generalized lipodystrophies are a group of rare genetically heterogeneous disorders characterized by an almost absence of body fat. These disorders are also associated with dyslipidemia and insulin resistance. Congenital Generalized Lipodystrophy Type 4, also known as CGL4 is a newly identified extremely rare form of CGL. Like the classic forms, CGL4 is also associated with a marked lack of body fat, hirsutism, characteristics of insulin resistance, and muscular hypertrophy. However, these symptoms are more widespread. In addition, patients with CGL4 also show more advanced myopathy, smooth and skeletal muscle hypertrophy, cardiac arrhythmias, osteopenia, and distal metaphyseal deformation with joint stiffness. In addition, affected patients have large and weak muscles that show an involuntary rolling contraction called rippling. The cardiac arrhythmias can be fatal.
Rajab et al. (2010) undertook a clinical and genetic evaluation of 10 patients with CGL4 and their families from Oman. This included a newly described 14-year old male patient and nine patients described previously by Rajab et al. (2002). The new patient was born to consanguineous parents. At birth, he was noted to have lack of subcutaneous fat, a protruding abdomen, and a large tongue. Hypothyroidism was excluded. He was treated for a hypertrophic pyloric stenosis. He also suffered from frequent skin and pulmonary infections. He had frequent palpitations and syncope by 10-years of age, and was found to have ventricular and supraventricular tachycardia, as well as other features suggestive of long-QT syndrome. He also had difficulty esophageal dysmotility, back pain and joint stiffness, and mild splenomegaly with elevated transaminases. He was also found to have osteopenia with enlarged epiphyses, bone age reaterded by 1.5 years finger contractures with ulnar deviation, spinal rigidity and hyperlordosis. The patient showed muscular hypertrophy with limb girdle weakness, and mounding in all larger muscles. He also had insulin resistance in the absence of acanthosis nigricans. Whole genome scanning of this patient and the nine previously reported patients produced PTRF-CAVIN gene as a putative hit. Sequencing of the gene revealed a homozygous mutation (c.160delG) in the index patient and six affected Omani families. Western blot analysis of patient fibroblasts revealed a complete absence of caveolin-1 immunoreactivity in adipocyte cell membranes, and a severe reduction of caveolae on the surfaces of fibroblasts. Rajab et al. (2010) surmised that the multiple functions of caveolae correspond to the clinically diverse symptoms of CGL4. PTRF-CAVIN is expressed in adipocyte, muscle, and osteoblasts, where the caveolae play important roles in functioning of cardiac ion channels, propagation of action potentials through muscle fibers, an effective humoral immune reaction, and bone matrix calcification. Thus defects in the functioning of the protein could lead to cardiac defects, muscle weakness and rippling, increased susceptibility to bacterial infections, and osteoporosis.