Dermatologic Manifestations of Generalized Lipodystrophy

Updated: Jun 22, 2016
  • Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Generalized lipodystrophy syndrome is the association of acanthosis nigricans (AN) with the generalized complete absence of subcutaneous fat and the presence of muscle hypertrophy, hyperlipemia, diabetes mellitus, and hepatosplenomegaly with cirrhosis. Two forms of this syndrome exist, acquired and congenital. Note the image below.

Congenital generalized lipoatrophy in a 16-year-ol Congenital generalized lipoatrophy in a 16-year-old girl. In T1-weighted magnetic resonance imaging (MRI) scan, transverse sections of the torso at the fifth lumbar vertebra demonstrate markedly deficient subcutaneous and visceral fat (top left). Transverse sections of the midthigh demonstrate an absence of subcutaneous fat, deep fat, intrafascicular fat, and marrow fat (bottom left); note light-colored, lipid-filled muscle tissue. Note absence of fat throughout the body (right).

A number of syndromes are associated with AN. Of special interest are those linking diabetes mellitus with AN. In 1946, Lawrence described a 26-year-old English woman who first was observed with yellowish xanthomatosis of her arms, knees, and neck of a 2-month duration. She had classic diabetic symptoms for 9 months. Laboratory examination confirmed glucosuria without ketonuria and hyperlipemia. Over the next 3 years, a complete generalized loss of subcutaneous fat developed that began focally in the lower extremities. At this time, the patient had severe diabetes mellitus unassociated with ketosis, hepatosplenomegaly with hepatic cirrhosis, and hypermetabolism without signs of Graves disease.

In 1959, Seip described a similar congenital syndrome, but without diabetes mellitus, in 3 young Norwegian children. Two of the patients were siblings and the products of consanguinity. The 3 patients exhibited rapid growth with advanced bone age, dilation of the cerebral ventricles, hepatosplenomegaly with cirrhosis, generalized muscular overdevelopment, hypertrichosis, hypertension, punctate corneal opacities, and brownish pigmentation over the flexural creases. In 1960, Schwartz and coworkers first associated AN with the congenital syndrome described earlier, and since then, many more patients have been described. This entity is now known as generalized lipodystrophy or Lawrence-Seip syndrome. This syndrome is clearly distinct from those of partial lipodystrophy.

Some divide generalized lipodystrophy into a congenital and an acquired form, with Lawrence-Seip syndrome being acquired generalized lipodystrophy and Berardinelli-Seip syndrome being congenital generalized lipodystrophy.

  • Type 1 - AGPAT2 (1-acylglycerol-3-phosphate O-acyltransferase 2), band 9q34
  • Type 2 - BSCL2 (Seipin), band 11q13

A new syndrome of generalized lipodystrophy with a hypothalamic brain tumor (pilocytic astrocytoma) has been described in three children. [1]

Related articles include Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus, Acanthosis Nigricans, Dermatologic Manifestations of Localized Lipodystrophy, Progressive Lipodystrophy, and Lipodystrophy in HIV.

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Pathophysiology

Inheritance of the congenital form has been recognized as autosomal recessive with heterozygotes manifesting only hyperlipemia. Evidence for a simple monogenic defect is substantial. Some patients have been siblings, and parental consanguinity has been noted in several instances. Congenital generalized lipodystrophy has been linked with mutations of the AGPAT2, BSCL2, and PTRF genes. [2]

Of the first five patients whose cases were followed by Seip, four of them were from a small isolated area of southwestern Norway. Many of the patients have been of Portuguese or Norwegian ancestry, although this syndrome has been observed in all races. Norwegian genealogic records of the cluster of 5 of 6 affected families show that the mutation occurred at least 400 years ago. A decline in the intraregional marriage rate and inbreeding in the 6 adjacent municipalities of southwestern Norway where the congenital form is observed may account for the lack of new cases. A common normal chromosome variant, heterochromatic 9qh+, has been found in some affected individuals, but as would be expected, in 1 family, it also was observed in an unaffected sibling.

Hyperinsulinemia and insulin resistance characterize generalized lipodystrophy. This hyperinsulinemia also may account for acromegaly, enlargement of the kidneys, and hypertrichosis through cross-reactivity with somatomedin at the receptor level.

Many of the metabolic derangements of this syndrome seem to follow from lipoatrophy, but whether the lipoatrophy results from a failure to deposit fat or excessive mobilization of that fat is unclear. Seip favored the mechanism of excessive mobilization of fat due to a primary hypothalamic-hypophyseal disorder. Where investigation was undertaken, dilatation of the ventricular system was found in 6 of 7 children. Seip originally proposed that many of the features could be explained by an increased production of anterior pituitary hormones, including somatotropin, adrenocorticotropic hormone, and melanocyte-stimulating hormone. One theory states that the constant release of hypothalamic-releasing factors in this syndrome may be due to an inborn error of metabolism in the enzyme dopamine-B-hydroxylase. Fat-mobilizing polypeptides are produced in the hypothalamus and elsewhere in the central nervous system. Interestingly, somatostatinlike immunoreactivity has been detected in diabetic lipodystrophic skin.

A novel Berardinelli-Seip congenital lipodystrophy type 2 gene mutation, E189X, has been described in a Chinese family with a child with congenital generalized lipodystrophy and early-onset diabetes mellitus. [3]

In one patient with congenital generalized lipodystrophy (Berardinelli–Seip congenital lipodystrophy), a homozygous de novo point mutation was described in the c-fos promoter. [4] Several candidate genes (BSCL1, BSCL2, BSCL3, BSCL4) have been linked with this syndrome, but not all carry mutations in these genes.

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Epidemiology

Race

Many of the cases have involved individuals of Portuguese or Norwegian ancestry, although generalized lipodystrophy can affect any race.

Sex

Males and females are affected equally in the congenital form. A female predominance appears to exist with the acquired form. A survey of 54 patients with Berardinelli-Seip congenital lipodystrophy found a predominance of females (27 patients), and the mean age was 21.3 ± 13.7 years. [5] The majority of patients (30 [68.2%] of 44) were diabetic, and almost half of them (14 [46.7%] of 30) were on insulin.

Age

The congenital form of generalized lipodystrophy is obvious from birth, but the acquired form usually becomes apparent before age 15 years, often before age 5 years. Acquired generalized lipodystrophy is rare in people older than 65 years. [6] A survey of 54 patients with Berardinelli-Seip congenital lipodystrophy found the mean age was 21.3 ± 13.7 years. [5]

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Prognosis

Patients with the congenital form of generalized lipodystrophy tend to survive into young adulthood or early middle age. A common cause of death has been GI hemorrhage caused by esophageal varices in association with hepatic failure. Renal complications are frequent causes of death in the congenital form. Frequently, patients with the acquired form also die in middle age because of GI hemorrhage due to esophageal varices.

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