Syndromic lipodystrophies

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Lipodystrophies associated with various syndromes with multiple clinical defects have also been identified. Most prominent among them are syndromes of mandibu-loacral dysplasia (MAD) and SHORT, an acronym for short stature, hyperextensibility ofjoints and/or inguinal hernia, ocular depression, Reiger anomaly, and teething delays. Although two genetic loci, LMNA (42) and ZMPSTE24 (7) have been identified in MAD, identification of a genetic derangement for SHORT syndrome remains lacking.

Worldwide, only 40 patients with MAD, an autosomal-recessive disorder, have been observed so far. The characteristic features of this syndrome include postnatal resorption of bone in the mandible, clavicles, and terminal phalanges (acro-osteolysis) in addition to AT loss, suggesting a common genetic or metabolic defect affecting both the skeleton and AT (43). In addition, these patients also have short stature, delayed closure of cranial sutures, joint contractures, mottled skin pigmentation, and, more important, features of premature aging.

Two patterns of lipodystrophy have been described in patients with MAD (43). Type A pattern is characterized by partial loss of subcutaneous AT from the extremities, with normal or excess fat over the face and neck. This pattern is similar to the fat loss seen in FPLD patients and, not surprisingly, LMNA mutations have been described in MAD patients with Type A lipodystrophy (42). Type B pattern involves a more generalized loss of subcutaneous fat; these patients have compound, heterozygous mutations in ZMPSTE24, a gene encoding a zinc metalloproteinase, a microsomal protein, that is essential in post-translational modification of prelamin A (7). The detrimental effects of ZMPSTE24 mutations may be caused by either accumulation of prenylated prelamin A or lack of mature lamin A. Some MAD patients have no mutations in either LMNA or ZMPSTE24, suggesting additional, as yet unmapped, loci.

The genetic locus for SHORT and some of the neonatal progeroid syndromes has not been identified. The changes in body AT distribution are also not well defined, mainly because of the rarity of these syndromes. Patients with the autosomal dominant form of SHORT syndrome are described to have lipodystrophy affecting only the face, gluteal region, and elbows (44). Patients with neonatal progeroid syndrome have been described to have generalized lipodystrophy, with sparing of fat over the sacral and gluteal areas (45). There have been no reports of either skinfold measurements or MRI studies in patients with these rare syndromes.

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