Marie-Cécile Manière

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.

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.

Sedation with 50% nitrous oxide/oxygen for outpatient dental treatment in individuals with intellectual disability.

Persons with intellectual disability have difficulty in cooperating with outpatient care, and many are referred for general anaesthesia. Intellectual disability has traditionally been a contraindication for conscious sedation. We evaluated the behavioural impact, effectiveness, and tolerance of sedation in this population using a fixed 50% nitrous oxide/oxygen mixture as a single agent. We used dental treatment as a model of outpatient care; 349 patients (192 males, 157 females; mean age 22y [SD 14]; range 3–81y) were recruited over a 12‐month period at seven centres. Sedation was deemed successful if planned dental treatment was completed. Behaviour was scored with the modified Venham scale. Out of 605 sessions, 91.4% were successful. No serious adverse effects occurred. Minor adverse events (such as nausea) occurred in 10.1% of sessions. We conclude that the use of safe and effective conscious sedation may reduce the indications for general anaesthesia.

Evaluation of safe and effective administration of nitrous oxide after a postgraduate training course

BackgroundConscious sedation is used in dentistry to improve access and quality of care in patients who have difficulty coping with treatment. The aim of this prospective study was to describe a postgraduate training course in conscious sedation for dentists, with specific evaluation of the safe and effective administration of a 50% nitrous oxide in oxygen premix.Methods45 practitioners were trained between 2002 and 2004. They carried out 826 sessions of inhalation sedation in 662 patients. The clinical competency of this group was compared with an expert group.ResultsThere was no difference between trainees and experts in ability to complete the planned dental treatment under sedation (89.6% vs 93.2%). Trainees were less successful than experts for patients with intellectual disability (87.4% vs 94.2%, p < 0.01). For both groups, the degree of cooperation improved between initial induction and each perioperative step (Wilcoxon test, p < 0.01). However, for trainees, Venham behaviour scores varied with the type of patient (Kruskal Wallis test, p < 0.001). No major adverse effects were recorded. Trainees reported more minor adverse effects than experts (13% vs. 5.3% respectively, Fisher exact test, p < 0.001)ConclusionThe trainee practitioners provided effective and safe inhalation sedation. This challenges the current French restriction of the 50% nitrous oxide in oxygen premix to the hospital setting. Further emphasis is required on the teaching of behaviour management skills for patients with intellectual disability.

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.

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.

A Novel Mutation in the ROGDI Gene in a Patient with Kohlschütter-Tönz Syndrome

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.