Acroscyphodysplasia as a phenotypic variation of pseudohypoparathyroidism and acrodysostosis type 2

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

(wileyonlinelibrary.com): 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

INTRODUCTION

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

Height

Z score

Weight

Z score Phenotypic feature

1 Female, 4 years,

Japanese

2.0 3.5 Round face, stubby digsubcutaneous calcifi

short stature, obesit

intellectual impairme

bilateral patellar

dislocation

2 Female, 7 years,

Korean

0.5 1.5 Stubby digits, short staintellectual impairme

3 Female, 3 years,

Philipino

NA NA Stubby digits, hypoplas

nasal root, depresse

nasal tip, short philt

down-turned mouth,

heterochromia, tibial

bowing

4 Female, 15 years,

Malaysian

Chinese

8.8 2 Stubby digits, nasalhypoplasia, short sta

unequal leg and arm

lengths, intellectual

impairment

5 Female, 9 months,

Japanese

NA NA Stubby digits, nasal

hypoplasia, developm

delay, muscle weakn

apnea, failure to thr

Previously

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

its,

cation

y,

nt,

PTH resistance, TSH

resistance

Severe brachydactyly, severe

scypho-deformity of the

knees and shoulders

GNAS, Q19X

ture,

nt

PTH resistance, TSH

resistance

Severe brachydactyly, mild

and asymmetric scypho-

deformity of the knees

GNAS, R231C

tic

d

rum,

iris

PTH resistance,

normal thyroid

function

Severe brachydactyly, severe

scypho-deformity of the

knees

PDE4D, T224I

ture,

Normal thyroid and

parathyroid

function

Severe brachydactyly,

calvarial thickening, severe

scypho-deformity of the

knees and shoulders

PDE4D, T224I

ental

ess,

ive

Normal thyroid and

parathyroid

function

Severe brachydactyly,

moderate scypho-

deformity of the knees and

shoulders

PDE4D, I333T

sal

thic

Normal thyroid and

parathyroid

function

Severe brachydactyly,

scypho-deformity of the

knees

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