Dental and extra‐oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype–phenotype study

WNT10A gene encodes a canonical wingless pathway signaling molecule involved in cell fate specification as well as morphogenetic patterning of the developing ectoderm, nervous system, skeleton, and tooth. In patients, WNT10A mutations are responsible for ectodermal‐derived pathologies including isolated hypo‐oligodontia, tricho‐odonto‐onycho‐dermal dysplasia and Schöpf‐Schulz‐Passarge syndrome (SSPS). Here we describe the dental, ectodermal, and extra‐ectodermal phenotypic features of a cohort of 41 patients from 32 unrelated families. Correlations with WNT10A molecular status (heterozygous carrier, compound heterozygous, homozygous) and patient's phenotypes were performed. Mild to severe oligodontia was observed in all patients bearing biallelic WNT10A mutations. However, patients with compound heterozygous mutations presented no significant difference in phenotypes compared with homozygous individuals. Anomalies in tooth morphology were frequently observed with heterozygous patients displaying hypodontia. No signs of SSPS, especially eyelids cysts, were detected in our cohort. Interestingly, extra‐ectodermal signs consisted of skeletal, neurological and vascular anomalies, the latter suggesting a wider phenotypic spectrum associated with WNT10A mutations. Indeed, the Wnt pathway plays a crucial role in skeletal development, lipid metabolism, and neurogenesis, potentially explaining patient's clinical manifestations.     

Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia

Ectodermal dysplasias (ED) are a clinically and genetically heterogeneous group of hereditary disorders that have in common abnormal development of ectodermal derivatives. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of eccrine sweat glands, hair, and teeth. The X‐linked form of the disease, caused by mutations in the EDA gene, represents the majority of patients with the hypohidrotic form. Autosomal dominant and autosomal recessive forms are occasionally seen, and result from mutations in at least three genes (WNT10A, EDAR, or more rarely EDARADD). We have screened for mutations in EDAR (commonly involved in the hypohidrotic form) and WNT10A (involved in a wide spectrum of ED and in isolated hypodontia) in a cohort of 36 patients referred for EDA molecular screening, which failed to identify any mutation. We identified eight EDAR mutations in five patients (two with homozygous mutations, one with compound heterozygous mutations, and two with heterozygous mutation), four of which were novel variants. We identified 28 WNT10A mutations in 16 patients (5 with homozygous mutations, 7 with compound heterozygous mutations, and 4 with heterozygous mutations), seven of which were novel variants. Our study allows a more precise definition of the phenotypic spectrum associated with EDAR and WNT10A mutations and underlines the importance of the implication of WNT10A among patients with ED. © 2013 Wiley Periodicals, Inc.     

Phenotypic heterogeneity and mutational spectrum in a cohort of 45 Italian males subjects with X‐linked ectodermal dysplasia

Ectodermal dysplasias (EDs) are a group of genetic disorders characterized by the abnormal development of the ectodermal‐derived structures. X‐linked hypohidrotic ectodermal dysplasia, resulting from mutations in ED1 gene, is the most common form. The main purpose of this study was to characterize the phenotype spectrum in 45 males harboring ED1 mutations. The study showed that in addition to the involvement of the major ectodermal tissues, the majority of patients also have alterations of several minor ectodermal‐derived structures. Characterizing the clinical spectrum resulting from ED1 gene mutations improves diagnosis and can direct clinical care.     

Distinct impacts of bi‐allelic WNT10A mutations on the permanent and primary dentitions in odonto‐onycho‐dermal dysplasia

Odonto‐onycho‐dermal dysplasia (OODD) is a rare autosomal recessive syndrome characterized by multiple ectodermal abnormalities. Mutations of the wingless‐type MMTV integration site family member 10A (WNT10A) gene have been associated with OODD. To date, only 11 OODD‐associated WNT10A mutations have been reported. In this report, we Characterized the clinical manifestations with focusing on dental phenotypes in four unrelated OODD patients. By Sanger sequencing, we identified five novel mutations in the WNT10A gene, including two homozygous nonsense mutations c.1176C>A (p.Cys392*) and c.742C>T (p.Arg248*), one homozygous frame‐shift mutation c.898‐899delAT (p.Ile300Profs*126), and a compound heterozygous mutation c.826T>A (p.Cys276Ser) and c.949delG (p.Ala317Hisfs*121). Our findings confirmed that bi‐allelic mutations of WNT10A were responsible for OODD and greatly expanded the mutation spectrum of OODD. For the first time, we demonstrated that bi‐allelic WNT10A mutations could lead to anodontia of permanent teeth, which enhanced the phenotypic spectrum of WNT10A mutations. Interestingly, we found that bi‐allelic mutations in the WNT10A gene preferentially affect the permanent dentition rather the primary dentition, suggesting that the molecular mechanisms regulated by WNT10A in the development of permanent teeth and deciduous teeth might be different.     

WNT10A missense mutation associated with a complete Odonto-Onycho-Dermal Dysplasia syndrome

Wnt signalling is one of a few pathways that are crucial for controlling genetic programs during embryonic development as well as in adult tissues. WNT10A is expressed in the skin and epidermis and it has shown to be critical for the development of ectodermal appendages. A nonsense mutation in WNT10A was recently identified in odonto-onycho-dermal dysplasia (OODD; MIM 257980), a rare syndrome characterised by severe hypodontia, nail dystrophy, smooth tongue, dry skin, keratoderma and hyperhydrosis of palms and soles. We identified a large consanguineous Pakistani pedigree comprising six individuals affected by a complete OODD syndrome. Autozygosity mapping using SNP array analysis showed that the affected individuals are homozygous for the WNT10A gene region. Subsequent mutation screening showed a homozygous c.392C>T transition in exon 3 of WNT10A, which predicts a p.A131V substitution in a conserved α-helix domain. We report here on the first inherited missense mutation in WNT10A with associated ectodermal features.     

Variability in dentofacial phenotypes in four families with WNT10A mutations

This article describes the inter- and intra-familial phenotypic variability in four families with WNT10A mutations. Clinical characteristics of the patients range from mild to severe isolated tooth agenesis, over mild symptoms of ectodermal dysplasia, to more severe syndromic forms like odonto-onycho-dermal dysplasia (OODD) and Schöpf–Schulz–Passarge syndrome (SSPS). Recurrent WNT10A mutations were identified in all affected family members and the associated symptoms are presented with emphasis on the dentofacial phenotypes obtained with inter alia three-dimensional facial stereophotogrammetry. A comprehensive overview of the literature regarding WNT10A mutations, associated conditions and developmental defects is presented. We conclude that OODD and SSPS should be considered as variable expressions of the same WNT10A genotype. In all affected individuals, a dished-in facial appearance was observed which might be helpful in the clinical setting as a clue to the underlying genetic etiology.     

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. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of ectodermal structures and its molecular etiology corresponds to mutations of EDA‐EDAR genes. The aim of this study was first to investigate the genotype and dental phenotype associated with HED and second, to explore possible correlations between dental features and molecular defects. A total of 27 patients from 24 unrelated families exhibiting clinical signs of HED (22 XLHED males, 5 autosomal recessive forms) were retrospectively included. In the sample, 25 different mutations on EDA and EDAR genes were detected; 10 were not previously described. EDA and EDAR mutations corresponded respectively to 80.0% and 20.0% of the mutations. The dental phenotype analysis revealed a mean number of primary and permanent missing teeth ranging respectively from 14.5 (4–20) to 22.5 (10–28); the majority of the patients exhibited dysmorphic teeth. Overall, no differential expression in the degree of oligodontia according to either the mutated gene, the mutated functional sub‐domains, or the mutation type, could be observed. Nevertheless, the furin group exhibited severe phenotypes unobserved in the TNF group. Significant differences in the number of some primary missing teeth (incisor and canine) related to EDA‐EDAR genes defects were detected for the first time between XLHED and autosomal recessive HED, suggesting differential local effects of EDA‐EDAR genes during odontogenesis. The present genotypic‐phenotypic findings may add to the knowledge of the consequences of the molecular dysfunction of EDA‐NF‐k B in odontogenesis, and could be helpful in genetic counseling to distinguish autosomal forms from other HED syndromes.     

Ectodermal dysplasias: Classification and organization by phenotype,genotype and molecular pathway

An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non‐syndromic traits of the causative gene (e.g., non‐syndromic hypodontia or missing teeth associated with pathogenic variants of EDA “ectodysplasin”). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT “wingless‐type,” TP63 “tumor protein p63”) or the components of complex molecular structures (e.g., connexins, keratins, cadherins).     

Recombinant EDA or Sonic Hedgehog rescue the branching defect in Ectodysplasin A pathway mutant salivary glands in vitro

Hypohidrotic ectodermal dysplasia (HED) is characterized by defective ectodermal organ development. This includes the salivary glands (SGs), which have an important role in lubricating the oral cavity. In humans and mice, HED is caused by mutations in Ectodysplasin A (Eda) pathway genes. Various phenotypes of the mutant mouse Eda^Ta/Ta, which lacks the ligand Eda, can be rescued by maternal injection or in vitro culture supplementation with recombinant EDA. However, the response of the SGs to this treatment has not been investigated. Here, we show that the submandibular glands (SMGs) of Eda^Ta/Ta mice exhibit impaired branching morphogenesis, and that supplementation of Eda^Ta/Ta SMG explants with recombinant EDA rescues the defect. Supplementation of Edar^dlJ/dlJ SMGs with recombinant Sonic hedgehog (Shh) also rescues the defect, whereas treatment with recombinant Fgf8 does not. This work is the first to test the ability of putative Eda target molecules to rescue Eda pathway mutant SMGs. Developmental Dynamics 239:2674–2684, 2010. © 2010 Wiley‐Liss, Inc.     

WNT10B mutations associated with isolated dental anomalies

Isolated hypodontia is the most common human malformation. It is caused by heterozygous variants in various genes, with heterozygous WNT10A variants being the most common cause. WNT10A and WNT10B are paralogs that likely evolved from a common ancestral gene after its duplication. Recently, an association of WNT10B variants with oligodontia (severe tooth agenesis) has been reported. We performed mutational analysis in our cohort of 256 unrelated Thai families with various kinds of isolated dental anomalies. In 7 families afflicted with dental anomalies we detected 4 heterozygous missense variants in WNT10B. We performed whole exome sequencing in the patients who had WNT10B mutations and found no mutations in other known hypodontia‐associated genes, including WNT10A, MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, LPR6, TFAP2B, LPR6, NEMO, KRT17, and GREM2. Our findings indicate that the variants c.475G>C [p.(Ala159Pro)], found in 4 families, and c.1052G>A [p.(Arg351His)], found in 1 family, are most probably causative. They also show that WNT10B variants are associated not only with oligodontia and isolated tooth agenesis, but also with microdontia, short tooth roots, dental pulp stones, and taurodontism.     

Biallelic loss‐of‐function WNT5A mutations in an infant with severe and atypical manifestations of Robinow syndrome

Robinow syndrome (RS) is a well‐recognized Mendelian disorder known to demonstrate both autosomal dominant and autosomal recessive inheritance. Typical manifestations include short stature, characteristic facies, and skeletal anomalies. Recessive inheritance has been associated with mutations in ROR2 while dominant inheritance has been observed for mutations in WNT5A, DVL1, and DVL3. Through trio whole genome sequencing, we identified a homozygous frameshifting single nucleotide deletion in WNT5A in a previously reported, deceased infant with a unique constellation of features comprising a 46,XY disorder of sex development with multiple congenital malformations including congenital diaphragmatic hernia, ambiguous genitalia, dysmorphic facies, shortened long bones, adactyly, and ventricular septal defect. The parents, who are both heterozygous for the deletion, appear clinically unaffected. In conjunction with published observations of Wnt5a double knockout mice, we provide evidence for the possibility of autosomal recessive inheritance in association with WNT5A loss‐of‐function mutations in RS.     

EEC‐ and ADULT‐Associated TP63 Mutations Exhibit Functional Heterogeneity Toward P63 Responsive Sequences

TP63 germ‐line mutations are responsible for a group of human ectodermal dysplasia syndromes, underlining the key role of P63 in the development of ectoderm‐derived tissues. Here, we report the identification of two TP63 alleles, G134V (p.Gly173Val) and insR155 (p.Thr193_Tyr194insArg), associated to ADULT and EEC syndromes, respectively. These alleles, along with previously identified G134D (p.Gly173Asp) and R204W (p.Arg243Trp), were functionally characterized in yeast, studied in a mammalian cell line and modeled based on the crystal structure of the P63 DNA‐binding domain. Although the p.Arg243Trp mutant showed both complete loss of transactivation function and ability to interfere over wild‐type P63, the impact of p.Gly173Asp, p.Gly173Val, and p.Thr193_Tyr194insArg varied depending on the response element (RE) tested. Interestingly, p.Gly173Asp and p.Gly173Val mutants were characterized by a severe defect in transactivation along with interfering ability on two DN‐P63α‐specific REs derived from genes closely related to the clinical manifestations of the TP63‐associated syndromes, namely PERP and COL18A1. The modeling of the mutations supported the distinct functional effect of each mutant. The present results highlight the importance of integrating different functional endpoints that take in account the features of P63 proteins' target sequences to examine the impact of TP63 mutations and the associated clinical variability.     

Pseudohypoparathyroidism Type Ia and Pseudo‐Pseudohypoparathyroidism: The Growing Spectrum of GNAS Inactivating Mutations

Pseudohypoparathyroidism (PHP) is a rare heterogeneous genetic disorder characterized by end‐organ resistance to parathyroid hormone due to partial deficiency of the α subunit of the stimulatory G protein (Gsα), encoded by the GNAS gene. Heterozygous inactivating GNAS mutations lead to either PHP type Ia (PHP‐Ia), when maternally inherited, or pseudo‐pseudohypoparathroidism (PPHP), if paternally derived. Both diseases feature typical physical traits identified as Albright's hereditary osteodystrophy in the presence or absence of multihormone resistance, respectively. GNAS mutations are detected in 60–70% of affected subjects, most patients/families harbor private mutations and no genotype–phenotype correlation has been found to date. We investigated Gsα‐coding GNAS exons in a large panel of PHP‐Ia–PPHP patients collected over the past decade in the two Italian referring centers for PHP. Of 49 patients carrying GNAS mutations, we identified 15 novel mutations in 19 patients. No apparent correlation was found between clinical/biochemical data and results of molecular analysis. Furthermore, we summarized the current knowledge of GNAS molecular pathology and updated the GNAS‐locus‐specific database. These results further expand the spectrum of GNAS mutations associated with PHP/PPHP and underline the importance of identifying such genetic alterations to supplement clinical evaluation and genetic counseling.     

Genetic Variants in the Wnt Signaling Pathway Are Not Associated with Survival Outcome of Non-Small Cell Lung Cancer in a Korean Population

Recently, genetic variants in the WNT signaling pathway have been reported to affect the survival outcome of Caucasian patients with early stage non-small cell lung cancer (NSCLC). We therefore attempted to determine whether these same WNT signaling pathway gene variants had similar impacts on the survival outcome of NSCLC patients in a Korean population. A total of 761 patients with stages I–IIIA NSCLC were enrolled in this study. Eight variants of WNT pathway genes were genotyped and their association with overall survival and disease-free survival were analyzed. None of the eight variants were significantly associated with overall survival or disease-free survival. There were no differences in survival outcome after stratifying the subjects according to age, gender, smoking status, and histological type. These results suggest that genetic variants in the WNT signaling pathway may not affect the survival outcome of NSCLC in a Korean population.     

Ptosis as a unique hallmark for autosomal recessive WNT1‐associated osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder, mainly characterized by bone fragility and low bone mass. Defects in the type I procollagen‐encoding genes account for the majority of OI, but increasingly more rare autosomal recessive (AR) forms are being identified, which are caused by defects in genes involved in collagen metabolism, bone mineralization, or osteoblast differentiation. Bi‐allelic mutations in WNT1 have been associated with a rare form of AR OI, characterized by severe osteoporosis, vertebral compression, scoliosis, fractures, short stature, and variable neurological problems. Heterozygous WNT1 mutations have been linked to autosomal dominant early‐onset osteoporosis. In this study, we describe the clinical and molecular findings in 10 new patients with AR WNT1‐related OI. Thorough revision of the clinical symptoms of these 10 novel patients and previously published AR WNT1 OI cases highlight ptosis as a unique hallmark in the diagnosis of this OI subtype.