ameloblastic layer restored. After eruption, white opaque areas with intact enamel surface were found occlusally at similar anatomical locations as late secretory stage cysts were seen pre-eruptively. We conclude that at this moderate F dose, the opaque sub-surface defects with intact surface enamel (white spots) are the consequence of the fluoride-induced cystic lesions formed earlier under the late secretory–transitional stage ameloblasts. PMID:21277565

  13. Molecular, Phenotypic Aspects and Therapeutic Horizons of Rare Genetic Bone Disorders

    PubMed Central

    Dhawan, Naveen; Vohra, Shivani; Tu, Khin; Abdelmagid, Samir M.

    2014-01-01

    A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities. PMID:25530967

  14. Mapping the Effect of Gly Mutations in Collagen on α2β1 Integrin Binding*

    PubMed Central

    Yigit, Sezin; Yu, Hongtao; An, Bo; Hamaia, Samir; Farndale, Richard W.; Kaplan, David L.; Lin, Yu-Shan; Brodsky, Barbara

    2016-01-01

    The replacement of one Gly in the essential repeating tripeptide sequence of the type I collagen triple helix results in the dominant hereditary bone disorder osteogenesis imperfecta. The mechanism leading to pathology likely involves misfolding and autophagy, although it has been hypothesized that some mutations interfere with known collagen interactions. Here, the effect of Gly replacements within and nearby the integrin binding GFPGER sequence was investigated using a recombinant bacterial collagen system. When a six-triplet human type I collagen sequence containing GFPGER was introduced into a bacterial collagen-like protein, this chimeric protein bound to integrin. Constructs with Gly to Ser substitutions within and nearby the inserted human sequence still formed a trypsin-resistant triple helix, suggesting a small local conformational perturbation. Gly to Ser mutations within the two Gly residues in the essential GFPGER sequence prevented integrin binding and cell attachment as predicted from molecular dynamics studies of the complex. Replacement of Gly residues C-terminal to GFPGER did not affect integrin binding. In contrast, Gly replacements N-terminal to the GFPGER sequence, up to four triplets away, decreased integrin binding and cell adhesion. This pattern suggests either an involvement of the triplets N-terminal to GFPGER in initial binding or a propagation of the perturbation of the triple helix C-terminal to a mutation site. The asymmetry in biological consequences relative to the mutation site may relate to the observed pattern of osteogenesis imperfecta mutations near the integrin binding site. PMID:27432884

  15. Molecular, phenotypic aspects and therapeutic horizons of rare genetic bone disorders.

    PubMed

    Faruqi, Taha; Dhawan, Naveen; Bahl, Jaya; Gupta, Vineet; Vohra, Shivani; Tu, Khin; Abdelmagid, Samir M

    2014-01-01

    A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

  16. CRTAP mutation in a patient with Cole-Carpenter syndrome.

    PubMed

    Balasubramanian, Meena; Pollitt, Rebecca C; Chandler, Kate E; Mughal, M Z; Parker, Michael J; Dalton, Ann; Arundel, Paul; Offiah, Amaka C; Bishop, Nicholas J

    2015-03-01

    In 1987, Cole and Carpenter reported two unrelated infants with multiple fractures and deformities of bone, with a skeletal phenotype similar to severe osteogenesis imperfecta. In addition, these patients also had proptosis, blue sclerae, hydrocephalus, and a distinct facial gestalt. They were reported to be of normal intelligence. Radiologically, these patients had characteristic skeletal manifestations including craniosynostosis and deformities similar to severe progressive osteogenesis imperfecta. Since the first description, there have only been a few other reports of patients with a similar phenotype. Collagen studies performed in reported patients have been normal. The molecular basis of this syndrome has not been elucidated and the inheritance pattern is still unknown. We report on a child with Cole-Carpenter syndrome phenotype who has a homozygous c.118G>T mutation in exon 1 of the CRTAP gene. We describe the clinical features and correlate this with her molecular results. This is the first report towards elucidating the molecular basis of Cole-Carpenter syndrome.

  17. Radiographic analysis of zebrafish skeletal defects.

    PubMed

    Fisher, Shannon; Jagadeeswaran, Pudur; Halpern, Marnie E

    2003-12-01

    Systematic identification of skeletal dysplasias in model vertebrates provides insight into the pathogenesis of human skeletal disorders and can aid in the identification of orthologous human genes. We are undertaking a mutagenesis screen for skeletal dysplasias in adult zebrafish, using radiography to detect abnormalities in skeletal anatomy and bone morphology. We have isolated chihuahua, a dominant mutation causing a general defect in bone growth. Heterozygous chihuahua fish have phenotypic similarities to human osteogenesis imperfecta, a skeletal dysplasia caused by mutations in the type I collagen genes. Mapping and molecular characterization of the chihuahua mutation indicates that the defect resides in the gene encoding the collagen I(alpha1) chain. Thus, chihuahua accurately models osteogenesis imperfecta at the biologic and molecular levels, and will prove an important resource for studies on the disease pathophysiology. Radiography is a practical screening tool to detect subtle skeletal abnormalities in the adult zebrafish. The identification of chihuahua demonstrates that mutant phenotypes analogous to human skeletal dysplasias will be discovered.

  18. Transformation of the mechanism of triple-helix peptide folding in the absence of a C-terminal nucleation domain and its implications for mutations in collagen disorders.

    PubMed

    Buevich, Alexei V; Silva, Teresita; Brodsky, Barbara; Baum, Jean

    2004-11-05

    Folding abnormalities of the triple helix have been demonstrated in collagen diseases such as osteogenesis imperfecta in which the mutation leads to the substitution of a single Gly in the (Gly-X-Y)n sequence pattern by a larger residue. Model peptides can be used to clarify the details of normal collagen folding and the consequences of the interruption of that folding by a Gly substitution. NMR and CD studies show that placement of a (GPO)4 nucleation domain at the N terminus rather than the C terminus of a native collagen sequence allows the formation of a stable triple helix but alters the folding mechanism. Although C- to N-terminal directional folding occurs when the nucleation domain is at the C terminus, there is no preferential folding direction when the nucleation domain is at the N terminus. The lack of zipper-like directional folding does not interfere with triple-helix formation, and when a Gly residue is replaced by Ser to model an osteogenesis imperfecta mutation, the peptide with the N-terminal (GPO)4 domain can still form a good triple helix N-terminal to the mutation site. These peptide studies raise the possibility that mutant collagen could fold in a C to N direction in a zipper-like manner up to the mutation site and that completion of the triple helix N-terminal to the mutation would involve an alternative mechanism.

  19. Ex-vivo assessment and non-invasive in vivo imaging of internal hemorrhages in Aga2/+ mutant mice

    SciTech Connect

    Ermolayev, Vladimir; Cohrs, Christian M.; Mohajerani, Pouyan; Ale, Angelique; Hrabé de Angelis, Martin; Ntziachristos, Vasilis

    2013-03-08

    Highlights: ► Aga2/+ mice, model for Osteogenesis imperfecta, have type I collagen mutation. ► Aga2/+ mice display both moderate and severe phenotypes lethal 6–11th postnatal. ► Internal hemorrhages studied in Aga2/+ vs. control mice at 6 and 9 days postnatal. ► Anatomical and functional findings in-vivo contrasted to the ex-vivo appearance. -- Abstract: Mutations in type I collagen genes (COL1A1/2) typically lead to Osteogenesis imperfecta, the most common heritable cause of skeletal fractures and bone deformation in humans. Heterozygous Col1a1{sup Aga2/+}, animals with a dominant mutation in the terminal C-propeptide domain of type I collagen develop typical skeletal hallmarks and internal hemorrhages starting from 6 day after birth. The disease progression for Aga2/+ mice, however, is not uniform differing between severe phenotype lethal at the 6–11th day of life, and moderate-to-severe one with survival to adulthood. Herein we investigated whether a new modality that combines X-ray computer tomography with fluorescence tomography in one hybrid system can be employed to study internal bleedings in relation to bone fractures and obtain insights into disease progression. The disease phenotype was characterized on Aga2/+ vs. wild type mice between 6 and 9 days postnatal. Anatomical and functional findings obtained in-vivo were contrasted to the ex-vivo appearance of the same tissues under cryo-slicing.

  20. Chemical composition of modern and fossil hippopotamid teeth and implications for paleoenvironmental reconstructions and enamel formation - Part 2: Alkaline earth elements as tracers of watershed hydrochemistry and provenance

    NASA Astrophysics Data System (ADS)

    Brügmann, G.; Krause, J.; Brachert, T. C.; Stoll, B.; Weis, U.; Kullmer, O.; Ssemmanda, I.; Mertz, D. F.

    2012-11-01

    This study demonstrates that alkaline earth elements in enamel of hippopotamids, in particular Ba and Sr, are tracers for water provenance and hydrochemistry in terrestrial settings. The studied specimens are permanent premolar and molar teeth found in modern and fossil lacustrine sediments of the Western Branch of the East African Rift system (Lake Kikorongo, Lake Albert, and Lake Malawi) and from modern fluvial environments of the Nile River. Concentrations in enamel vary by two orders of magnitude for Ba (120-9336 μg g-1) as well as for Sr (9-2150 μg g-1). The variations are partially induced during post-mortem alteration and during amelogenesis, but the major contribution originates ultimately from the variable water chemistry in the habitats of the hippopotamids which is controlled by the lithologies and weathering processes in the watershed areas. Amelogenesis causes a distinct distribution of MgO, Ba and Sr in modern and fossil enamel, in that element concentrations increase along profiles from the outer rim towards the enamel-dentin junction by a factor of 1.3-1.9. These elements are well correlated in single specimens, thus suggesting that their distribution is determined by a common, single process, which can be described by closed system Rayleigh crystallization of bioapatite in vivo. Enamel from most hippopotamid specimens has Sr/Ca and Ba/Ca which are typical for herbivores. However, Ba/Sr ranges from 0.1 to 3 and varies on spatial and temporal scales. Thus, Sr concentrations and Ba/Sr in enamel differentiate between habitats having basaltic mantle rocks or Archean crustal rocks as the ultimate sources of Sr and Ba. This provenance signal is modulated by climate change. In Miocene to Pleistocene enamel from the Lake Albert region, Ba/Sr decreases systematically with time from 2 to 0.5. This trend can be correlated with changes in climate from humid to arid, in vegetation from C3 to C4 biomass as well as with increasing evaporation of the lake water