Inherited disorder with hyperinsulinemia caused by insulin resistance combined with lipodystrophy and acromegaloid features.
Berardinelli-Seip Syndrome; Berardinelli-Seip-Lawrence Syndrome; Berardinelli Syndrome; Seip Syndrome; Seip-Lawrence Syndrome; Congenital Generalized Lipodystrophy; (Congenital) Lipoatrophic Diabetes; Lipodystrophy-Acromegaloid Gigantism Syndrome.
First described in 1954 by Waldemar Berardinelli in two Brazilian children and 5 years later by Martin Seip who described three additional cases from Norway.
Estimated prevalence is 0.2 to 0.3:100,000 in the general population. Worldwide, around 500 cases have been described. BSCL2 (see below) is more common and severe than BSCL1, with onset already in the neonatal period or early infancy and a higher prevalence in the Middle East (in Oman 1:25,000), Portugal and Norway. BSCL1 has a higher prevalence among the African-American population. BSCL 1 and 2 account for approximately 95% of all patients.
Autosomal recessive disorder. At least four genetic loci (7q31.2, 9q34, 11q13, and 17q21.2) are associated with the syndrome.
Based on the clinical picture, including hyperinsulinemia and in some cases a positive family history. BSCL commonly refers to the congenital form of generalized lipodystrophy, whereas Seip-Lawrence Syndrome usually refers to the acquired form (in which the anabolic syndrome is more variable and immunologic disturbances more common; see also “Other conditions to be considered”).
Currently, there are four known types of congenital generalized lipodystrophy:
Congenital Generalized Lipodystrophy Type I (Berardinelli-Seip Congenital Lipodystrophy Type 1; AGPAT2-related Brunzell Syndrome): Caused by mutations in the gene encoding AGPAT2 (1-acylglycerol-3-phosphate-O-acyltransferase-2) located on chromosome 9q34. This endoplasmic reticular enzyme is involved in the de novo phospholipid and triglyceride biosynthesis and holds a critical role in the growth and development of adipocytes. Thus, dysfunctional AGPAT2 enzyme may lead to reduced biosynthesis of triglycerides in adipocytes and cause lipodystrophy. Affected patients lack the metabolically active adipose tissue in subcutaneous areas, visceral regions (intrathoracic, intraabdominal, and perinephric), and bone marrow. However, the protective and cushioning mechanical adipose tissue in palms and soles, scalp, orbits, joints, and perineum is typically spared.
Congenital Generalized Lipodystrophy Type II (Berardinelli-Seip Congenital Lipodystrophy Type 2; Total Lipodystrophy and Acromegaloid Gigantism; Congenital Lipoatrophic Diabetes; BSCL2-related Brunzell Syndrome): Caused by mutations in the BSCL2 (Berardinelli-Seip Congenital Lipodystrophy Type 2 or Seipin) gene located on chromosome 11q12.3. Seipin is an endoplasmatic reticular protein found in abundance in adipocytes (where it plays a role in the generation and morphology of lipid droplets), motor neurons and brain. This type is more severe than Type I and typically affected patients lack both metabolically active and mechanical adipose tissue.
Congenital Generalized Lipodystrophy Type III (Berardinelli-Seip Congenital Lipodystrophy Type 3): Caused by mutations in the Cav1 (Caveolin-1) gene located on chromosome 7q31.2. Caveolae are invaginations of cell-surface membranes with a ...