Desbuquois dysplasia is a rare autosomal recessive chondrodysplasia
characterized by markedly short stature of prenatal onset, joint laxity,
facial dysmorphism including round face, prominent bulging eyes and
midface hypoplasia.
The radiological findings include a ‘Swedish key’
appearance of the proximal femur, advanced carpal and tarsal bone age and
typical hand changes consisting in an extra o...
Desbuquois dysplasia is a rare autosomal recessive chondrodysplasia
characterized by markedly short stature of prenatal onset, joint laxity,
facial dysmorphism including round face, prominent bulging eyes and
midface hypoplasia.
The radiological findings include a ‘Swedish key’
appearance of the proximal femur, advanced carpal and tarsal bone age and
typical hand changes consisting in an extra ossification center distal to
the second metacarpal, delta phalanx, bifid distal phalanx of the thumb,
and phalangeal dislocations.[1-3] However, those typical hand anomalies are
only observed in a third to a half of all Desbuquois patients.[3-4] We have recently reported linkage of a Desbuquois dysplasia disease gene to
chromosome 17q25.3 in a group of patients with typical hand
abnormalities.[5]
Here, we report on the exclusion of the 17q25.3 locus in
three inbred Desbuquois families without typical hand abnormalities. The
families originate from Turkey, Asia and Morocco. Two out of the three
families had been previously reported.[3,6] Their main clinical and
radiological features are summarized in Table 1 (see below).
All affected individuals
fulfilled the criteria for Desbuquois dysplasia, namely short stature of
prenatal onset, joint laxity, specific facial dysmorphism (see Figure 1), a
‘Swedish key’ appearance of the proximal femur and advanced carpal and
tarsal bone age. None of the patients presented any typical hand changes
(absence of extra ossification center distal to the second metacarpal,
absence of delta phalanx or bifid distal phalanx of the thumb, see Figure 2a).
Informed consent and blood samples were obtained from the probant and
other family members when available. Genomic DNA was purified from
peripheral blood leukocytes according to standard techniques.
Microsatellite DNA markers from the 17q25.3 region were used at an average
spacing of 2 cM and were chosen from the Généthon map. PCR analyses were
performed using a single set of primers in each amplification reaction.
The homozygosity mapping strategy was based on the assumption that
affected individuals of the same kindred are homozygous by descent.[7] The
three affected individuals from families 1-3 were heterozygous for the
17q25.3 region (see Figure 3). These results allow us to exclude this region
as the disease locus in Desbuquois families with no hand anomalies and
demonstrate a genetic heterogeneity. Reviewing the 6 sibship reported in
the literature with Desbuquois dysplasia,[1,2,8] we found a complete
intrafamilial concordance regarding the presence or absence of typical
hand anomalies. Indeed, those anomalies were present in all individuals
within the 2 sibships reported by Puissan and in the 3 sibships reported
by Shohat.[8] Moreover, they were absent in the sibpair reported by
Desbuquois. Those findings together with our molecular results suggests
that the presence or absence of hands anomalies define two distinct
entities within Desbuquois dysplasia. These results emphasise the
importance of defining subgroups prior to any linkage analyses. Additional
families will be necessary to confirm this result.
Figure 1 [View Figure 1]
Clinical presentation of patient 1 at age 1 and age 11.
Note typical facial dysmorphism (round and flat face, prominent bulging eyes and midface hypoplasia), prominent sternum, micromelia and brachydactyly.
Figure 2 [View Figure 2] (a,b) X-rays of the hands of patient 2 (a) and 3 (b), respectively at age
5 years and 15 days. Note the advanced bone age and the generalised
brachydactyly but the absence of typical hand changes (ie extra
ossification center distal to the second metacarpal, delta phalanx, bifid
distal phalanx of the thumb.) (c) X-rays of the pelvis in patient 2 at 6 years of age. Note the typical
'Swedish key' appearance of the proximal femur.
Figure 3 [View Figure 3]
Pedigrees and haplotypes of the 17q25.3 region in families
1-3. The microsatellite polymorphic markers were placed according to the
Généthon and the Human Genome working Draft databases, from D17S802 to
D17S784, centromere to telomere. Genetic intervals between following
markers were respectively of 4.1, 1.7, 1.4, 2.3 and 0 cM. Two additional
microsatellite DNA markers were chosen on clones AC016182 and AC099804
between D17S802 and D17S1847 in order to establish heterozygosity for the
17q25.3 region in family 1.
References
(1) Desbuquois G, Grenier B, Michel J, Rossignol C. Nanisme
chondrodystrophique avec ossification anarchique et polymalformations chez
deux sœurs. Arch Fr Pediatr 1966; 23: 573-587.
(2) Puissan C, Maroteaux P, Castroviejo I, Risbourg B. Dysplasie osseuse
avec nanisme et altérations squelettiques diffuses. Six observations. Arch
Fr Pediatr 1975;32:541-550.
(3) Gillessen-Kaesbach G, Meinecke P, Ausems MGEM, Nöthen M, Albrecht B,
Beemer FA, Zerres K. Desbuquois syndrome: three further cases and review
of the literature. Clin Dysmorphol 1995;4:136-144.
(4) Faivre L, Cormier-Daire V, Eliot A, Field F, Munnich A, Maroteaux P, Le
Merrer M, Lachman R. Desbuquois dysplasia, a reevaluation with abnormal
and “ normal ” hands : Radiographic manifestations. Am J Med Genet; in
press.
(5) Faivre L, Le Merrer M, Al Gazali LI, Aussems MGEM, Bitoun P, Munnich A,
Cormier-Daire V. Homozygosity mapping of a Desbuquois dysplasia locus to
chromosome 17q25.3. J Med Genet 2003;40:282-284.
(6) Le Merrer M, Young ID, Stanescu V, Maroteaux P. Desbuquois syndrome. Eur
J Pediatr 1991;150:793-796.
(7) Lander ES, Botstein D. Homozygosity mapping: a way to map human
recessive traits with the DNA of inbred children. Science 1987;236:1567-1570.
(8) Shohat M, Lachman R, Gruber HE, Hsia YE, Golbus MS, Witt DR, Bodell A,
Bryke CR, Hogge WA, Rimoin DL. Desbuquois syndrome: clinical,
radiographic, and morphologic characterization. Am J Med Genet 1994;52:9-18.
Dear Editor
Desbuquois dysplasia is a rare autosomal recessive chondrodysplasia characterized by markedly short stature of prenatal onset, joint laxity, facial dysmorphism including round face, prominent bulging eyes and midface hypoplasia.
The radiological findings include a ‘Swedish key’ appearance of the proximal femur, advanced carpal and tarsal bone age and typical hand changes consisting in an extra o...
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