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RESEARCH ARTICLE

Acroscyphodysplasia 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 Children’s Hospital NHS Foundation Trust, Sheffield, United Kingdom5Sheffield Clinical Genetics Service, Sheffield Children’s 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 Children’s Medical Center, Tokyo, Japan

Manuscript Received: 15 March 2014; Manuscript Accepted: 3 May 2014

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.�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.36669

Acroscyphodysplasia (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”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 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-shaped

2014 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 A

ing 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 Albright’s 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 þ3.5 Round face, stubby dig

subcutaneous calcifi

short stature, obesit

intellectual impairme

bilateral patellar

dislocation

2 Female, 7 years,

Korean

�0.5 þ1.5 Stubby digits, short sta

intellectual 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, nasal

hypoplasia, 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 weight

2,360 g (�2.0 SD). She had a history of delay in gross motor

development, 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; þ3.5 SD), patellar dislocation, and intellectual

Findings 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


knees

PDE4D, T224I

ture,

Normal thyroid and

parathyroid

function

Severe brachydactyly,

calvarial thickening, severe


knees and shoulders

PDE4D, T224I

ental

ess,

ive

Normal thyroid and

parathyroid

function


moderate scypho-

deformity of the knees and

shoulders

PDE4D, I333T

sal

thic

Normal thyroid and

parathyroid

function



knees

PDE4D, A227S

MITSUI ET AL. 2531

impairment. 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: 10–65), 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 gastric

perforation, imperforate anus, intestinal neuronal dysplasia, and

syndactyly of right third and fourth and left third–fifth fingers

during the neonatal period. She had borderline hypothyroidism on

the neonatal screening of (fT4 0.8 ng/dl, TSH 1.39mIU/ml). PTH

resistance (Ca 8.9mg/dl, IP 0.6mg/dl, and intact PTH 132 pg/ml)

was suspected in the early childhood based on the history of short

stature, severe brachydactyly, and intellectual impairment. At age

4 years and 9 months, her height was 95 cm (�2.5 SD) and weight

20.6 kg (þ1.0 SD). She had persistent intellectual impairment,

sluggish speech, and awkward movement. At age 71/2 years, her

height was 116.7 cm (�0.5 SD) and weight was 30.1 kg (þ1.5 SD).

FIG. 1. Photographs of patients with pseudohypoparathyroidism (PHP) o

B1), Patient 2 at the age of 4 years (A2 and B2), Patient 3 at the age o

B4), and Patient 5 at the age of 9 months (A5 and B5). Typical acrodyso

in A3–A5. Generalized and extremely short fingers are demonstrated in B

The affected mother had mild brachydactyly and short stature

(138 cm; <�2.0 SD).

Patient 3A Philipino girl was the first child of a healthy nonconsanguineous

couple. She was born at 42 weeks of gestation. Her birth length was

55 cm (þ2.4 SD) and birth weight 2,400 g (�2.0 SD). She had a

history of gross motor delay, and she only started crawling at

14 months. At the age of 3 years, she was noted to have bow

legs, brachydactyly, and facial dysmorphism including a hypoplas-

tic nasal root, depressed nasal tip, short philtrum, downturned

mouth, and iris heterochromia. Laboratory examination showed

normal thyroid function and compensated PTH resistance (PTH

170 pg/ml, normal serum Ca and IP level, 25-hydroxy-vitamin D

44.6 ng/ml: optimum level, 20–80).

Patient 4AMalaysian Chinese girl was born to a nonconsanguineous couple,

with a birth lengthwas of 47.0 cm (�1.0 SD), birthweight of 2,500 g

(�1.8 SD), and head circumference of 32.0 cm (between �1.5 and

r acrodysostosis type 2. Patient 1 at the age of 37 months (A1 and

f 15 months (A3 and B3), Patient 4 at the age of 15 years (A4 and

stosis features including nasal and maxillary hypoplasia are shown

1–B4.


�2.0 SD). Nasal hypoplasia, short stubby fingers, grayish eyes, and

brown hair were noted at birth. Both parents and two other siblings

(including one female) were all well, without any dysmorphic

features. At 4 months of age, she was extensively investigated for

chronic diarrhea, which started at 1 month of age, with failure to

thrive (weightof 3.94 kg,<�2.0 SD, andheight of 57 cm,�1.5 SD),

and oculo-cutaneous albinism. The diagnosis of Chediak Higashi

was ruled out, and duodenal biopsy showed non-specific inflam-

mation with partial villous atrophy, suggestive of post-infective or

cow’s milk intolerance. Chromosome analysis, immunological

blood tests, rectal biopsy, and barium enema performed around

the same time were all normal. Her subsequent growth and devel-

opment were slow and complicated by recurrent ear infection,

although the diarrhea had resolved. Tibia vara was recorded at age

5 years, and by 8 years of age, she had developed contralateral limb

length discrepancy. At the age of 15 years, she was short (102.6 cm,

�8.8 SD) and small in size (36.5 kg,�2.0 SD). The right upper limb

was shorter by 11 cm, whereas left leg was shorter by 4 cm. She also

hadmild intellectual impairment. Laboratory examination showed

intact PTH and TSH levels (Ca 10.1mg/dl, IP 3.9mg/dl, and PTH

45 pg/ml, fT4 1.32 ng/dl, TSH 3.02mIU/ml).

Patient 5A Japanese girl was born to a healthy nonconsanguineous couple at

35 weeks of gestation. Her birth length was 35 cm (�6.1 SD) and

weight 1,240 g (�4.3 SD). She had dysmorphic features which

included severe brachydactyly and nasal hypoplasia. She was on

nasal-gastric tube feeding because of failure to thrive, feeding

difficulty, muscular weakness, and repeated apneas. She was on

home oxygen therapy due to hypotonia and periodic respiration.

Biochemical and endocrine studies did not show any abnormality.

At 6 months of age, she had developmental delay, and developed

frequent convulsions. At 9 months, she presented with cardiopul-

monary arrest and is under treatment.

Radiological FindingsThe radiological findings are summarized in the Table I and

Figure 2. Scypho-deformity of the knee was severe in Patients 1,

3, and 4 and moderate in Patient 5. Patient 5 is still young, and she

may developmore severe deformity in later life. The knee deformity

was mild and asymmetric in Patient 2. Patients 1, 4, and 5 had

scypho-deformity of the proximal humerus. All patients showed

generalized brachydactyly with advanced carpal skeletal age. The

mothers of Patients 1 and 2 had only mild brachydactyly with no

scypho-deformity. Additional images of CT or MRI scan of the

knees in Patients 1 and 3 are shown in Supplementary Figure S1 (see

supporting information online).

Mutation AnalysisWe obtained written informed consent for molecular studies from

parents of the probands. We extracted genomic DNA from periph-

eral lymphocytes of patients or their parents using a standard

technique (Gentra system; QIAGEN, Hilden, Germany). We per-

formed direct sequencing for all coding exons and flanking introns

of GNAS, PRKAR1A, and PDE4D with an automated sequencer

ABI3130xl (Applied Biosystems, Foster City, CA). The PCR con-

ditions and primer sequences are available upon request.

We found heterozygous mutations in either GNAS or PDE4D

gene in all the five patients, including one novel mutation

(c.55C>T; p.Q19X) and one recurrent mutation (c.691C>T;

p.R231C) in the GNAS gene both of which were inherited from

theirmothers, and twonovel de novomutations in thePDE4D gene

(c.671C>T; p.T224I and c.998T>C; p.I333T) (Table I).

DISCUSSION

Acroscyphodysplasia is caused by mutations in either the GNAS or

PDE4D gene. GNAS and PDE4D encode key regulators of the

cAMP/PKA signal transduction pathway, Gs alpha and cAMP-

specific 30,50-cyclic phosphodiesterase 4D, respectively. Another

major regulator in this pathway is cAMP-dependent protein kinase

type I-alpha regulatory subunit encoded by PRKAR1A that is

responsible for acrodysostosis type 1 (MIM101800) [Linglart

et al., 2011]. Both cAMP-specific 30,50-cyclic phosphodiesterase

4D and cAMP-dependent protein kinase type I-alpha regulatory

subunit act downstreamofGs alpha. Interestingly, there are skeletal

phenotypic overlaps among patients with mutation in these cAMP

signaling pathway components (e.g., metacarpal abnormalities).

However, a broad phenotypic variation has also been reported

[Linglart et al., 2012]. In our patients with acroscyphodysplasia, we

identified mutations in the genes associated with cAMP-signaling

pathway. All the patients were diagnosed as either acrodysostosis or

PHP. Thus, acroscyphodysplasia is not a disease entity rather a

component manifestation of PHP or acrodysostosis type 2.

Premature fusion of the growth plates is likely to be responsible

for both the scypho-deformity and brachydactyly. It is known that

the PTH/PTHrP receptor signal acts on chondrocytes of the growth

plate as an inhibitor of terminal differentiation [Linglart et al.,

2012]. Thus, it seems plausible that the unresponsiveness of growth

plate chondrocytes to PTH/PTHrP contributes to early closure of

the growth plates in aGNASmutation. It is tempting to assume that

aPDE4Dmutation creates the same skeletal phenotype through the

same mechanism. It is as yet unexplained why only certain specific

growth plates (in the hands and feet, proximal femoral, tibial, and

proximal humeral) show such a phenomenon. One patient with

PHP has been described with unilateral humeral shortening and

varus deformity and short digits, but without the scypho-deformi-

ties at the knees [Cho et al., 2005].

The correlation between the phenotype of acroscyphodysplasia

and the genotype of GNAS/PDE4D is not yet feasible because of a

small number of cases. In our series, there might be genotype–

phenotype correlation in PDE4D, but not in GNAS. In PDE4D,

identified mutations (T224I and I333T) and previously reported

(A227S) leading to acroscyphodysplasia were located in upstream

conservation regions (UCR) (Supplementary Fig. S2 in supporting

informationonline).On theotherhand, inGNAS,we identifiedone

recurrent (R231;Patient2)andonenonsensenovel (Q19X;Patient1).

Previously reported cases; R231C [Ahrens et al., 2001] and non-

sense mutations of GNAS (Q12X [Eddy et al., 2000] and a GNAS

wholedeletion [Mitsui et al., 2012])didnot showscypho-deformity

of the knee. Even mothers of Patients 1 and 2 did not have any

FIG. 2. Radiographs of the hands (A1–A5), knees (B1–B5), and shoulders (C1, C4, and C5). Patient 1 at the age of 25 months (A1 and C1),

and at the age of 37 months (B1); Patient 2 at the age of 4 years (A2 and B2); Patient 3 at the age of 15 months (A3 and B3); Patient 4 at

the age of 8 years (A4, B4, and C4); and Patient 5 at the age of 6 months (A5, B5, and C5). All patients demonstrated shortening of

metacarpals, metatarsals, and phalanges. Scypho-deformity of the knee was severe in Patients 1, 3, and 4 and moderate in Patient 5.

Scypho-deformity of the proximal humerus was found in Patients 1, 4, and 5.

MITSUI ET AL. 2533

scypho-deformities. Thus, the genotype alone is not enough to lead

to distinctive scypho-deformity. Interestingly, all patients with

acroscyphodysplasia including the previous case [Linglart et al.,

2012] are female. This might be consistent with previous observa-

tions that females with PHP seem to be more severely affected than

males [Cohen and Donnell, 1960]. These findings indicate other

genetic and secondary factors, such as gender difference, mechani-

cal loading, SNP in cAMP pathway, and calcium metabolism

may contribute to the phenotypic variability. It needs further

investigation with more cases to confirm the correlation between

the phenotype and the genotype.

Metaphyseal scypho-deformity at the knees is also seen as a

feature of other congenital or acquired disorders. Thedeformity has

been described as a congenital phenomenon in all patients tricho-

scyphodysplasia with alopecia (MIM609990) [Bellini and

Bardare, 1966], metaphyseal scyphodysplasia without hand in-

volvement (MIM609989) [Kozlowski et al., 1995], XL-SEMD

type Camera (MIM300106) [Camera et al., 1994], and spondylo-

scypho-dysplasia with platyspondyly and brachydactyly [Spranger

et al., 1993] and as an acquired phenomenon in some patients

following neonatal septicemia with meningococcus or pneumo-

coccus [Damry et al., 1993], hypervitaminosis A, adverse effect of

retinoic acid [Nishimura et al., 1997], scurvy [Hoeffel et al., 1993],

or trauma [Caffey, 1970]. The differential diagnosis of GNAS- or

PDE4D-related disorders from others requires the accurate assess-

ment for features of acrodysostosis type 2 (depressed nasal root,

short nose with broad nasal tip, and short philtrum), PHP (round

face, brachydactyly, short stature, obesity, and intellectual im-

pairment), and endocrinological abnormality.

In conclusion, we have delineated metaphyseal acroscyphodys-

plasia as a phenotypic variation of PHP or acrodysostosis type 2;

and elucidated that metaphyseal acroscypho deformity in PHP or

acrodysostosis type 2 is caused by either a GNAS or PDE4D

mutation, respectively.


ACKNOWLEDGMENTS

The authors thank the patients and their parents for their coopera-

tion. The authors are grateful to Prof. Takao Takahashi for fruitful

discussion. This work was supported by the Health Science Re-

search Grant for Research on Applying Health Technology (Jit-

suyoka [Nanbyo]-Ippan-014) from theMinistry of Health, Labour

and Welfare, Japan. The funders had no role in study design, data

collection and analysis, decision to publish, or preparation of the

manuscript.

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