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: thaseg@a6.keio.jp
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
