Mandibuloacral dysplasia (MAD), a rare autosomal recessive disorder is characterized by progressive skeletal abnormalities such as delayed closure of cranial sutures,mandibular hypoplasia leading to dental crowding, clavicular hypoplasia, resorption of terminal phalanges (tips of the fingers and toes) called acro-osteolysis. These patients usually have a small face with beaked nose, a high-pitched voice, stiff joints, and mottled pigmentation of the skin . Some patients present with progeroid (premature aging) features such as sparse, brittle hair, early loss of hair and sclerodermatous (stiff and parched) skin. About 40 patients have been described in the literature, of which nearly half have abnormalities in body fat distribution. It is however likely that lipodystrophy in patients with mandibuloacral dysplasia is under-reported. In our experience, there are two patterns of lipodystrophy associated with this condition: Type A characterized by loss of fat from the upper and lower extremities with normal or slight excess in the neck and truncal regions and type B characterized by generalized loss of subcutaneous fat involving face, trunk and extremities. Both types of lipodystrophy are associated with resistance to the action of hormone insulin, diabetes and high levels of blood lipids. Growth retardation and short adult height are commonly associated with this syndrome.

Genetic Basis

Mutations in Lamin A/C and ZMPSTE24 which is involved in the post-translational proteolytic cleavage of prelamin A to form mature lamin A have been reported in patients with mandibuloacral dysplasia. Patients with MAD and type A (partial)lipodystrophy have mutations in lamin A/C gene, while ZMPSTE24 mutations have been noted in patients with MAD and type B (generalized)lipodystrophy.

Initially, we had reported compound heterozygous mutations in ZMPSTE24 gene in a Belgian woman who had severe MAD with type B lipodystrophy. Subsequently,in collaboration with other groups, we have reported 3 other patients with mutations in the same gene. Some patients with MAD due to ZMPSTE24 mutations have been observed to have focal segmental glomerulosclerosis. Complete loss of ZMPSTE24 protein  function causes autosomal recessive “Restrictive dermopathy” charactersied by intra-uterine growth retardation, tight and rigid skin with prominent superficial vessels, characteristic facial features, generalized joint contractures, enlarged fontanelle, dysplasia of clavicles, respiratory insufficiency and an enlarged placenta with short umbilical cord.

Some patients with mandibuloacral dysplasia have no apparent alterations in either the LMNA or ZMPSTE24 gene, suggesting the existence of other as yet unmapped loci for this disorder.

References

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