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Acrodysplasia severe ossification abnormalities with short stature and fibular hypoplasia

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American Journal of Medical Genetics 84:68–73 (1999)
Acrodysplasia, Severe Ossification Abnormalities
With Short Stature, and Fibular Hypoplasia
Alessandro Castriota-Scanderbeg,1* Leopoldo Zelante,2 Salvatore Masala,1 Paolo Gasparini,2 and
Ralph S. Lachman3
Department of Radiology, Scientific Institute S. Lucia, Rome, Italy
Department of Human Genetics, Scientific Institute CSS, S. Giovanni Rotondo, Italy
Department of Radiology and Pediatrics, UCLA School of Medicine, Los Angeles, California
We present a girl with short stature, growth
hormone neurosecretory dysfunction, severe hypoplastic/aplastic changes of the
bones of the hands and feet with dysharmonic ossification, severely delayed bone
age, microcrania, and fibular hypoplasia.
Parental consanguinity suggests autosomal
recessive inheritance. An additional three
cases [Eiken et al., 1984: Eur J Pediatr 141:
231–235] sharing some of the radiographic
manifestations of this patient have been reported. However, distinctive findings in the
present case seem to outline a separate entity. Am. J. Med. Genet. 84:68–73, 1999.
© 1999 Wiley-Liss, Inc.
KEY WORDS: acrodysplasia; ossification
delay; brachydactyly
The proposita was the first child of healthy, related
parents (first cousins) from southern Italy. Both parents were of normal height, body proportions, and intelligence. The family history was unremarkable. The
girl was born at term after an uneventful pregnancy
and normal delivery. Birth weight was 2,750 g (>10th
centile), birth length 43 cm (<3rd centile), and occipitofrontal circumference (OFC) 32 cm (10th centile).
Physical examination showed mild limb shortness and
a sacral lipoma. A chromosomal study showed a normal
The first radiographic examination at birth (Fig. 1)
demonstrated poorly modeled metaphyses, short
clavicles, epiphyseal ossification delay of the knees,
and fibular hypoplasia. There were increased height
and decreased width of the iliac wings, widened sacrosciatic notches, hypoplastic acetabular roofs, and unos-
*Correspondence to: A. Castriota-Scanderbeg, M.D., Department of Radiology, Scientific Institute S. Lucia, via Ardeatina
306, I-00179 Rome, Italy. E-mail: [email protected]
Received 10 August 1998; Accepted 23 December 1998
© 1999 Wiley-Liss, Inc.
sified pubic bones. The sacral bones showed severely
delayed ossification. There was also severe brachydactyly, with radiologically nonvisible metacarpals and
phalanges. In the feet, the metatarsals were short, and
the phalanges hypoplastic (great toes and 2nd middle
phalanges) or missing (all other phalanges). At 8
months (Fig. 2), there was hypoplasia and flattening of
metacarpals (especially the 4th and 5th), and phalanges (especially the middle 2nd and 4th). The 1st metacarpals, the right 4th metacarpal, and the 5th middle
phalanges were missing. The ossification center of the
talus was hypoplastic, and that of the calcaneus was
duplicated and very hypoplastic. The thoracolumbar
spine was only mildly affected, with rounded vertebral
bodies. The clavicles were mildly hypoplastic. Microcrania was also present. Psychomotor development was
Further clinical evaluation disclosed severe growth
deficiency, with weight and length being 6,700 g (<3rd
centile) and 65 cm (<3rd centile), respectively, at 14
months, and 13,200 g (<3rd centile) and 98 cm (<3rd
centile), respectively, at 6 years. At 7 years the radiographic findings (Fig. 3) included unossified carpal
bones; hypoplastic or absent epiphyseal ossification of
the metacarpals at their normal site with proximal
“epiphyseal” ossification (pseudoepiphyses) of the 2nd
and 3rd metacarpals; absent epiphyseal ossification of
the 5th middle, 1st proximal, and all distal phalanges;
double epiphyses of 2nd, 3rd, and 4th proximal and
middle phalanges; and marked hypoplasia of the first
metacarpals (which appeared ovoid in shape), the 4th
right metacarpal, and the 5th middle phalanges. There
was also angel-shaped configuration of the 2nd middle
phalanges. The complete lack of carpal ossification at
this age made it impossible to establish the girl’s skeletal age. When she was 8 years old, the diagnosis of
growth hormone (GH) neurosecretory dysfunction was
made on the basis of the low nocturnal GH secretion
with abnormal 24-hour GH secretory patterns (responses to pharmacological stimuli were normal). No
other endocrinologic abnormalities were found. A brain
magnetic resonance imaging demonstrated normal pituitary gland and hypothalamus. After 2 years of
therapy with recombinant human GH (at the daily
dose of 15 U/m2/week, administered subcutaneously),
Acrodysplasia, Ossification Delay, Short Stature
Fig. 1. Skeletal radiograph at birth, showing epiphyseal ossification delay at the knee, unossified pubic bones, and fibular hypoplasia (A), ossification
delay of the sacral bones (B), and changes in the hands (C) and feet (D). Continued on the overleaf.
the girl’s height had increased 12 cm (growth velocity
before treatment, 3 cm/year) and ossification had occurred within most of the previously unossified centers
of the hands and feet. At the age of 10 6/12 years (Fig.
4), her height was 124 cm (<3rd centile), weight 24 kg
(3rd centile), OFC 50.5 cm (50th centile), and skeletal
age about 4 years, as measured by the TannerWhitehouse method. The pattern of carpal bone ossifi-
cation was very irregular. Distinctive radiographic
findings at this age included the presence of proximal
and distal epiphyses in the metacarpals (except the
1st), and in the proximal and middle phalanges (except
the 5th middle); ivory pseudoepiphyses (proximal 1st
phalanges, proximal 2nd right phalanx, and middle 3rd
left phalanx); clinodactyly of the 5th digits; fibular hypoplasia; widening and flaring of the proximal hu-
Castriota-Scanderbeg et al.
Fig. 1.
Continued from the overleaf.
merus; and undermodeling and clubbing of the ulnar
shaft. The lower part of the sacrum showed severe ossification delay.
The most striking manifestations of this case are
short stature and changes in the bones of the hands
and feet (acrodysplasia) with severe brachydactyly and
severe ossification delay. Other findings include fibular
hypoplasia, epiphyseal changes at multiple sites, and
characteristic changes of the spine and pelvis.
The brachydactyly seen in the present case is characterized by shortness of metacarpals (especially the
4th and 5th) and phalanges (especially the middle 2nd
and 4th), rudimentary 1st metacarpal and 5th middle
phalanx, and by either shortness or lacking metatarsals and phalanges of the feet. This pattern of malformation does not fit any of the types of brachydactyly
described so far [Bell, 1951; Temtamy and McKusick,
1978], and the hand and foot malformation in this case
appears to be a unique type.
Another remarkable finding in this case was the generalized, severely retarded bone maturation. The satisfactory response achieved in our patient after 2 years
of GH therapy, with an increase in height of 6 cm per
year and acceleration of bone maturation, confirms
that GH neurosecretory dysfunction played a role in
determining bone maturation delay.
Inactivating and activating mutations in the gene
encoding G alpha s protein (GNAS1) have been shown
to cause both skeletal abnormalities and alterations of
GH secretory activity in Albright hereditary osteodystrophy (AHO) [Stirling et al., 1991] and in McCuneAlbright syndrome [Nakagawa et al., 1985]. Interestingly, marked shortness of the 4th and 5th metacarpals, a characteristic aspect of brachydactyly
associated with AHO, was also found in our patient.
However, autosomal dominant inheritance and the
constellation of associated manifestations in AHO, including mental retardation, metabolic derangements,
cataract and ectopic calcifications, unambiguously distinguish this disorder from the condition found in the
present patient. Deletions of 2q37 are associated with a
distinctive syndrome characterized by brachymetacarpalia and mental deficiency [Wilson et al., 1995]. This
syndrome is indistinguishable from AHO except for the
levels of GNAS1, which are normal, unlike in AHO.
Since type E brachydactyly, a condition characterized
by short stature, round facies, and short metacarpals,
is also difficult to distinguish from AHO [Ablow et al.,
1977; Poznanski et al., 1977], it may be that type E
brachydactyly is indeed due to a mutation in the 2q37
region. However, unlike patients with type E brachydactyly, our patient had a normal face, generalized
skeletal abnormalities, including fibular hypoplasia
and changes in the spine and pelvis, and shortness of
metacarpals and phalanges without cone epiphyses.
Changes in the hands similar to those encountered in
our patient can also be observed in acrodysostosis and
Ullrich-Turner syndrome. However, distinct findings
in acrodysostosis are peculiar facies (short nose, open
mouth, and prognathism), mental deficiency, advanced
skeletal maturation, and cone-shaped epiphyses. Ullrich-Turner syndrome or cryptic mosaicism in UllrichTurner syndrome, disorders in which short stature and
brachydactyly are frequent clinical stigmata, were
ruled out by repeated karyotypic studies on peripheral
blood lymphocyte and skin fibroblast cultures.
Eiken et al. [1984] described three brothers, the offspring of consanguineous parents, with radiographic
findings similar to those observed in our patient. In the
youngest of these patients, who underwent careful
clinical and radiographic survey at birth and at 1 year,
the similarities are strikingly evident. They include:
short stature, severe degree of delayed ossification, especially pronounced in the hands, feet, and pelvis, but
involving virtually all bony elements; absent ossifica-
Acrodysplasia, Ossification Delay, Short Stature
Fig. 2. Roentgenogram at 8 months. Several metacarpals and phalanges are short, some others are radiologically not visible (A); hypoplasia of
the talus and calcaneus (B), epiphyseal ossification delay of the knees and
fibular hypoplasia are also evident (C).
Castriota-Scanderbeg et al.
Fig. 3. At 7 years, the carpal bones appear unossified. Epiphyseal abnormalities and variable shortness of the tubular bones are also seen.
Fig. 4. Hand radiograph at 10 years and 6 months shows irregular
carpal bone ossification, shortening of some tubular bones, angel-shaped
phalanges, and ivory pseudoepiphyses. The skeletal age is about 4 years,
according to the Tanner-Whitehouse criteria.
tion of some tubular bones of the hand; absence in the
feet of all but the ossification centers of metatarsals
and phalanges of the great toes, and short fibulae.
However, specific anomalies either in the patients of
Eiken et al. [1984] (cubitus varus/valgus, distal conical
tapering of metacarpals, accessory or duplicated phalanges and metatarsals) or in our patient (shortening of
the 1st, 4th, and 5th metacarpals and of the middle
2nd, 4th, and 5th phalanges, microcrania, and clavicle
hypoplasia) suggest that we are dealing with similar,
but probably different, disorders (Table I). Further-
more, none of their patients was reported to have endocrine abnormalities, although the authors did not
mention if the GH production was assessed after provocative tests and/or during the 24 hours. Interestingly, the oldest boy experienced an “amazingly” accelerated bone maturation in the 2 years following his
first admission (at 12 years of age), similar to that we
TABLE I. Summary of Clinical and Radiographic Manifestations in the Patients of Eiken et al. [1984] and in the Present Patient
Eiken et al.
Clinical and radiographic
Mental development
Endocrine abnormalities
Limited elbow flexion
Painful joints
Parental consanguinity
Short stature
Ossification delay at multiple
skeletal sites
Pelvic abnormalities
Spinal abnormalities
Clavicle hypoplasia
Cubitus varus/valgus
Short fibulae
Short hands and feet
Hypoplastic phalanges of
Hypoplastic phalanges of toes
Metacarpal abnormalities
Metatarsal abnormalities
Duplicated phalanges or
Metaphyseal abnormalities
Patient 1
Patient 2
Patient 3
This report
GH deficiency
Middle, proximal 1st,
4th, 5th
All but 1st distal
Middle 5th, distal
Middle 5th, distal
Middle 2nd, 4th, 5th
Distal tapering
Short 4th
Thumb, 5th
Distal tapering
Short 4th
1st Metatarsal
All but proximal 1st and
middle 2nd
Ovoid 1st, short 4th and 5th
Short all
Short 4th
Acrodysplasia, Ossification Delay, Short Stature
noted in our patient after 2 years of recombinant GH
replacement therapy.
In conclusion, the patient described here displays a
malformation pattern, characterized by severely delayed bone age, acrodysplasia, and short stature, which
seems to outline an entirely new syndrome, probably
autosomal recessive, given parental consanguinity.
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Gigantism associated with McCune-Albright’s syndrome. Horm Metab
Res 17:522–527.
Poznanski AK, Werder EA, Giedion A, Martin A, Shaw H. 1977. The pattern of shortening of the bones of the hand in PHP and PPHP: A comparison with brachydactyly E, Turner syndrome, and acrodysostosis.
Radiology 123:707–718.
Stirling HF, Barr DG, Kelnar CJ. 1991. Familial growth hormone releasing
factor deficiency in pseudopseudohypoparathyroidism. Arch Dis Child
66: 533–535.
Temtamy S, McKusick V. 1978. The genetics of hand malformations. Birth
Defects 3:187–225.
Wilson LC, Leverton K, Oude Luttikhuis MEM, Oley CA, Flint J, Wolstenholme J, Duckett DP, Barrow MA, Leonard JV, Read AP, Trembath
RC. 1995. Brachydactyly and mental retardation: An Albright hereditary osteodystrophy-like syndrome localized to 2q37. Am J Hum Genet
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severa, short, acrodysplasia, hypoplasia, fibular, stature, abnormalities, ossification
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