Endocrine Abstracts

Introduction: Congenital generalized lipodystrophy (CGL) is a heterogeneous, rare, monogenic condition, characterized by loss of subcutaneous fat, muscular hypertrophy, acanthosis, hepatomegaly and impaired lipid metabolism. Four types have been identified, caused by mutations in AGPAT2, BSCL2, CAV1 and, PTRF, respectively. Mutations in PTRF cause CGL type 4, characterized by muscular dystrophy, myopathy, cervical spine instability, high CK levels, cardiac arrhythmias, skeletal abnormalities and gastrointestinal dysmotility.

Case report: We report a 10 year old girl of Somali origin, with generalised lack of subcutaneous fat, acanthosis nigricans and, contractures. Parents were distantly related (3rd grade cousins). Father’s sister has a similar phenotype but lives in Somalia. At the age of 9 years, genetic evaluation revealed a novel homozygous frameshift mutation in PTRF (exon 2 c.519dup p(Glu174fs)), consistent with a diagnosis of CGL type 4. She had normal glucose tolerance (OGTT: glucose 5.0→6.6 mmol/l; insulin 6.6→36 mU/l), raised ALT of 87 U/l and high CK of 2980 U/l, lipid profile was normal. Physical examination: Height 128 cm (−2.11SDS), weight 28.5kg, BMI 17.7 (+0.17SDS). Generalised lipodystrophy with obvious lack of subcutaneous fat and prominent muscles. Restricted movements and contractures in wrists, shoulders, elbows, knees and, ankles. Lordosis and thoracolumbar scoliosis. Mild umbilical hernia. Tanner A3 B2 P refused. Neurological review showed normal neurology with no signs of muscle weakness. Cardiac and orthopaedic review is pending.

Conclusions: CGL type 4 is an extremely rare autosomal recessive disorder caused by mutations in PTRF. So far, 11 mutations have been described. PTRF encodes the cavin protein, which is a highly abundant caveolae component and plays a role in the stabilization of caveolins. Caveolae are invaginations of the plasma membrane involved in many cellular processes (endocytosis, cholesterol transport, signal transduction). Knockdown of PTRF in mammalian cells and zebrafish leads to a reduction in caveolae density, and PTRF knockout mice mimic lypodystrophy in humans. Whilst the metabolic phenotype in CGL type 4 is mild, cardiac arrhythmias have been described, highlighting the importance of obtaining a genetic diagnosis and other specialist review.