OJHAS: 2010-4-28. Dal AI, Patel H. Berardinelli-Seip Syndrome

Abstract:

We have reported two cases of Berardinelli-syndrome in a family which is a rare autosomal recessive disorder of the adipose tissue, originally described by Berardinelli and Seip, has been reported in approximately 120 patients of various ethnic origins. Assuming that only 1 in 4 patients is reported.Patients present with acanthosis nigricans (dark velvety pigmentation of the skin) in the axilla, neck or groin, severe insulin resistance, high levels of serum insulin and serum triglycerides.The other clinical features consist of enlarged hands, feet and prominent mandible (acromegaloid features), increased sweating, umbilical hernia and lytic lesions (bone appear to be eaten-up on X-rays) in long bones of the upper and lower extremities (arms, forearm, hands, thigh, calf, legs and feet) such as humerus, femur, etc. Hepatomegaly from fatty liver is almost universal and may ultimately lead to cirrhosis. Splenomegaly is common. Nearly all patients have a prominent umbilicus or frank umbilical hernia. Females present with enlarged clitoris, increased body hair, absence of or irregular menstrual cycles, and polycystic ovaries (enlarged ovaries). Only a few affected women have had successful pregnancies, whereas affected men have normal fertility.
Key Words: Berardinelli-Siep syndrome; Lipodystrophy

Berardinelli-Seip syndrome or ‘Congenital generalized lipodystrophy’ is an autosomal recessive disorder characterized by the generalized complete absence of subcutaneous fat and the presence of muscle hypertrophy, hyperlipemia, diabetes mellitus,acanthosis nigricans and hepatosplenomegaly with cirrhosis. Approximately 120 patients of various ethnic backgrounds have been reported.[1]

Lipodystrophies represent a heterogeneous group of diseases characterized by generalized or partial alterations in body fat development or distribution and insulin resistance. The other cardinal clinical signs of these syndromes are acanthosis nigricans, frequent hypergonadism in females, muscular hypertrophy and liver steatosis.[2] Lipodystrophies are classified as congenital or acquired (depending on origin) and, generalized or partial (based on clinical pattern).

Congenital generalized lipodystrophy (Berardinelli-Seip syndrome) is transmitted as an autosomal recessive trait and is linked to two genetic loci, on chromosomes 9q34 and 11q13.[2,3] Recently, the 11q13 locus has been identified as the BSCL2 gene, encoding seipin, a protein of unknown function mainly expressed in brain.[4]

The pathophysiology of lipodystrophies is still unknown. However, murine models of lipoatrophic diabetes revealed that primary genetic alterations in fat development resulted in diabetes and dyslipidemia.[5] Leptin deficiency, caused by the absence of adiposetissue, could be an important determinant of the metabolic abnormalities since exogenous administration ortransgenic overexpression of leptin has been shown to markedly improve insulin sensitivity, glycemic control, dyslipidemia and hepatic steatosis in mice. Similarly, the defect in adinopectin, another fat derived hormone, has recently been shown to be involved in insulin resistance.[6]

Males and females are equally affected and the clinical manifestations are obvious from birth, because of the lack of subcutaneous fat. Fat cells are present but are reduced in number and size, containing little fat. Anabolic features are observed at birth, with enlarged visceral organs. Toddlers may have potentially dangerous hyperplasia of pharyngeal tonsils and adenoids. Lipodystrophies produce a distinctive facies. A well defined musculature with prominent superficial veins is one of the earliest manifestations. Clitoral or penile hypertrophy has been evident at birth, but genitomegaly is not apparent after puberty. The earliest skin manifestations include acanthosis nigricans, eruptive xanthomas and hirsutism. All patients have acanthosis nigricans to some degree.[7]

Acanthosis nigricans can diminish and disappear with puberty and is said to be prominent on the elbows, knees, waist, neck and axilla. Acromegalic gigantism with advanced dentition is an early and constant feature.

The growth rate is most marked in the first 4 years, and these children may attain 90 percent of their adult growth within the first 10 years of their life. Growth subsequently slows and adults are normal or short stature. Females have a masculine habitus with marked muscularity. Liver disease with fatty steatosis and cirrhosis is another constant feature. Hepatosplenomegaly tends to produce a markedly protuberant abdomen.

Diabetes mellitus usually begins in teenage years. The diabetes is insulin resistant and despite poor control ketosis is absent. Hyperlipidemia usually precedes the diabetes. An increased basal metabolic rate is a frequent finding. Intelligence may range from normal to subnormal. Kidneys may be enlarged without apparent histologic cause and renal failure may ensue. Cardiomegaly is frequently observed with muscular hypertrophy and ventricular dysfunction.

Common causes of death renal failure and GI hemorrhage from oesophageal varices in association with hepatic failure.Patients survive into young adulthood or early middle age.

Treatment for acanthosis nigricans can be accomplished with etretinate (beginning at 75 mg/day and increased gradually to 0.5 mg/kg/day after 10-12 weeks).[8] Dietary fish oil may also be useful in acanthosis nigricans.

Substitution of eucaloric medium chain triglycerides for long chain fatty acids can lead to improvement of chylomicronemia, xanthomatosis, hypertriglyceridemia, hepatomegaly, and carbohydrate tolerance hyperinsulinemia, but not lipoatrophy. The limited ability to store energy as fat means patients must maintain a rigid special diet with 4 regular sized meals each day and avoid large meals. Easily digestible carbohydrate should be restricted and dietary fibre is important.[9]