Acromicric dysplasia (ACMICD)

Geleophysic dysplasia 1, geleophysic dysplasia 2 and acromicric dysplasia

Geleophysic dysplasia is a genetically heterogeneous disorder caused by autosomal recessive mutations in the ADAMTSL2 gene (GPHYSD1; MIM 231050) or autosomal dominant mutations in exons 41 and 42 of the FBN1 gene (GPHYSD2; MIM 614185).  Typical findings in GPHYSD1 and GPHYSD2  include: mild facial abnormalities consisting of upturned corners of the mouth, a depressed nasal bridge and a flat, long philtrum, progressive growth retardation resulting in short stature, shortened tubular bones, small hands and feet, talipes equinovarus, restricted joint mobility, stenosis of cardiac valves, thick skin and hepatomegaly. Tracheal stenosis can result in respiratory insufficiency.  Death often occurs before 5 years of age.  Although few differences are noted between GPHYSD1 and GPHYSD2, a broad nasal bridge, narrow palpebral fissures and tip-toe walking have been more consistently observed in GPHYSD1.

ADAMTSL2 interacts with latent transforming growth factor β binding protein-1 (LTBP1).  LTBP1 in turn plays a critical role in the storage and release of latent transforming growth factor β (TGFB) in the extracellular matrix.  Mutations in ADAMTSL2 are suspected to result in increased bioavailability of TGFB and activation of various pathways. Exons 41 and 42 of FBN1 encode TGFB-binding protein-like domain 5.  The TGFB-binding protein-like domains of FBN1 are implicated in transforming growth factor signaling pathways.

Acromicric dysplasia (ACMICD; MIM 102370) is an autosomal dominant disorder caused by mutations in exons 41 and 42 of the FBN1 gene.  ACMICD shares many of the characteristic of geleophysic dysplasia including progressive growth retardation resulting in severe short stature, short hands and feet, generalized joint limitation and skin thickening.  Mild, but distinctive facial anomalies are a round face, well defined eyebrows with long eyelashes, a bulbous nose with anteverted nostrils, a long and prominent philtrum and thick lips with a small mouth. Some distinctive skeletal features have been reported to include notching of the femoral head, the second metacarpal and the fifth metacarpal. Other findings may include spine abnormalities, cone shaped epiphyses, delayed bone age, hoarse voice, and respiratory, tracheal and ear complications.  Acromicric dysplasia is allelic to Marfan syndrome, autosomal dominant Weill-Marchesani syndrome and autosomal dominant geleophysic dysplasia 2.