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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,5Dong-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
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. 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.
2532 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
�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.
2534 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
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.
REFERENCES
Ahrens W, Hiort O, Staedt P, Kirschner T, Marschke C, Kruse K. 2001.Analysis of the GNAS1 gene in Albright’s hereditary osteodystrophy. JClin Endocrinol Metab 86:4630–4634.
Bellini F, Bardare M. 1966. On a case of peripheral dysostosis. MinervaPediatr 18:106–110.
Caffey J. 1970. Traumatic cupping of themetaphyses of growing bones. AmJ Roentgenol Radium Ther Nucl Med 108:451–460.
Camera G, Stella G, Camera A. 1994. New X linked spondyloepimetaphy-seal dysplasia: Report on eight affected males in the same family. J MedGenet 31:371–376.
Cho TJ, Choi IH, Chung CY, YooWJ, Yang SW. 2005. Humerus varus in apatient with pseudohypoparathyroidism. J Korean Med Sci 20:158–161.
CohenML, Donnell GN. 1960. Pseudohypoparathyroidism with hypothy-roidism. A case report and review of literature. J Pediatr 56:369–382.
Damry N, Schurmans T, Perlmutter N. 1993. MRI evaluation and follow-up of bone necrosis after meningococcal infection and disseminatedintravascular coagulation. Pediatr Radiol 23:429–431.
EddyMC, JanDeBeur SM,YandowSM,McAlisterWH, Shore EM,KaplanFS, Whyte MP, Levine MA. 2000. Deficiency of the alpha-subunit of thestimulatory G protein and severe extraskeletal ossification. J BoneMinerRes 15:2074–2083.
Hall C, Nishimura G, Kim O-H, Wilson L, Johnson D, Offiah A. 2013.Metaphyseal acroscypho deformity due to pseudohypoparathyroidismandacrodysostosis. International SkeletalDysplasia Society 11thBiennialMeeting. Bologna, Italy. p 25.
Hoeffel JC, Lascombes P, Mainard L, Durup de Baleine D. 1993. Coneepiphysis of the knee and scurvy. Eur J Pediatr Surg 3:186–189.
Kozlowski K, Beemer F, Lipson A, Bellemore M. 1995. Metaphysealdysplasia-Bellini type. Report of two cases. Radiol Med 89:330–333.
Linglart A, Fryssira H, Hiort O, Holterhus PM, Perez de Nanclares G,Argente J, Heinrichs C, Kuechler A, Mantovani G, Leheup B, Wicart P,Chassot V, Schmidt D, Rubio-Cabezas O, Richter-Unruh A, Berrade S,Pereda A, Boros E, Munoz-Calvo MT, Castori M, Gunes Y, Bertrand G,Bougneres P, Clauser E, Silve C. 2012. PRKAR1A and PDE4Dmutationscause acrodysostosis but twodistinct syndromeswith orwithoutGPCR-signaling hormone resistance. J Clin Endocrinol Metab 97:E2328–E2338.
LinglartA,MenguyC,CouvineauA,AuzanC,GunesY,CancelM,Motte E,Pinto G, Chanson P, Bougneres P, Clauser E, Silve C. 2011. RecurrentPRKAR1Amutation in acrodysostosis with hormone resistance. N Engl JMed 364:2218–2226.
Michot C, Goff CL, Alanay Y, Baujat G, Goldenberg A, Isidor B, KayserilrH, Merrer ML, Simon M, Cormier-Daire V. 2013. Clinical and molec-ular review of 26 cases with acrodysostosis or acroscyphodysplasia:Phenotypic spectrum of PDE4D and PRKAR1A mutations. Interna-tional Skeletal Dysplasia Society 11th Biennial Meeting. Bologna, Italy.p 50.
Mitsui T, Nagasaki K, Takagi M, Narumi S, Ishii T, Hasegawa T. 2012. Afamily of pseudohypoparathyroidism type Ia with an 850-kb submicro-scopic deletion encompassing the whole GNAS locus. Am J Med GenetPart A 158A:261–264.
Nishimura G, Mugishima H, Hirao J, Yamato M. 1997. Generalizedmetaphyseal modification with cone-shaped epiphyses following long-term administration of 13-cis-retinoic acid. Eur J Pediatr 156:432–435.
Spranger J, Mundlos S, Muntefering H. 1993. Spondylo-scypho-dyspla.Proceedings of the Greenwood Genetic Center. pp 74–75.
Verloes A, Le Merrer M, Farriaux JP, Maroteaux P. 1991. Metaphysealacroscyphodysplasia. Clin Genet 39:362–369.
SUPPORTING INFORMATION
Additional supporting information may be found in the online
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