Lipodystrophy, Congenital Generalized, Type 4

A number sign (#) is used with this entry because congenital generalized lipodystrophy type 4 (CGL4) is caused by homozygous or compound heterozygous mutation in the PTRF gene (603198) on chromosome 17q21.

Description

Congenital generalized lipodystrophy type 4 combines the phenotype of classic Berardinelli-Seip lipodystrophy (608594) with muscular dystrophy and cardiac conduction anomalies (Hayashi et al., 2009).

For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).

Clinical Features

Rajab et al. (2002) described 10 patients from Oman who had congenital generalized lipodystrophy as well as striking abnormalities in both skeletal and nonskeletal muscle, including reduced exercise tolerance and percussion myoedema. Ghanem (1993) had described percussion myoedema in Berardinelli-Seip lipodystrophy. None of the children reported by Rajab et al. (2002) had insulin resistance or early endocrine abnormalities. All 10 had had hypertrophic pyloric stenosis operated on in the first 6 weeks of life. The veins were very prominent (phlebomegaly) in the skin and cutis marmorata was present. Cardiac abnormalities with cardiac hypertrophy and arrhythmias were features later in childhood, including a history of sudden death in some of the sibs. Rajab et al. (2002) suggested that this group may represent a new clinical syndrome with lipodystrophy at a novel locus. In a follow-up report of these patients, Rajab et al. (2010) emphasized that 1 had multiple cardiac conduction defects, including ventricular and supraventricular tachycardia, bradycardia, and features of long QT syndrome. In addition to skeletal muscle involvement manifest as exercise intolerance and percussion-induced rapid contractions, there was also evidence of smooth muscle involvement, including hypertrophic pyloric stenosis and esophageal dysmotility. There was also spinal rigidity, hyperlordosis, osteopenia, delayed bone age, and recurrent bacterial infections.

Rajab et al. (2010) reported a 12-year-old girl from the U.K. who had a similar phenotype. Her parents were related as first cousins. She had neonatal hypotonia, increased serum creatine kinase, lack of subcutaneous fat, and pronounced muscle bulk. She later developed proximal muscle weakness, muscle stiffness, and exercise-induced myalgia, as well as rippling muscles. Other features included massive smooth muscle hypertrophy, frequent infections, atlantoaxial instability, osteoporosis, hepatomegaly with elevated transaminases, insulin resistance, and elevated triglycerides. She died at age 13 years from sudden cardiac death due to ventricular fibrillation. Skeletal muscle biopsy showed absent PTRF immunostaining; adipose cells showed lack of caveolin-1 (CAV1; 601253) expression; and fibroblasts showed a severe reduction of caveolae.

Simha et al. (2008) reported 2 sibs, born of nonconsanguineous Mexican parents, with CGL and no mutations in known lipodystrophy genes. Clinical features included generalized loss of subcutaneous fat from birth, acanthosis nigricans, acromegaloid habitus, umbilical prominence, hepatosplenomegaly, and hypoleptinemia. One sib had insulin resistance. Features unusual for congenital lipodystrophy included preservation of bone marrow fat, generalized muscle weakness associated with increased serum creatine kinase, and atlantoaxial dislocation requiring surgical intervention. Simha et al. (2008) concluded that the disorder represented a novel subtype of CGL. Rajab et al. (2010) suggested that the family reported by Simha et al. (2008) may have had this form of CGL. Shastry et al. (2010) reported follow-up of the sibs reported by Simha et al. (2008), who were 14 and 8 years old, respectively. The sister had developed worsening hypertension and ventricular tachycardia resembling catecholaminergic polymorphic ventricular tachycardia (CPVT). She also had increased hepatic fat. The brother had learning disabilities and a complex tachycardia resembling polymorphic ventricular tachycardia. Neither had evidence of QT prolongation, and both had percussion-induced muscle mounding. The carrier parents had slightly high serum triglycerides, although neither had lipodystrophy.

Hayashi et al. (2009) reported 5 unrelated Japanese patients with CGL4 and muscular dystrophy. All had generalized loss of subcutaneous adipose tissue in several areas, including the face, from infancy or early childhood. Two patients had distal muscle weakness, 1 had generalized muscle weakness, and all 3 had muscle hypertrophy and percussion-induced muscle mounding. One patient had myalgia and muscle stiffness. One patient had cardiac arrhythmia, and another had atrial fibrillation, but 3 had no cardiac abnormalities. Skeletal anomalies included lordosis in 1, contractures in 2, and scoliosis in 2. None had intellectual deficit or acanthosis nigricans. Variable features included hepatosplenomegaly, fatty liver, acromegaloid features, and advanced bone age. Laboratory studies showed moderate fasting hyperinsulinemia in 2 patients and increased triglycerides in 2. All had moderately increased serum creatine kinase. Skeletal muscle biopsy showed chronic dystrophic changes with marked variation in muscle fiber size, internalized nuclei, a few necrotic and regenerating fibers, and increased interstitial fibrosis. Caveolin-3 (CAV3; 601253) immunoreactivity was greatly reduced in the sarcolemma, but cytoplasmic staining was remarkably increased, a pattern similar to that seen in the patients with muscular dystrophy caused by CAV3 mutations (see, e.g., RMD2, 606072).

Shastry et al. (2010) reported a Mexican brother and sister with CGL4, who were 11 years and 16 months old, respectively, at the time of the report. Both had pyloric stenosis in infancy and then developed loss of subcutaneous fat from the face and extremities. Other features included umbilical prominence with protuberant abdomen, hepatomegaly, painless muscle mounding, and systolic murmur, but no arrhythmias or prolonged QT interval. Laboratory studies showed hypertriglyceridemia and increased serum creatine kinase. The brother had postprandial hyperinsulinemia, restricted joint movement, muscle weakness, and atlantoaxial instability. The sister showed mild developmental delay. The carrier parents showed some metabolic abnormalities, including increased serum triglycerides and insulin intolerance, although neither had lipodystrophy.

Molecular Genetics

In 4 unrelated Japanese patients with congenital generalized lipodystrophy type 4 and muscular dystrophy, Hayashi et al. (2009) identified a homozygous truncating mutation in exon 2 of the PTRF gene (696insC; 603198.0001). A fifth Japanese patient was compound heterozygous for the 696insC mutation and another truncating mutation (525delG; 603198.0002).

In 10 patients from Oman with lipodystrophy, muscular dystrophy, and cardiac conduction defects reported by Rajab et al. (2002), Rajab et al. (2010) identified a homozygous truncating mutation in the PTRF gene (160delG; 603198.0003), resulting in complete loss of protein function. A girl from the U.K. with a similar phenotype was homozygous for another truncating mutation (362dupT; 603198.0004). Rajab et al. (2010) noted that the symptoms of the patients combine the features in individuals with CAV1 mutations, such as those in CGL3 (612526), and features in individuals with CAV3 mutations, such as those in rippling muscle disease (RMD2; 606072), since the PTRF gene product in essential for caveolae biogenesis. PTRF is expressed in many tissues, but highest mRNA levels are found in adipocytes, smooth muscle, skeletal muscle, heart, and osteoblasts, consistent with the tissues affected in patients with CGL4. The nervous system is spared.

In 3 patients, including 2 sibs, with CGL4, Shastry et al. (2010) identified 2 different homozygous truncating mutations in the PTRF gene (603198.0005-603198.0006). In addition, the affected sibs reported by Simha et al. (2008) were found to be compound heterozygous for 2 truncating PTRF mutations (603198.0007 and 603198.0008).

Animal Model

Liu et al. (2008) found that Ptrf-knockout mice were viable and of normal weight, but had a metabolic phenotype of significantly reduced adipose tissue mass, higher circulating triglyceride levels, glucose intolerance, and hyperinsulinemia, consistent with a lipodystrophy. Cells from various tissues of Ptrf-knockout mice, including lung epithelium, intestinal smooth muscle, skeletal muscle, and endothelial cells showed no detectable caveolae cells. These cells also had markedly decreased expression of all 3 caveolin isoforms, although some tissues showed increased mRNA, a possible compensatory response. The findings indicated that cavin, which is encoded by the PTRF gene, is required for the formation and/or stabilization of morphologically defined caveolae. Liu et al. (2008) suggested that the absence of cavin impairs the ability of adipocyte to store triglycerides, which in turn leads an increase in circulating lipids, glucose intolerance, and insulin resistance.