Congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, is a rare autosomal recessive disease characterized by a near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biologic features include acanthosis nigricans, ... Congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, is a rare autosomal recessive disease characterized by a near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia (Garg, 2004). - Genetic Heterogeneity of Congenital Generalized Lipodystrophy Congenital generalized lipodystrophy type 2 (269700) is caused by mutation in the BSCL2 gene (606158). Congenital generalized lipodystrophy type 3 (612526) is caused by mutation in the CAV1 gene (601047). Congenital generalized lipodystrophy type 4 (613327) is caused by mutation in the PTRF gene (603198).
Congenital generalized lipodystrophy was originally described by Berardinelli (1954) and Seip (1959) as a disorder of metabolism, lipodystrophy, and endocrine abnormalities. Seip (1959) reported affected brother and sister, and suggested diencephalic origin. Lipodystrophic muscular hypertrophy (Senior, 1961) may ... Congenital generalized lipodystrophy was originally described by Berardinelli (1954) and Seip (1959) as a disorder of metabolism, lipodystrophy, and endocrine abnormalities. Seip (1959) reported affected brother and sister, and suggested diencephalic origin. Lipodystrophic muscular hypertrophy (Senior, 1961) may be the same entity. Reed et al. (1965) reported congenital lipodystrophy with diabetes and acanthosis nigricans. Seip (1971) reviewed published cases. Hamwi et al. (1966) discussed lipoatrophic diabetes and noted that substances with insulin-antagonizing and fat-mobilizing properties have been found in the urine of affected patients. Mabry and Hollingsworth (1971) presented evidence for abnormal pituitary function with secretion of an abnormal hormone with melanotrophic and growth hormone properties. In 1 case, surgical hypophysectomy was followed by marked improvement. In postmortem examination of a case, Berge et al. (1976) found hypothalamic lesions judged to be of a malformative or hamartomatous nature. The authors pointed out that the Russell emaciation syndrome (Russell, 1951), which does not appear to be mendelian, had been shown to be due to a hypothalamic lesion, usually glioma, and that cerebral gigantism may likewise be of diencephalic origin. Brunzell et al. (1968) noted that 2 affected sibs had been reported in each of 5 families, and in 4 other families the parents were consanguineous, suggesting autosomal recessive inheritance. Brunzell et al. (1968) reported a family in which 5 of 12 sibs had a combination of congenital generalized lipodystrophy and cystic angiomatosis with progressive incapacitating bone involvement (termed by some as 'Brunzell syndrome'). Two had subcutaneous soft tissue angiomas. The lipodystrophy was accompanied by acanthosis nigricans, large hands and feet, acromegaloid facial features, lipemia, and hepatosplenomegaly, typical of Berardinelli-Seip congenital lipodystrophy. Huseman et al. (1978) reported 3 black sibs with congenital lipodystrophy with a severe disturbance in carbohydrate metabolism manifested by increased plasma levels of glucagon and insulin and resistance to exogenous insulin. Huseman et al. (1979) reported 3 sisters with congenital generalized lipodystrophy and cystic angiomatosis of the long bones. One girl had polycystic ovarian disease. Huseman et al. (1979) noted that labial hypertrophy, sexual precocity, and oligomenorrhea had also been described in this disorder (Brunzell et al., 1968). Dorasamy (1980) reported a case of an affected female infant with first-cousin parents. Van Maldergem et al. (1992) reported a girl, born of an uncle-niece mating, with features characteristic of total lipodystrophy, including absent subcutaneous fat, hyperlipidemia, acanthosis nigricans, facial dysmorphia, and mild mental retardation with an IQ of 50. At the age of 13 years, the girl was found to have large multilocular cysts at the ends of the long bones, particularly the humeri and femora. At the age of 17 years, oligospaniomenorrhea (few and scanty menses) was a complaint, and polycystic ovaries were demonstrated. Insulin resistance was progressive. Van Maldergem et al. (1992) considered Brunzell syndrome, which they suggested includes cystic angiomatosis, to be distinct from Berardinelli-Seip syndrome. Seip and Trygstad (1996) presented information on several patients with congenital generalized lipodystrophy followed for almost 40 years. They also described a patient with acquired generalized lipodystrophy, a disorder that was first reported by Ziegler (1928) and later by Lawrence (1946), which may represent an autoimmune disorder. In congenital lipodystrophy, insulin resistance is present from birth, resulting in hyperinsulinemia, dyslipidemia, and insulin-resistant diabetes with an anabolic syndrome worsened by a voracious appetite. Growth velocity is increased in preschool age children, and organomegaly is observed with hypertrophic cardiomyopathy that can be lethal in early adulthood. Three patients of Seip and Trygstad (1996) died at the ages of 24, 32, and 37 years. Another, alive at age 39 years, suffered from stenocardia (angina pectoris). Their first patient was born in 1952 of second-cousin parents. She had a healthy twin brother and an affected younger brother. She suffered from severe hyperhidrosis with moist and warm hands, attributable to an increased energy metabolism. Insulin-resistant diabetes (IDDM; 222100) developed at age 12 years and diabetic nephropathy and neuropathy (see 603933) were evident by age 16 years. She died at age 32. The affected brother was 192 cm tall at the age of 17 years. He was married with 3 healthy children. Bjornstad et al. (1996) reported that all patients of Seip and Trygstad (1996) had hypertrophic hearts, mostly with deranged diastolic, but also systolic, function. One had pulmonary hypertension. Conspicuous acanthosis nigricans was illustrated in 2 patients aged 8 and 9 years. One of the patients from a Finnish-derived population of Norway was described as 'not as athletic as the other patients,' and pneumoencephalography showed more extensive changes than in the other patients, with dilatation of both lateral ventricles, the third ventricle, and the basal cisterns. He was somewhat more mentally retarded. He died of heart failure at the age of 35 years. Uzun et al. (1997) described 3 patients with multiple peripheral pulmonary artery stenoses in association with congenital generalized lipodystrophy. Two were a brother and sister, aged 2 and 6 years, respectively; the third was a 14-year-old girl. Van Maldergem et al. (2002) studied 70 affected individuals from 44 unrelated families with congenital generalized lipodystrophy. Forty-five patients from 24 families had BSCL2 (269700) and 21 patients from 17 families had BSCL1. Two European families had no BSCL2 mutations and did not show linkage to chromosome 9q34, indicating the existence of an additional locus, which the authors termed BSCLX. All subjects of African ancestry (35%) were in the BSCL1 group. Congenital onset of lipoatrophy occurred in 79.5% of patients with BSCL2 compared to 61% of other cases. Onset of diabetes was the same in all patients. All patients had skeletal muscle hypertrophy, and the prevalence of hypertrophic cardiomyopathy was approximately 20% in all groups. Seven of 45 (15%) BSCL2 patients died prematurely (range, 4 months to 35 years of age), compared to no premature deaths in patients with BSCL1. The most significant finding was an increased frequency of mild or moderate intellectual impairment in the BSCL2 group (78%) compared to BSCL1 (10%), yielding an odds ratio of 23.5. There was no correlation between site and type of seipin mutation and intellectual impairment. Van Maldergem et al. (2002) concluded that BSCL1 is a milder disease than BSCL2. Simha and Garg (2003) compared whole-body adipose tissue distribution by magnetic resonance imaging (MRI) in 10 congenital generalized lipodystrophy patients, of whom 7 (6 females, 1 male) had CGL1 and 3 (2 males, 1 female) had CGL2 (269700). Both subtypes had marked lack of metabolically active adipose tissue located at most subcutaneous, intermuscular, bone marrow, intraabdominal, and intrathoracic regions. Paucity of mechanical adipose tissue in the palms, soles, orbits, scalp, and periarticular regions was noted in CGL2, whereas it was well preserved in CGL1 patients. The authors concluded that congenital generalized lipodystrophy patients with BSCL2 (606158) mutations have a more severe lack of body fat, which affects both metabolically active and mechanical adipose tissue.
In affected members of 11 pedigrees with autosomal recessive Berardinelli-Seip congenital lipodystrophy showing linkage to 9q34, Agarwal et al. (2002) identified 11 mutations in the AGPAT2 gene (see, e.g., 603100.0001-603100.0005). All affected members carried homozygous or compound heterozygous ... In affected members of 11 pedigrees with autosomal recessive Berardinelli-Seip congenital lipodystrophy showing linkage to 9q34, Agarwal et al. (2002) identified 11 mutations in the AGPAT2 gene (see, e.g., 603100.0001-603100.0005). All affected members carried homozygous or compound heterozygous mutations. Fu et al. (2004) screened for mutations in AGPAT2 and BSCL2 (606158) in 27 families with congenital generalized lipodystrophy. They found mutations in either AGPAT2 or BSCL2 in all but 4 probands, including 3 novel mutations in AGPAT2, lys215 to ter (603100.0006), IVS3-1G-C (603100.0007), and phe189 to ter (603100.0008). In 3 sibs with congenital generalized lipodystrophy and cystic angiomatosis of the long bones, a phenotype designated Brunzell syndrome, they identified a splice site mutation in AGPAT2 (IVS4-2A-G; 603100.0002). The authors concluded that there did not appear to be any distinguishing clinical characteristics between congenital generalized lipodystrophy subjects with AGPAT2 or BSCL2 mutations, with the exception of mental retardation in carriers of BSCL2. Agarwal et al. (2002) pointed out that individuals with congenital generalized lipodystrophy type 2 who carry mutations in the BSCL2 gene tend to have mild mental retardation and cardiomyopathy, features not seen in families with congenital generalized lipodystrophy type 1 who have mutations in the AGPAT2 gene. Based on the high expression of seipin in brain and weak expression in adipocytes, Magre et al. (2001) suggested a primary defect in hypothalamic pituitary axis. Agarwal et al. (2002) suggested that different forms of congenital generalized lipodystrophy may be caused by disruption of different pathways.