Acromicric Dysplasia

A number sign (#) is used with this entry because of evidence that acromicric dysplasia (ACMICD) is caused by heterozygous mutation in exon 41 or 42 of the FBN1 gene (134797) on chromosome 15q21.

Description

Acromicric dysplasia is an autosomal dominant disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have distinct facial features, including round face, well-defined eyebrows, long eyelashes, bulbous nose with anteverted nostrils, long and prominent philtrum, and thick lips with a small mouth. Other characteristic features include hoarse voice and pseudomuscular build, and there are distinct skeletal features as well, including an internal notch of the femoral head, internal notch of the second metacarpal, and external notch of the fifth metacarpal (summary by Le Goff et al., 2011).

Allelic disorders with overlapping skeletal and joint features include geleophysic dysplasia-2 (GPHYSD2; 614185) and the autosomal dominant form of Weill-Marchesani syndrome (608328).

Clinical Features

Maroteaux et al. (1986) described and named a 'new' entity on the basis of 6 patients. Features were mild facial anomalies, markedly shortened hands and feet, and growth retardation that was severe in most. The metacarpals and phalanges were short and stubby; the proximal portion of the second metacarpal showed a notch on its radial side and the fifth metacarpal had a notch on its ulnar side. Similar histologic changes were found in biopsy of the proximal tibial growth cartilage in 2 cases: disorganization of the growth zone with islands of cells and abnormal arrangement of collagen. Both sexes were affected. All 6 cases were sporadic (with normal parental age and no parental consanguinity). In an addendum, Maroteaux et al. (1986) stated that they had observed acromicric dysplasia in mother and son.

Faivre et al. (2001) reported a series of 22 patients, 10 male and 12 female, with acromicric dysplasia. Length at birth was normal, but height fell progressively off the centiles postnatally; mean adult height was 130 cm. Intelligence was normal. Mild dysmorphic features were noted and became less obvious in adults. Other occasional features included well developed muscles, hoarse voice, generalized joint limitation in some patients, frequent ear, tracheal, and respiratory complications, and spine abnormalities. Apart from short metacarpals and phalanges, internal notch of the second metacarpal, external notch of the fifth metacarpal, and internal notch of the femoral heads, there were no major x-ray abnormalities. The condition appeared to be sporadic in 16 cases, but vertical transmission was seen in 3 families, consistent with an autosomal dominant mode of inheritance.

Inheritance

Le Goff et al. (2011) demonstrated that acromicric dysplasia is an autosomal dominant disorder.

Molecular Genetics

In 10 patients with acromicric dysplasia, Le Goff et al. (2011) performed exome sequencing followed by candidate gene analysis and identified heterozygosity for 9 different mutations in the FBN1 gene (see, e.g., 134797.0055, 134797.0057, and 134797.0059-134797.0061). Two of the mutations were also found in heterozygosity in patients with geleophysic dysplasia-2 (GPHYSD2), a disorder with similar skeletal, joint, and skin features but with cardiac involvement often leading to early death. Le Goff et al. (2011) concluded that geleophysic dysplasia and acromicric dysplasia are clinically distinct but allelic conditions.

Passarge et al. (2016) stated that all FBN1 mutations resulting in ACMICD or GPHYSD2 have been found in exon 41 or 42. These exons encode the TGF-beta-binding protein-like domain-5 (TB5) (Le Goff et al., 2011).