ß 2006 Wiley-Liss, Inc. American Journal of Medical Genetics 140A:887–891 (2006) Clinical Report Rapp–Hodgkin Ectodermal Dysplasia Syndrome: The Clinical and Molecular Overlap With Hay–Wells Syndrome Peter Kannu, 1,2,3 * Ravi Savarirayan, 1,2,3,4 Linda Ozoemena, 5 Susan M. White, 1,2,3 and John A. McGrath 5 1 Genetic Health Services Victoria, Flemington Road, Parkville, Australia 2 Royal Children’s Hospital, Melbourne, Australia 3 Murdoch Children’s Research Institute, Flemington Road, Parkville, Australia 4 University of Melbourne, Melbourne, Australia 5 Genetic Skin Diseases Group, St John’s Institute of Dermatology, The Guy’s, King’s College and St Thomas’ Hospitals’ Medical School, London, UK Received 24 October 2005; Accepted 31 January 2006 We report on the clinical and molecular abnormalities in a 7- month-old girl and her mother with an ectodermal dysplasia disorder that most closely resembles Rapp–Hodgkin syn- drome (RHS). At birth, the child had bilateral cleft palate, a narrow pinched nose, small chin, and hypoplastic nipples, and suffered from respiratory distress, feeding difficulties, and poor weight gain, although developmental progress was normal. Her mother had a cleft palate, sparse hair, high forehead, dental anomalies, a narrow nose, dysplastic nails, and reduced sweating. Sequencing of the p63 gene in genomic DNA from both individuals revealed a heterozy- gous frameshift mutation, 1721delC, in exon 14. This mutation has not been described previously and is the seventh report of a pathogenic p63 gene mutation in RHS. The frameshift results in changes to the tail of p63 with the addition of 90 missense amino acids downstream and a delayed termination codon that extends the protein by 21 amino acids. This mutation is predicted to disrupt the normal repressive function of the transactivation inhibitory domain leading to gain-of-function for at least two isoforms of the p63 transcription factor. The expanding p63 mutation database demonstrates that there is considerable overlap between the molecular pathology of RHS and Hay–Wells syndrome, with identical mutations in some cases, and that these two disorders may in fact be synonymous. ß 2006 Wiley-Liss, Inc. Key words: p63; gene mutation; skin; hair; clefting INTRODUCTION Ectodermal dysplasia syndromes represent a com- plex group of poorly classified developmental disorders that affect approximately 7 per 10,000 live births [Lamartine, 2003]. There is no universally accepted classification of these conditions and the literature lists over 170 different subtypes that are largely based on case reports or series containing detailed clinical descriptions of various inherited abnormalities in hair, teeth, nails, skin, sweating, and other developmental anomalies. Recently, however, new understanding of the molecular pathology of some forms of ectodermal dysplasia has led to fresh attempts to re-classify these syndromes based on mechanisms of disease rather than just the clinical features [Priolo and Lagana, 2001; Lamartine, 2003]. One significant discovery has involved identification of inherited abnormalities in the transcription factor, p63, in several ectodermal dysplasia syndromes [van Bokhoven and Brunner, 2002]. Initial clues to the link between p63 and ectodermal dysplasia syn- dromes came from the phenotype of p63 À/À mice which, although embryonic lethal, had a thin skin, facial clefting, and abnormal limb development [Mills et al., 1999; Yang et al., 1999]. The p63 gene is transcribed into isoforms that either contain (TA) or lack (DeltaN) a transactivation domain. The TA isoforms are expressed in uncommitted surface *Correspondence to: Peter Kannu, Genetic Health Services Victoria, 10th Floor, Royal Children’s Hospital, Victoria 3052, Australia. E-mail: peter.kannu@ghsv.org.au DOI 10.1002/ajmg.a.31187