Rapp–Hodgkin ectodermal dysplasia syndrome: The clinical and molecular overlap with Hay–Wells syndrome

American Journal of Medical Genetics Part AVolume 140A, Issue 8 p. 887-891 Clinical Report Rapp–Hodgkin ectodermal dysplasia syndrome: The clinical and molecular overlap with Hay–Wells syndrome Peter Kannu, Corresponding Author Peter Kannu [email protected] Genetic Health Services Victoria, Flemington Road, Parkville, Australia Royal Children's Hospital, Melbourne, Australia Murdoch Children's Research Institute, Flemington Road, Parkville, AustraliaGenetic Health Services Victoria, 10th Floor, Royal Children's Hospital, Victoria 3052, Australia.Search for more papers by this authorRavi Savarirayan, Ravi Savarirayan Genetic Health Services Victoria, Flemington Road, Parkville, Australia Royal Children's Hospital, Melbourne, Australia Murdoch Children's Research Institute, Flemington Road, Parkville, Australia University of Melbourne, Melbourne, AustraliaSearch for more papers by this authorLinda Ozoemena, Linda Ozoemena Genetic Skin Diseases Group, St John's Institute of Dermatology, The Guy's, King's College and St Thomas' Hospitals' Medical School, London, UKSearch for more papers by this authorSusan M. White, Susan M. White Genetic Health Services Victoria, Flemington Road, Parkville, Australia Royal Children's Hospital, Melbourne, Australia Murdoch Children's Research Institute, Flemington Road, Parkville, AustraliaSearch for more papers by this authorJohn A. McGrath, John A. McGrath Genetic Skin Diseases Group, St John's Institute of Dermatology, The Guy's, King's College and St Thomas' Hospitals' Medical School, London, UKSearch for more papers by this author Peter Kannu, Corresponding Author Peter Kannu [email protected] Genetic Health Services Victoria, Flemington Road, Parkville, Australia Royal Children's Hospital, Melbourne, Australia Murdoch Children's Research Institute, Flemington Road, Parkville, AustraliaGenetic Health Services Victoria, 10th Floor, Royal Children's Hospital, Victoria 3052, Australia.Search for more papers by this authorRavi Savarirayan, Ravi Savarirayan Genetic Health Services Victoria, Flemington Road, Parkville, Australia Royal Children's Hospital, Melbourne, Australia Murdoch Children's Research Institute, Flemington Road, Parkville, Australia University of Melbourne, Melbourne, AustraliaSearch for more papers by this authorLinda Ozoemena, Linda Ozoemena Genetic Skin Diseases Group, St John's Institute of Dermatology, The Guy's, King's College and St Thomas' Hospitals' Medical School, London, UKSearch for more papers by this authorSusan M. White, Susan M. White Genetic Health Services Victoria, Flemington Road, Parkville, Australia Royal Children's Hospital, Melbourne, Australia Murdoch Children's Research Institute, Flemington Road, Parkville, AustraliaSearch for more papers by this authorJohn A. McGrath, John A. McGrath Genetic Skin Diseases Group, St John's Institute of Dermatology, The Guy's, King's College and St Thomas' Hospitals' Medical School, London, UKSearch for more papers by this author First published: 10 March 2006 https://doi.org/10.1002/ajmg.a.31187Citations: 15Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract 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 syndrome (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 heterozygous 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. © 2006 Wiley-Liss, Inc. REFERENCES Barrow LL, van Bokhoven H, Daack-Hirsch S, Andersen T, van Beersum SEC, Gorlin R, Murray JC. 2002. Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts. J Med Genet 39: 559–566. 10.1136/jmg.39.8.559 CASPubMedWeb of Science®Google Scholar Bertola DR, Kim CA, Albano LM, Scheffer H, Meijer R, van Bokhoven H. 2004. Molecular evidence that AEC syndrome and Rapp-Hodgkin syndrome are variable expression of a single genetic disorder. Clin Genet 66: 79–80. 10.1111/j.0009-9163.2004.00278.x CASPubMedWeb of Science®Google Scholar Bougeard G, Hadj-Rabia S, Faivre L, Sarafan-Vasseur N, Frebourg T. 2003. The Rapp-Hodgkin syndrome results from mutations of the TP63 gene. Eur J Hum Genet 11: 700–704. 10.1038/sj.ejhg.5201004 CASPubMedWeb of Science®Google Scholar Brunner HG, Hamel BC, van Bokhoven H. 2002. P63 gene mutations and human developmental syndromes. Am J Med Genet 112: 284–290. 10.1002/ajmg.10778 PubMedWeb of Science®Google Scholar Cambiaghi S, Tadini G, Barbareschi M, Menni S, Caputo R. 1994. RappHodgkin syndrome and AEC syndrome: Are they the same entity? Br J Dermatol 130: 97–101. 10.1111/j.1365-2133.1994.tb06891.x PubMedWeb of Science®Google Scholar Chan I, McGrath JA, Kivirikko S. 2005. Rapp-Hodgkin syndrome and the tail of p63. Clin Exp Dermatol 30: 183–186. 10.1111/j.1365-2230.2004.01715.x CASPubMedWeb of Science®Google Scholar Cliff S, Holden CA. 1997. What syndrome is this? Rapp-Hodgkin syndrome. Pediatr Dermatol 14: 149–150. 10.1111/j.1525-1470.1997.tb00224.x CASPubMedWeb of Science®Google Scholar Dianzani I, Garelli E, Gustavsson P, Carando A, Gustafsson B, Dahl N, Anneren G. 2003. Rapp-Hodgkin and AEC syndromes due to a new frameshift mutation in the TP63 gene. J Med Genet 40: e133. 10.1136/jmg.40.12.e133 CASPubMedWeb of Science®Google Scholar Felding IB, Bjorkland LJ. 1990. Rapp-Hodgkin ectodermal dysplasia. Pediatr Dermatol 7: 126–131. 10.1111/j.1525-1470.1990.tb00668.x PubMedWeb of Science®Google Scholar Fomenkov A, Huang Y-P, Topaloglu O, Brechman A, Osada M, Fomenkova T, Yuriditsky E, Trink B, Sidransky D, Ratovitski E. 2003. p63 mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome. J Biol Chem 278: 23906–23914. 10.1074/jbc.M300746200 CASPubMedWeb of Science®Google Scholar Hay RJ, Wells RS. 1976. The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: An autosomal dominant condition. Br J Dermatol 94: 277–289. 10.1111/j.1365-2133.1976.tb04384.x CASPubMedWeb of Science®Google Scholar Kantaputra PN, Hamada T, Kumchai T, McGrath JA. 2003. Heterozygous mutation in the SAM domain of p63 underlies Rapp-Hodgkin ectodermal dysplasia. J Dent Res 82: 433–437. 10.1177/154405910308200606 CASPubMedWeb of Science®Google Scholar Koster MI, Roop DR. 2004a. The role of p63 in development and differentiation of the epidermis. J Dermatol Sci 34: 3–9. 10.1016/j.jdermsci.2003.10.003 CASPubMedWeb of Science®Google Scholar Koster MI, Roop DR. 2004b. Transgenic mouse models provide new insights into the role of p63 in epidermal development. Cell Cycle 3: 411–413. 10.4161/cc.3.4.793 CASPubMedWeb of Science®Google Scholar Lamartine J. 2003. Towards a new classification of ectodermal dysplasias. Clin Exp Dermatol 28: 351–355. 10.1046/j.1365-2230.2003.01319.x CASPubMedWeb of Science®Google Scholar McGrath JA, Duijf PH, Doetsch V, Irvine AD, de Waal R, Vanmolkot KR, Wessagowit V, Kelly A, Atherton DJ, Griffiths WA, Orlow SJ, van Haeringen A, Ausems MG, Yang A, McKeon F, Bamshad MA, Brunner HG, Hamel BC, van Bokhoven H. 2001. Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. Hum Mol Genet 10: 221–229. 10.1093/hmg/10.3.221 CASPubMedWeb of Science®Google Scholar Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. 1999. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398: 708–713. 10.1038/19531 CASPubMedWeb of Science®Google Scholar Priolo M, Lagana C. 2001. Ectodermal dysplasias: A new clinical-genetic classification. J Med Genet 38: 579–585. 10.1136/jmg.38.9.579 CASPubMedWeb of Science®Google Scholar Rapp RS, Hodgkin WE. 1968. Anhidrotic ectodermal dysplasia: Autosomal dominant inheritance with palate and lip anomalies. J Med Genet 5: 269–272. 10.1136/jmg.5.4.269 PubMedGoogle Scholar Shotelersuk V, Janklat S, Siriwan P, Tongkobpetch S. 2005. De novo missense mutation, S541Y, in the p63 gene underlying Rapp-Hodgkin ectodermal dysplasia syndrome. Clin Exp Dermatol 30: 282–285. 10.1111/j.1365-2230.2005.01722.x CASPubMedWeb of Science®Google Scholar Tsutsui K, Asai Y, Fujimoto A, Yamamoto M, Kubo M, Hatta N. 2003. A novel p63 sterile alpha motif (SAM) domain mutation in a Japanese patient with ankyloblepharon, ectodermal defects and cleft lip and palate (AEC) syndrome without ankyloblepharon. Br J Dermatol 149: 395–399. 10.1046/j.1365-2133.2003.05423.x CASPubMedWeb of Science®Google Scholar van Bokhoven H, Brunner HG. 2002. Splitting p63. Am J Hum Genet 71: 1–13. 10.1086/341450 CASPubMedWeb of Science®Google Scholar van Bokhoven H, Hamel BC, Bamshad M, Sangiorgi E, Gurrieri F, Duijf PH, Vanmolkot KR, van Beusekom E, van Beersum SE, Celli J, Merkx GF, Tenconi R, Fryns JP, Verloes A, Newbury-Ecob RA, Raas-Rotschild A, Majewski F, Beemer FA, Janecke A, Chitayat D, Crisponi G, Kayserili H, Yates JR, Neri G, Brunner HG. 2001. p63 Gene mutations in EEC syndrome, limbmammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet 69: 481–492. 10.1086/323123 CASPubMedWeb of Science®Google Scholar Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V, Andrews NC, Caput D, McKeon F. 1998. P63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 2: 305–316. 10.1016/S1097-2765(00)80275-0 CASPubMedWeb of Science®Google Scholar Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C, McKeon F. 1999. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398: 714–718. 10.1038/19539 CASPubMedWeb of Science®Google Scholar Citing Literature Volume140A, Issue815 April 2006Pages 887-891 ReferencesRelatedInformation