European Journal of Human Genetics (2014) 22, 1063–1070 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg ARTICLE Variability in dentofacial phenotypes in four families with WNT10A mutations Christian P Vink1, Charlotte W Ockeloen2,3, Sietske ten Kate2, David A Koolen2, Johannes Kristian Ploos van Amstel4, Anne-Marie Kuijpers-Jagtman1,3, Celeste C van Heumen3,5, Tjitske Kleefstra2,3 and Carine EL Carels*,1,3,6,7 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 Scho¨pf–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. European Journal of Human Genetics (2014) 22, 1063–1070; doi:10.1038/ejhg.2013.300; published online 8 January 2014 Keywords: ectodermal dysplasia; odonto-onycho-dermal dysplasia; Scho¨pf–Schulz–Passarge syndrome; tooth agenesis; WNT10A INTRODUCTION including homozygous, compound heterozygous and heterozygous Tooth agenesis (TA) is the most common, often heritable, develop- mutations. mental anomaly of the human dentition. Depending on the tooth It has been shown that specific facial features can differ significantly type and number of teeth involved, the prevalence of TA ranges from between patients with and without isolated TA.12 Therefore, in 10 to 30% for TA of third molars to 0.2% for severe TA of six teeth or addition to the description of the dental and general syndromic ED more (excluding the third molars).1 An overall incidence of TA of features, the aim in this study was to document the facial phenotypic permanent teeth excluding third molars of 2.6–11.3% was reported, variations in four families with WNT10A mutations and to give a depending on demographic and geographic profiles.1 comprehensive overview of the literature regarding WNT10A As tooth formation shares mechanisms with the development of mutations, associated conditions and developmental defects. other ectodermal appendages, TA often occurs as part of a variety of ectodermal dysplasia (ED) syndromes including Witkop syndrome, PATIENTS AND METHODS hypohydrotic ectodermal dysplasia, odonto-onycho-dermal dysplasia In four families at least one member, referred to as proband or index patient, (OODD), Scho¨pf–Schulz–Passarge syndrome (SSPS) and others. For was referred for diagnosis or treatment to the Department of Orthodontics and these human TA syndromes, mutations have been identified, respec- Craniofacial Biology, the Radboud Center for Cleft Palate and Craniofacial tively, in MSX1,2 EDA, EDAR,3–5 EDARADD,6 and WNT10A.7,8 Anomalies and/or the Center for Special Dental Care or the Department of WNT10A mutations were identified in a family of which four Human Genetics, Radboud University Medical Center (RUMC). Informed members were affected with isolated TA or microdontia,9 whereas consent for publication of data and photographs was obtained from all more recently in a larger cohort of 34 patients with isolated TA, 56% patients and their enrolled relatives. appeared to have WNT10A mutations.10 Patients referred for orthodontic treatment received full diagnostic records, including digital or plaster dental casts, a lateral headfilm and orthopantomo- Besides pathogenic mutations within the coding regions of the gram (OPT) (In order to allow an exact quantitative phenotype profiling, the WNT10A gene in 62% of the tested patients, a significant association term TA with addition of the exact number of teeth which failed to develop 11 between SNPs in the WNT10A gene and the risk for TA was found. (excluding the third molars) is used as the terms hypodontia and oligodontia These recent studies indicate that changes in WNT10A are highly can be misleading.13 To identify the present/absent teeth, the Fe´de´ration frequent in terms of the risk or the presence of isolated or syndromic Dentaire Internationale tooth numbering system is used.). Both intra- and hypodontia, presenting with variable phenotypes and genotypes, extra-oral two-dimensional (2D) photographs as well as facial 3D 1Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands; 2Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; 3Radboud Center for Cleft Palate and Craniofacial Anomalies, Radboud University Medical Center, Nijmegen, The Netherlands; 4Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; 5Center for Special Dental Care, Radboud University Medical Center, Nijmegen, The Netherlands and 6Department of Oral Health Sciences, KU Leuven, Leuven, Belgium *Correspondence: Profesor CEL Carels, Department of Orthodontics & Craniofacial Biology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Tel: þ 31 24 361 4005; Fax: þ 31 24 354 0631; E-mail: [email protected] 7Shipping address: Philips van Leijdenlaan 25, 6525 EX Nijmegen, The Netherlands. Received 7 June 2013; revised 16 October 2013; accepted 20 November 2013; published online 8 January 2014 Dentofacial phenotypes with WNT10A mutations CP Vink et al 1064 stereophotogrammetry images were made. The 3D surface images were taken relative to the maxillary dental arch (Class II/1 relation). The 3D facial with a 3dMDface system (3dMD, Atlanta, GA, USA). All data were separately image demonstrates an underlying hypodivergent skeletal pattern, evaluated by two staff orthodontists of the Department of Orthodontics and with a retrusive mandible and a deepened plica mentalis. Craniofacial Biology of the RUMC. Additional ED features are present, comprising nail dystrophy and A medical and dental history was taken, including the family history; a full keratodermata at his feet. Temporary alopecia of the skull hair had physical examination was also performed by a clinical geneticist. The patients’ occurred at the age of 7. He was clinically diagnosed with OODD. DNA was isolated from leukocytes from their peripheral blood samples according to a standard protocol. Sequence analysis of WNT10A (RefSeq: Clinical examination of the first degree relatives. Both the proband’s NM_025216.2) was performed at the DNA diagnostics laboratory of the University Medical Center Utrecht, The Netherlands, using the standard Sanger father and his brother show no clinical symptoms of ED and all teeth sequencing technique. After identifying the mutations in the probands their are present. His mother however misses one tooth (35), and shows first degree relatives were contacted and were asked to participate in the study. generalized small-sized teeth with various diastemas in both jaws. Like The clinical examination and blood samples of the enrolled family members her youngest son, she showed some retroclination of her maxillary were taken in the same way as in the index patient while the oral and facial front teeth, prior to her orthodontic treatment. documentation in the family members was limited to a clinical examination and 2D facial photographs. Genetic diagnosis. A compound heterozygous mutation was identi- Complete documentation was obtained with regard to all index patients fied in WNT10A:c.321C4A;682T4A, p.(Cys107*);(Phe228Ile). In except one (patient D II-1). At the time of inclusion this patient was already either parent the presence of a heterozygous change in WNT10A was treated prosthodontically and no adequate documentation could be retrieved confirmed, the asymptomatic father harbored the c.321C4A, from the period before treatment. Also for some of the first degree relatives p.(Cys107*) mutation and the c.682T4A, p.(Phe228Ile) mutation included in this study, only limited data were available. was identified in the mother who was missing one tooth. The mutation analysis in the proband’s brother revealed he is a hetero- RESULTS zygous carrier of the c.321C4A, p.(Cys107*) mutation, which was Overview literature regarding WNT10A mutations inherited from the father (see Table 2). On the 13th of March 2013, a literature search was performed, screening the NCBI database for WNT10A mutations. Filters only Family B allowing articles in English, German or Dutch, yielded 90 articles. This Dutch family was referred to the Department of Orthodontics When adding Tooth Agenesis AND Ectodermal Dysplasia, and Craniofacial Biology because of TA in their three children. In all Odonto-Onycho-Dermal Dysplasia, Scho¨pf–Schulz–Passarge Syndrome family members, the deciduous dentition was either not affected or AND/OR derivates to WNT10A mutations, 14 articles7–11,14–22 met could not be verified. the inclusion criteria and suggested a causative relationship of WNT10A mutations with isolated TA or/and ED phenotypes. Clinical examination proband. The proband was 19 years old at the Adaimy et