Clinical Information

Lipodystrophies are rare conditions characterized primarily by the inability to properly store adipose tissue in the absence of nutritional deficit or catabolic state.(1) Lipodystrophies can be genetic (hereditary) or acquired (caused by environmental factors such as illness). The two most common forms of hereditary lipodystrophies are congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPLD), which are named according to the regions of the body they affect.(1)

CGL (also known as Berardinelli-Seip congenital lipodystrophy) is an autosomal recessive condition characterized by generalized absence fat throughout the entire body, generalized muscular appearance, and metabolic complications such as diabetes mellitus and dyslipidemia.(1,2) The prevalence of autosomal recessive CGL is not well-established, with estimates ranging from 1:10,000,000 to 1:25,000 depending on the population being considered.(2) Severe CGL is also a feature of Keppen-Lubinsky syndrome (KPLBS), an extremely rare autosomal dominant condition caused by biallelic, disease-causing variants in the KCNJ6 gene. KPLBS is a syndromic condition characterized by severe generalized lipodystrophy, microcephaly, progeroid appearance, and intellectual disability.(3)

FPLD can be inherited in an autosomal dominant or autosomal recessive manner and is characterized by localized absence of fat in the limbs with possible metabolic complications.(1,4) FPLD can be isolated or can be a feature of a syndromic condition such as autosomal dominant SHORT syndrome (short stature, hyperextensibility of joints, ocular depression, Rieger anomaly, and teething delay) and autosomal recessive Mandibuloacral dysplasia with type B lipodystrophy.(4) The prevalence of FPLD is not known but thought to be rare.(4)

Disease-causing variants in the LMNA gene can lead to autosomal recessive and autosomal dominant forms of lipodystrophies, but variants in this gene are also associated with several autosomal dominant cardiac, connective tissue, and muscular dystrophy phenotypes.(4) Often, lipodystrophy is a single feature of a more syndromic condition when caused by disease-causing LMNA variants.(4)

The FBN1 gene is primarily associated with autosomal dominant Marfan syndrome without features of lipodystrophy. However, literature suggests that specific disease-causing variants in the FBN1 gene may lead to an overlapping phenotype characterized by partial features of Marfan syndrome, progeroid appearance, and clinical features of lipodystrophy.(5)