RESEARCH ARTICLE Acroscyphodysplasia as a Phenotypic Variation of Pseudohypoparathyroidism and Acrodysostosis type 2 Toshikatsu Mitsui, 1 Ok-Hwa Kim, 2 Christine M. Hall, 3 Amaka Offiah, 4 Diana Johnson, 5 Dong-Kyu Jin, 6 Teck-Hock Toh, 7 Shun Soneda, 8 Dai Keino, 8 Shohei Matsubayashi, 9 Tomohiro Ishii, 1 Gen Nishimura, 10 and Tomonobu Hasegawa 1 * 1 Department of Pediatrics, School of Medicine, Keio University, Tokyo, Japan 2 Department of Radiology, Gachon University Gil Medical Center, Incheon, Korea 3 Institute of Child Health, University of London, London, United Kingdom 4 Academic Unit of Child Health, Sheffield Children’s Hospital NHS Foundation Trust, Sheffield, United Kingdom 5 Sheffield Clinical Genetics Service, Sheffield Children’s Hospital NHS Foundation Trust, Sheffield, United Kingdom 6 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 7 Department of Pediatrics and Clinical Research Centre, Sibu Hospital, Sibu, Sarawak, Malaysia 8 Department of Pediatrics, St. Marianna University School of Medicine, Kanagawa, Japan 9 Department of Orthopedic Surgery, Nagasaki Prefectural Center of Medicine and Welfare for Children, Nagasaki, Japan 10 Department of Pediatric Imaging, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan Manuscript Received: 15 March 2014; Manuscript Accepted: 3 May 2014 Acroscyphodysplasia (OMIM250215) is a distinctive form of meta- physeal dysplasia characterized by the distal femoral and proximal tibial epiphyses embedded in cup-shaped, large metaphyses known as metaphyseal scypho (“scypho” ¼ cup) deformity. It is also associated with severe growth retardation and brachydactyly. The underlying molecular mechanism of acroscyphodysplasia has not yet been elucidated, although scypho-deformity of the knee has been reported in three patients with acrodysostosis due to a mutation in the PDE4D gene. We report on the clinical, radiologi- cal, and molecular findings of five female patients with acroscy- phodysplasia; two were diagnosed as pseudohypoparathyroidism (PHP) or Albright hereditary osteodystropy, and the other three as acrodysostosis. They all had radiological findings consistent with severe metaphyseal scypho-deformity and brachydactyly. Hetero- zygous mutations were identified in the PHP patients consisting of one novel (p.Q19X) and one recurrent (p.R231C) mutation of the GNAS gene, as well as, in the acrodysostosis patients consisting of two novel mutations (p.T224I and p.I333T) of the PDE4D gene. We conclude that metaphyseal acroscyphodysplasia is a phenotypic variation of PHP or acrodysostosis caused by either a GNAS or PDE4D mutation, respectively. Ó 2014 Wiley Periodicals, Inc. Key words: acroscyphodysplasia; pseudohypoparathyroidism; acrodysostosis; GNAS; PDE4D INTRODUCTION Metaphyseal scypho-deformity is the combination of specific strik- ing changes at the knees with a cone, “chevron” or wedge-shaped invagination of the distal femoral epiphysis into the adjacent metaphysis and a milder cup-shaped deformity of the proximal tibial metaphysis [Verloes et al., 1991]. “Scyphos” is Greek for “cup- shaped.” The V-shaped epiphyses are embedded in the correspond- How to Cite this Article: Mitsui T, Kim O-H, Hall CM, Offiah A, Johnson D, Jin D-K, Toh T-H, Soneda S, Keino D, Matsubayashi S, Ishii T, Nishimura G, Hasegawa T. 2014. Acroscyphodysplasia as a phenotypic variation of pseudohypoparathyroidism and acrodysostosis type 2. Am J Med Genet Part A 164A:2529–2534. Grant sponsor: Health Science Research Grant for Research on Applying Health Technology (Jitsuyoka [Nanbyo]-Ippan-014), Ministry of Health, Labour and Welfare, Japan. Ã Correspondence to: Tomonobu Hasegawa, M.D., Ph.D., Department of Pediatrics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160- 8582, Japan. E-mail: thaseg@a6.keio.jp Article first published online in Wiley Online Library (wileyonlinelibrary.com): 10 July 2014 DOI 10.1002/ajmg.a.36669 Ó 2014 Wiley Periodicals, Inc. 2529