François Clauss

Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases.

Hypohidrotic and anhidrotic ectodermal dysplasia (HED/EDA) is a rare genodermatosis characterized by abnormal development of sweat glands, teeth, and hair. Three disease‐causing genes have been hitherto identified, namely, (1) EDA1 accounting for X‐linked forms, (2) EDAR, and (3) EDARADD, causing both autosomal dominant and recessive forms. Recently, WNT10A gene was identified as responsible for various autosomal recessive forms of ectodermal dysplasias, including onycho‐odonto‐dermal dysplasia (OODD) and Schöpf‐Schulz‐Passarge syndrome. We systematically studied EDA1, EDAR, EDARADD, and WNT10A genes in a large cohort of 65 unrelated patients, of which 61 presented with HED/EDA. A total of 50 mutations (including 32 novel mutations) accounted for 60/65 cases in our series. These four genes accounted for 92% (56/61 patients) of HED/EDA cases: (1) the EDA1 gene was the most common disease‐causing gene (58% of cases), (2)WNT10A and EDAR were each responsible for 16% of cases. Moreover, a novel disease locus for dominant HED/EDA mapped to chromosome 14q12–q13.1. Although no clinical differences between patients carrying EDA1, EDAR, or EDARADD mutations could be identified, patients harboring WNT10A mutations displayed distinctive clinical features (marked dental phenotype, no facial dysmorphism), helping to decide which gene should be first investigated in HED/EDA. Hum Mutat 31:1–8, 2010.

Orodental phenotype and genotype findings in all subtypes of hypophosphatasia

BackgroundHypophosphatasia (HP) is a rare inherited disorder characterized by a wide spectrum of defects in mineralized tissues and caused by deficiency in the tissue non-specific alkaline phosphatase gene (ALPL). The symptoms are highly variable in their clinical expression, and relate to numerous mutations in this gene. The first clinical sign of the disease is often a premature loss of deciduous teeth, mostly in the moderate forms.AimThe purpose of this study was to document the oral features of HP patients and to relate theses features to the six recognized forms of HP in 5 patients with known genotype and to investigate the genotype-phenotype correlations.MethodsClinical and radiographic examinations were carried out. We collected medical and dental history in the kindred and biochemical data. Finally, mutations in the ALPL gene were tested by DNA sequencing in SESEP laboratory.ResultsWe have for the first time related the known dental anomalies which occur as integral features of HP to the recognized clinical forms of HP. We also pointed out striking dental abnormalities which were never described in association with this rare disease. Accurate genotype-phenotype severity correlations were observed.ConclusionThis work allowed us to compare orodental manifestations in all the clinical forms of HP within the patients sample. According to the severity of the disorder, some dental defects were infrequent, while other were always present. The long term prognosis of the permanent teeth varies from a patient to another. As premature loss of primary teeth is often the first, and sometimes the only visible symptom of the milder forms, the paediatric dentist plays a critical role in the detection and diagnosis of the disease.

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.

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.

X-linked and autosomal recessive Hypohidrotic Ectodermal Dysplasia: genotypic-dental phenotypic findings

Clauss F, Chassaing N, Smahi A, Vincent MC, Calvas P, Molla M, Lesot H, Alembik Y, Hadj‐Rabia S, Bodemer C, Manière MC, Schmittbuhl M. X‐linked and autosomal recessive Hypohidrotic Ectodermal Dysplasia: genotypic‐dental phenotypic findings.

Cytokines during periodontal wound healing: potential application for new therapeutic approach.

Regeneration of periodontal tissues is one of the main goals of periodontal therapy. However, current treatment, including surgical approach, use of membrane to allow maturation of all periodontal tissues, or use of enamel matrix derivatives, presents limitations in their indications and outcomes leading to the development of new tissue engineering strategies. Several cytokines are considered as key molecules during periodontal destruction process. However, their role during each phase of periodontal wound healing remains unclear. Control and modulation of the inflammatory response and especially, release of cytokines or activation/inhibition in a time- and spatial-controlled manner may be a potential perspective for periodontal tissue engineering. The aim of this review was to summarize the specific role of several cytokines during periodontal wound healing and the potential therapeutic interest of inflammatory modulation for periodontal regeneration especially related to the expression sequence of cytokines.

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

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.

Consequences of X-Linked Hypohidrotic Ectodermal Dysplasia for the Human Jaw Bone

Mutations of the Eda gene, which encodes for ectodysplasin-A1, result in X-linked hypohydrotic ectodermal dysplasia (XLHED). This pathology may lead to severe oligodontia, subsequently requiring implant therapy. Since Eda is suspected to participate in bone development, the jaw bone status was investigated in XLHED patients in order to adjust the surgical protocol. Using computed tomography, densitometric profiles and 3D reconstructions, the bone structure was analyzed and compared to that of control individuals; our results showed that the morphological changes comprised mandibular bone flattening. Craniofacial CT scans showed medullary bone hyperdensity, including in the mandibular symphysis area, where implants must be placed. These alterations in bone structure were also observed in locations where the presence/absence of teeth cannot interfere. If the changes in jaw bone morphology can be a consequence of oligodontia, the changes in bone structure seem to be tooth-independent and suggest a direct effect of the mutation on bone formation and/or remodeling.

Subtle Morphological Changes in the Mandible of Tabby Mice Revealed by Micro-CT Imaging and Elliptical Fourier Quantification.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a genetic disorder due to a mutation of the EDA gene and is mainly characterized by an impaired formation of hair, teeth and sweat glands, and craniofacial dysmorphologies. Although tooth abnormalities in Tabby (Ta) mutant mice – the murine model of XLHED – have been extensively studied, characterization of the craniofacial complex, and more specifically the mandibular morphology has received less attention. From 3D micro-CT reconstructions of the left mandible, the mandibular outline observed in lateral view, was quantified using 2D elliptical Fourier analysis. Comparisons between Ta specimens and their wild-type controls were carried out showing significant shape differences between mouse strains enabling a clear distinction between hemizygous Ta specimens and the other mouse groups (WT and heterozygous EdaTa/+ specimens). Morphological differences associated with HED correspond not only to global mandibular features (restrained development of that bone along dorsoventral axis), but also to subtle aspects such as the marked backward projection of the coronoid process or the narrowing of the mandibular condylar neck. These modifications provide for the first time, evidence of a predominant effect of the Ta mutation on the mandibular morphology. These findings parallel the well described abnormalities of jugal tooth row and skeletal defects in Ta mice, and underline the role played by EDA-A in the reciprocal epithelial–mesenchymal interactions that are of critical importance in normal dental and craniofacial development.

Quantification of taurodontism: interests in the early diagnosis of hypohidrotic ectodermal dysplasia

OBJECTIVE The aim of this study was to provide a quantification of taurodontism in Hypohidrotic Ectodermal Dysplasia (HED) and to report its occurrence in a cohort of HED patients to assess phenotypic-genotypic correlations. PATIENTS AND METHODS Of 68 HED patients retrospectively reviewed, 16 patients aged 7-51 years were selected and compared with a control sample (n = 351). The pulp surface index of the first lower permanent molar was calculated from the panoramic radiograph of each individual, and statistical comparisons between the HED patients and the control sample were performed. RESULTS Whatever the genetic disorder, 81.25% of the HED patients exhibited a relative enlargement (>or=1 s.d.) of the pulp. Major deviations (>5 s.d.) were respectively related to men affected by large deletion of the EDA gene or missense mutation. The autosomal recessive form was linked to a relative moderate pulp enlargement (3.44 s.d.). In NEMO forms, the increase of pulp size in men appeared to be less marked than in EDA mutations. CONCLUSION This study provides for the first time an objective assessment of pulp enlargement in HED patients, and the various degrees of taurodontism depicted could be interesting dental phenotypic markers of HED forms.

Dento-maxillo-facial phenotype and implants-based oral rehabilitation in Ectodermal Dysplasia with WNT10A gene mutation: Report of a case and literature review

PURPOSE To report the dento-craniofacial phenotype of a family affected by a WNT10A HED and to describe the implant-based oral rehabilitation of a patient presenting a severe oligodontia linked to this mutation. A molecular hypothesis concerning the involvement of Wnt-β-catenin pathway in implant osteointegration will be proposed. MATERIAL AND METHODS Patients affected by a WNT10A mutation were included from a large group of HED patients. WNT10A gene was sequenced in second intention for patients negative for EDA-EDAR-EDARADD mutations. Dento-craniofacial phenotype was described based on clinical and radiological data. RESULTS Severe oligodontia was observed in the patient affected by a compound heterozygous mutation of WNT10A gene. CT exams showed marked maxillary bone hypoplasia in the posterior areas with a sub-normal mandible treatment consisted in the placement of 4 mandibular implants and in 2 implant-supported bridges. In the maxilla, an autogenous bone graft was indicated. The post-operative radiological follow-up showed partial bone resorption of the grafts, treated with ramus bone shaving and a membrane, followed by the placement of 4 maxillary implants. CONCLUSION Patients affected by WNT10A HED require multi-disciplinary dental diagnosis and treatment. A close post-operative radiological follow-up appears necessary given the biological functions of Wnt-β-catenin in bone repair.