BSCL is a condition characterized by absence of functional adipocytes to store fat. As a result of this defect, fat is stored in tissues like muscle and liver. Hepatomegaly and muscle hypertrophy ensue due to excessive deposition of circulating triglycerides (5
). Insulin resistance can become severe by the second decade of life, making the diabetes difficult to control with conventional therapy (3
). Pathogenesis of the generalized lipodystrophy is secondary to adipocyte deficiency (6
). The result is a distinct phenotypic appearance of generalized lipoatrophy that is exacerbated by the severity of the diabetes and subsequent insulin resistance. Major diagnostic criteria of CGL include trunk, limb, and facial lipoatrophy. Acromegaloid features are characteristic and consist of prognathism, enlarged hands/feet, macrogenitosomia, which are all thought to be a result of insulin cross−reacting with insulin−like growth factor−1 (IGF−1) receptors (5
). Minor criteria include hypertrophic cardiomyopathy, psychomotor or mental retardation, hypertrichosis, hirsutism, and bone cysts with premature closure of the epiphyseal plates (3
). Renal disorders may include nephromegaly and nephropathy (5
). Our patient had most of the above features, except for bone cyst and cardiomyopathy. Her echocardiogram showed aortic regurgitation and left ventricular hypertrophy. Her left ventricular hypertrophy may be secondary to long−standing poorly controlled hypertension. Other features unique to our patient include polydactyly in the right upper and lower extremities as well as arthropathy with contractures at proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints. The arthropathy may be secondary to poorly controlled long−standing diabetes or other undiagnosed etiology.
Infants with BSCL usually present with findings secondary to lipoatrophy, failure to thrive or gigantism, developmental delay, and dysmorphism (3
). Alternate diagnoses to be considered in the differential diagnosis are progeria, Russell’s diencephalic syndrome, leprechaunism and lysosomal storage disorders (3
Patients with CGL in the under−10 age group commonly present with accelerated growth, cognitive impairment, and abnormal fat distribution. By the second decade, symptoms of weight loss, polyuria, polydipsia, and polyphagia ensue and the diagnosis of diabetes is ultimately made. Our patient was diagnosed with diabetes at 8 years of age. Differential diagnosis in this age group is less extensive and includes: Dunningham lipodystrophy, a syndrome, which spares Bichat’s pads in the face; progeria, which is characterized by premature senility, sclerotic skin, joint contractures and alopecia; and Rabson−Medenhall syndrome, the prominent features of which are short stature, protuberant abdomen, abnormalities of teeth and nails, and pineal hyperplasia, with no organomegaly (3
). Laboratory evaluation usually reflects insulin resistance, with impaired glucose tolerance, dyslipidemia and hyperinsulinemia. Our patient had normal fasting insulin levels, mildly elevated C−peptide, elevated triglyceride and low HDL cholesterol levels. Other features of insulin resistance in our patient were acanthosis nigricans and hirsutism. Hepatic steatosis will commonly result in a mild transaminitis as triglycerides deposit into the liver secondary to a paucity of generalized fat tissue (5
). As a consequence of near−total loss of body fat, serum levels of adipocytokines such as leptin and adiponectin are low (15
DNA testing can help differentiate subtypes of BSCL. Mutation of band 13 (called locus BSCL2) on the long arm of chromosome 11 prevents the coding of the enzyme seipin. This mutation is found in patients with congenital lipodystropy Type 2 (5
). Conversely, a mutation on band 34 (called locus BSCL1) of the long arm of chromosome 9 inhibits the production of the enzyme 1−acylglycerol− 3−phosphate O−acyltransferase 2 (AGPAT2) (4
). This is indicative of congenital lipodystrophy Type 1. In contrast to type 1, unique features of type 2 are greater prevalence of cognitive dysfunction, cardiomyopathy, less lytic bone lesions and involvement of both metabolically active adipose tissue (found in most subcutaneous tissue sites, in intraabdominal, intrathoracic sites and in the bone marrow) and mechanical adipose tissue (located in the palms, soles of the exremities, under the scalp, in the retroorbital and periarticular regions) (5
). In Type 1, only metabolically active adipose tissue is involved. Our patient showed developmental delay, left ventricular hypertrophy and involvement of both metabolically active (less subcutaneous tissue, less intraabdominal fat revealed by abdominal CT scan) and mechanical adipose tissue (less fat in the palms and soles, enophthalmus). Management of lipodystrophy centers on controlling the diabetes, improving the insulin resistance, and reducing the triglyceride levels. Patients with CGL, as exemplified in this case report, are quite resistant to insulin therapy. Insulin doses as high as 1000 units daily may be required to control blood glucose levels (16
) and even these doses may not suffice. Metformin has been shown to have some effect in helping patients reduce their appetite and improve symptoms of polycystic ovarian syndrome (PCOS) and hepatic steatosis (17
). Our patient showed mild improvement in HbA1c on a combined regimen of insulin and metformin. Care should be taken in monitoring hepatic functions closely, as metformin is associated with hepatotoxicity. The most promising treatment for patients with CGL is recombinant leptin. This medication appears to improve insulin sensitivity, decrease triglyceride levels, and help control energy homeostasis. This results in less food intake, and lower fasting blood glucose levels as well as lower HbA1c levels (18
). Some reports show normoglycemia on leptin therapy even after other discontinuing hypoglycemic agents (19
).We are planning to enroll our patient in a leptin trial.
In summary, CGL is an uncommon genetic disorder. The patient described in this case report unfortunately went undiagnosed for many years. Maldistribution of body fat led to the pathological changes in the liver, kidneys, and muscles. Ultimately, diabetes and subsequent insulin resistance developed. With the exception of cardiomyopathy and lytic bone lesions, this patient meets all the major and minor criteria for the diagnosis of congenital generalized lipodystrophy type 2 (BSCL2).