Lipodystrophy, Partial, Acquired, Susceptibility To

A number sign (#) is used with this entry because of evidence that susceptibility to the development of acquired partial lipodystrophy (APLD) can be conferred in some cases by heterozygous mutation in the gene encoding the nuclear lamina protein lamin B2 (LMNB2; 150341) on chromosome 19p13.

Description

Acquired partial lipodystrophy is characterized clinically by the gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in the 'cephalocaudal' sequence, sparing the lower extremities (summary by Misra et al., 2004). The disorder is not inherited in a classic mendelian pattern; it rather represents a phenotype with a complex etiology. Affected individuals may have genetic susceptibility factors that require the additional presence of environmental factors or acquired disorders to be expressed (summary by Hegele et al., 2006). Most cases are sporadic, family history is negative, and females are more often affected than males (ratio, 4:1).

There is an association between APLD and autoimmune diseases (Misra and Garg, 2003; Misra et al., 2004), and a subset of patients have APLD associated with low serum complement component C3 and the autoantibody C3 nephritic factor, with or without membranoproliferative glomerulonephritis (APLDC3; 613913).

Acquired partial lipodystrophy is distinct from inherited forms of partial lipodystrophy, which are metabolic disorders that show clear mendelian inheritance (see, e.g., FPLD1, 608600).

Clinical Features

Early reports of this disorder include those of Barraquer (1907), Simons (1911), and Barraquer-Ferre (1935). Other early descriptions were published by Langhof and Zabel (1960) and Jeune et al. (1965).

Quecedo et al. (1996) reported 2 unrelated patients in whom partial lipodystrophy was associated with juvenile dermatomyositis. Other features in both patients included steatohepatitis, insulin resistance, and hypertrichosis. Renal function and complement levels were normal in both patients.

Ferrarini et al. (2004) reported 2 unrelated girls with Barraquer-Simons syndrome. Both had onset in late childhood of progressive loss of subcutaneous facial fat as an isolated finding. Renal function and C3 levels were normal.

Hegele et al. (2006) reported 4 unrelated patients with partial lipodystrophy without low serum C3 and without renal disease. Onset of fat loss ranged between 5 and 17 years. All had dyslipidemia, 3 had hypertension, and 3 had diabetes mellitus. One patient had evidence of autoimmune disease, manifest as dermatomyositis and alopecia. Two patients had polycystic ovary disease and hirsutism.

Gao et al. (2012) reported a 26-year-old Chinese woman with APLD. The patient had symmetric loss of subcutaneous fat from the face and upper part of the body beginning around age 14. Fat on the lower body was preserved. As a young adult, she had fatty liver, increased triglycerides, and mild metabolic disorder with increased insulin. She also developed early menopause with decreasing estrogen levels. There was no family history of a similar disorder.

Inheritance

Acquired partial lipodystrophy is not an inherited disorder in the classic mendelian sense; it rather represents a phenotype with a complex etiology (summary by Hegele et al., 2006).

Molecular Genetics

Susceptibility Alleles

Hegele et al. (2006) used a candidate-gene approach to find disease-associated mutations in APLD. Since structural abnormalities in the LMNA gene (150330) cause familial partial lipodystrophy type 2 (151660), the authors considered it possible that there are mutations in other genes encoding related nuclear envelope proteins. They demonstrated 3 variations in the LMNB2 gene (150341.0001-150341.0003) in 4 of 9 unrelated APLD patients. These variants were more common among patients compared to controls, suggesting that they conferred susceptibility to the development of APLD. None of the patients had a family history of the disorder. Three patients had diabetes mellitus, 1 had dermatomyositis and alopecia areata, and 2 had polycystic ovary disease. All had normal C3 levels and absence of the C3 nephritic factor, and none had renal disease.

In a 26-year-old Chinese woman with APLD, Gao et al. (2012) identified a de novo heterozygous missense mutation in the LMNB2 gene (Y232H; 150341.0004). Functional studies of the variant were not performed.