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Acroscyphodysplasia as a phenotypic variation of pseudohypoparathyroidism and acrodysostosis type 2

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  • RESEARCH ARTICLEAcroscyphodysplasia as a PhenotypicVariation of Pseudohypoparathyroidismand 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 Hasegawa1*1Department of Pediatrics, School of Medicine, Keio University, Tokyo, Japan2Department of Radiology, Gachon University Gil Medical Center, Incheon, Korea3Institute of Child Health, University of London, London, United Kingdom4Academic Unit of Child Health, Sheffield Childrens Hospital NHS Foundation Trust, Sheffield, United Kingdom5Sheffield Clinical Genetics Service, Sheffield Childrens Hospital NHS Foundation Trust, Sheffield, United Kingdom6Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea7Department of Pediatrics and Clinical Research Centre, Sibu Hospital, Sibu, Sarawak, Malaysia8Department of Pediatrics, St. Marianna University School of Medicine, Kanagawa, Japan9Department of Orthopedic Surgery, Nagasaki Prefectural Center of Medicine and Welfare for Children, Nagasaki, Japan10Department of Pediatric Imaging, Tokyo Metropolitan Childrens Medical Center, Tokyo, JapanManuscript Received: 15 March 2014; Manuscript Accepted: 3 May 2014How 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:25292534.

    Grant sponsor: Health Science Research Grant for Research on Applying

    Health Technology (Jitsuyoka [Nanbyo]-Ippan-014), Ministry of Health,

    Labour and Welfare, Japan.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: [email protected]

    Article first published online in Wiley Online Library

    ( 10 July 2014

    DOI 10.1002/ajmg.a.36669Acroscyphodysplasia (OMIM250215) is a distinctive formofmeta-

    physeal dysplasia characterized by the distal femoral and proximal

    tibial epiphyses embedded in cup-shaped, largemetaphyses known

    as metaphyseal scypho (scypho cup) deformity. It is alsoassociated 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 patientswith acrodysostosis due to

    amutation in thePDE4Dgene.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-

    zygousmutations 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

    twonovelmutations (p.T224I andp.I333T)of thePDE4D gene.We

    conclude that metaphyseal acroscyphodysplasia is a phenotypic

    variation of PHP or acrodysostosis caused by either a GNAS or

    PDE4D mutation, respectively. 2014 Wiley Periodicals, Inc.

    Key words: acroscyphodysplasia; pseudohypoparathyroidism;acrodysostosis; GNAS; PDE4D


    Metaphyseal scypho-deformity is the combination of specific strik-

    ing changes at the knees with a cone, chevron or wedge-shaped2014 Wiley Periodicals, Inc.invagination of the distal femoral epiphysis into the adjacent

    metaphysis and a milder cup-shaped deformity of the proximal

    tibialmetaphysis [Verloes et al., 1991]. Scyphos isGreek for cup-

    shaped. TheV-shaped epiphyses are embedded in the correspond-2529

  • 2530 AMERICAN JOURNAL OF MEDICAL GENETICS PART Aing cupped deformity of the metaphyses. The differential growth

    between thedistal femurandproximal tibiamakes themanifestation

    more marked at the distal femoral metaphyses. Proximal humeral

    metaphyses are similarly affected in some cases. Scypho-deformity

    of the knee is associated with brachydactyly that results from

    premature fusion of multiple cone-shaped epiphyses in the hands.

    The combination of scypho-deformity of the knee and brachydac-

    tyly is termed acroscyphodysplasia (OMIM250215). Some affected

    individuals with acroscyphodysplasia show the characteristic mid-

    face hypoplasia of acrodysostosis (OMIM101800; 614613). One

    patient in a cohort of 16 cases of acrodysostosis presented with

    scypho-deformity of the knee and had a PDE4Dmutation [Linglart

    et al., 2012]. The PDE4D mutations have been identified in seven

    cases with acrodysostosis and two cases with metaphyseal acroscy-

    phodysplasia [Michot et al., 2013]. In both cohorts, PDE4Dmuta-

    tions were less common than PRKAR1A mutations as a cause for

    acrodysostosis. Of the reported 9 patients with PDE4D mutations,

    three have had metaphyseal acroscyphodysplasia. We determined

    the underlyingmolecular abnormalities in five female patients with

    acroscyphodysplasia; two of whom had a heterozygous GNAS

    mutation (pseudohypoparathyroidism [PHP] or Albrights heredi-TABLE I. The Clinical, Radiological, and Molecular

    Patient Sex, age, race


    Z score


    Z score Phenotypic feature

    1 Female, 4 years,


    2.0 3.5 Round face, stubby digsubcutaneous calcifi

    short stature, obesit

    intellectual impairme

    bilateral patellar


    2 Female, 7 years,


    0.5 1.5 Stubby digits, short staintellectual impairme

    3 Female, 3 years,


    NA NA Stubby digits, hypoplas

    nasal root, depresse

    nasal tip, short philt

    down-turned mouth,

    heterochromia, tibial


    4 Female, 15 years,



    8.8 2 Stubby digits, nasalhypoplasia, short sta

    unequal leg and arm

    lengths, intellectual


    5 Female, 9 months,


    NA NA Stubby digits, nasal

    hypoplasia, developm

    delay, muscle weakn

    apnea, failure to thr


    reportedaFemale, 14 years 3.0 NA Stubby digits, maxillona

    hypoplasia, big toe

    enlargement, epican

    folds, Short stature

    NA, not available; PTH, parathyroid hormone; TSH, thyroid stimulating hormone.aLinglart et al. [2012].tary dystrophy; OMIM103580), and remaining three had a hetero-

    zygous PDE4D mutation (acrodysostosis type 2; OMIM614613).CLINICAL REPORTS

    The clinical manifestations are summarized in the Table I. Photo-

    graphs of the patients are shown in Figure 1. We reported on

    Patients 1, 2, and 3 at the 11th meeting of International Skeletal

    Dysplasia Society 2013 [Hall et al., 2013].Patient 1AJapanesegirlwasborn toanonconsanguineous couple at 38weeks

    of gestation. Her birth length was 46.5 cm (1.2 SD) and weight2,360 g (2.0 SD). She had a history of delay in gross motordevelopment, sitting alone at 9 months, crawling at 14 months,

    and standing alone at 18months. At age 18months, knee deformity

    came to medical attention. When she was 3-years-old, she was

    found to have a round face, severe brachydactyly, subcutaneous

    calcification at the left ankle, short stature (height; 2.0 SD),obesity (weight; 3.5 SD), patellar dislocation, and intellectualFindings of Patients With Acrosyphodysplasia

    s Endocrine features Radiological features Genotype





    PTH resistance, TSH


    Severe brachydactyly, severe

    scypho-deformity of the

    knees and shoulders

    GNAS, Q19X



    PTH resistance, TSH


    Severe brachydactyly, mild

    and asymmetric scypho-

    deformity of the knees

    GNAS, R231C





    PTH resistance,

    normal thyroid


    Severe brachydactyly, severe

    scypho-deformity of the


    PDE4D, T224I


    Normal thyroid and



    Severe brachydactyly,

    calvarial thickening, severe

    scypho-deformity of the

    knees and shoulders

    PDE4D, T224I




    Normal thyroid and



    Severe brachydactyly,

    moderate scypho-

    deformity of the knees and


    PDE4D, I333T



    Normal thyroid and



    Severe brachydactyly,

    scypho-deformity of the


    PDE4D, A227S

  • MITSUI ET AL. 2531impairment. Her laboratory examination was consistent with mild

    parathyroid hormone (PTH) and thyroid stimulating hormone

    (TSH)resistance (Ca9.5mg/dl, inorganicphosphorus (IP) 5.4mg/dl,

    and intact PTH 99 pg/ml (reference range: 1065), fT4 1.37 ng/dl,

    TSH 6.57mIU/ml). The affected mother only had mild brachydac-tyly with shortening of the fourth and fifth metacarpals.Patient 2AKorean girl was born to a nonconsanguineous couple at 39 weeks

    of gestation. Birth weight was 2,720 g (1.4 SD). She had gastricperforation, imperforate anus, intestinal neuronal dysplasia, and

    syndactyly of right third and fourth and left thirdfifth fingers

    during the neonatal period. S

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