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The
acromesomelic dysplasias are disorders in which there is
disproportionate shortening of skeletal elements, predominantly
affecting the middle segments (forearms and forelegs) and distal
segments (hands and feet) of the appendicular skeleton. Among those with
autosomal recessive inheritance, the specific designation 'acromesomelic
dwarfism' was used by Maroteaux et al. (1971) to describe a distinct
phenotype in 3 patients, 2 of whom were sibs. Hunter and Thompson (1976)
described a patient whose involvement also followed an acromesomelic
pattern and noted that their patient's features were different from
those reported by Maroteaux et al. (1971) but clinically similar to 2
sisters reported by Grebe (1952). Langer et al. (1989) concluded that
the acromesomelic dysplasia described by Hunter and Thompson (1976)
(AMDH; 201250) and that reported by Grebe
(1952) (AMDG; 200700) are radiologically related but not identical; this
relatedness was confirmed at the molecular genetic level by the
demonstration that the 2 disorders are caused by allelic mutations in
the cartilage-derived morphogenetic protein-1 gene (CDMP1; 601146), on human chromosome 20. Individuals
with either AMDH or AMDG have normal axial skeletons and missing or
fused skeletal elements within the hands and feet. This contrasts with
the radiologic features of acromesomelic dysplasia Maroteaux type
(AMDM), in which all skeletal elements are present but show abnormal
rates of linear growth (Langer and Garrett, 1980). In addition, axial
skeletal involvement occurs in individuals with AMDM, characterized by
wedging of vertebral bodies, with the dorsal margins being shorter than
the ventral margins. These clinical differences, which serve to
distinguish AMDM from AMDH and AMDG, suggested that AMDM is also
genetically distinct. Kant et al. (1998) demonstrated that this is the
case by showing that AMDM maps to 9p13-q12, not chromosome 20. A peak
lod score of 5.1 at a recombination fraction of 0.0 was obtained with
fully informative markers on chromosome 9. In 3 of the 4 families
studied, the affected offspring were products of consanguineous
marriages; if it was assumed that these affected offspring were
homozygous by descent for the region containing the AMDM locus, a 6.9-cM
AMDM candidate interval could be defined by markers D9S1853 and D9S1874.
Faivre et al. (2000) demonstrated linkage to 9p13-q12 in 4
consanguineous families with AMDM, but excluded this locus in a fifth
family with a mild form of AMDM with less marked shortening of the
extremities and almost normal vertebrae. Faivre et al. (2000) suggested
that genetic heterogeneity accounts for the variable severity of AMDM.
Kant et al. (1998) pointed out that familial hypomagnesemia (HOMG;
602014) maps to 9q12-q22.2, roughly the same region as AMDM.
Furthermore, Minty and Hall (1993) reported 2 sibs of consanguineous
parents who had both AMDM and familial hypomagnesemia.
St. Helena is an island in the South Atlantic that has a population
of approximately 5,500 persons derived from a small number of founders
(Shine, 1970; Eickhoff and Beighton, 1985). Shine (1970) described a
skeletal dysplasia in 6 relatives with dwarfism and brachydactyly. The
phenotype of 'pseudobrachydactylous dwarfism' was proposed, with
autosomal recessive inheritance. When later studied by Eickhoff and
Beighton (1985), a tentative diagnosis of pseudoachondroplasia was made,
although this could not be substantiated due to the unavailability of
radiographs. Ianakiev et al. (2000) restudied the family and on clinical
and radiographic grounds arrived at the diagnosis of acromesomelic
dysplasia. By homozygosity mapping, they assigned the responsible gene
to an approximately 5-cM region in the pericentromeric region of
chromosome 9, where the Maroteaux form of AMD had been mapped;
multipoint analysis generated a maximum lod score of 2.85. This study
raised the possibility that the St. Helena skeletal dysplasia is allelic
to the Maroteaux form of acromesomelic dysplasia.
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