Lipodystrophy, Familial Partial, Type 3

A number sign (#) is used with this entry because one form of familial partial lipodystrophy (FPLD3) is caused by heterozygous mutation in the PPARG gene (601487) on chromosome 3p25.

For a general phenotypic description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.

Clinical Features

Barroso et al. (1999) reported a 56-year-old female who presented at age 20 with irregular menstrual periods and primary infertility. She later had 2 pregnancies, one of them by assisted conception, that were complicated by gestational diabetes and preeclampsia. She continued to have frank type II diabetes (125853) requiring insulin treatment and severe sustained hypertension. Her son developed severe hypertension and diabetes. Barroso et al. (1999) reported another patient from a different kindred who had been identified at age 15 with primary amenorrhea, hirsutism, acanthosis nigricans, and elevated blood pressure. Her glucose tolerance was initially normal, but with markedly elevated fasting and postprandial insulin levels. By age 17, she had developed type II diabetes and her hypertension required treatment with beta-blockers. In a follow-up study, Savage et al. (2003) found that the patients reported by Barroso et al. (1999) had clinical features of partial lipodystrophy characterized by loss of subcutaneous limb and gluteal fat with preservation of visceral and subcutaneous abdominal fat. There was normal or mildly decreased facial fat. All patients had fatty infiltration of the liver, with 1 case of cirrhosis. Hyperuricemia was also noted.

Hegele et al. (2002) reported a 3-generation Canadian family in which 4 members had autosomal dominant familial partial lipodystrophy. The proband was a 46-year-old woman of Anglo-Saxon descent in whom the diagnosis of partial lipodystrophy had been based on prominent muscularity of her calves and lower arms, marked atrophy of gluteal fat, and marked centripetal distribution of adipose tissue, with accumulation of subcutaneous facial, neck, suprascapular, and abdominal fat. The same abnormal fat distribution was present in the other 3 affected members of the family and had been present since adolescence in the proband and her daughter, who was 22 years old when clinically diagnosed with FPLD. Clinically, the phenotype was similar to that seen in the Canadian FPLD index probands with missense mutations in LMNA; see 150330.0010. However, differentiating features included the presence of some subcutaneous upper arm fat to the level of the surgical neck of the humerus, no phlebectasia, and less prominent muscularity of the arms and calves. The proband had type II diabetes since age 38. She had a history of irregular menses and had bilateral polycystic ovary disease. She also had hyperinsulinemia and type IV hyperlipoproteinemia. The proband's father was 71 years old. He had prominent muscularity of calves and lower arms due to paucity of subcutaneous fat. He had treated hypertension of 20 years' duration and type II diabetes of 18 years' duration. Despite no history of smoking, he suffered an anterior wall myocardial infarction at age 56. The proband's youngest brother was 39 years old, with prominent muscularity of calves and lower arms. Clinically, there was no hepatosplenomegaly or acanthosis nigricans in any of the subjects. No female subject had hirsutism.

Agarwal and Garg (2002) reported a 64-year-old non-Hispanic Caucasian woman who developed diabetes mellitus and hypertriglyceridemia at age 32 years, and loss of adipose tissue from the extremities and face at age 50 years. She also had hirsutism. Anthropometry and whole body magnetic resonance imaging revealed marked loss of subcutaneous fat, particularly from the extremities, but subcutaneous truncal fat was slightly increased.

Molecular Genetics

In a mother and son and an unrelated patient with insulin-resistant diabetes mellitus, acanthosis nigricans, hypertension, and partial lipodystrophy, Barroso et al. (1999) identified heterozygous mutations in the PPARG gene (see 601487.0007 and 601487.0008).

In affected members of a family with familial partial lipodystrophy, Hegele et al. (2002) identified a heterozygous mutation in the PPARG gene (601487.0012).

In a patient with familial partial lipodystrophy, Agarwal and Garg (2002) identified a heterozygous mutation in the PPARG gene (601487.0013). None of the 4 unaffected family members had the mutation.