eMedicine Specialties > Dermatology > Pediatric Diseases

Lipodystrophy, Generalized

Author: Camila K Janniger, MD, Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, New Jersey Medical School
Coauthor(s): Cris Jagar, MD, Staff Physician, Department of Psychiatry, Saint Vincent Catholic Medical Centers
Contributor Information and Disclosures

Updated: Dec 7, 2009

Introduction

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.

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

Related eMedicine articles include Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Acanthosis Nigricans; Lipodystrophy, Localized; Lipodystrophy, Progressive; and Lipodystrophy, HIV.

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.

Of the first 5 patients whose cases were followed by Seip, 4 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.¹

Mortality/Morbidity

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.

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.

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.

Clinical

Physical

Two forms of generalized lipodystrophy exist, congenital and acquired, which have different clinical features.

• Congenital generalized lipodystrophy
  • The diagnosis of generalized lipodystrophy often is obvious from birth because of the extraordinary lack of subcutaneous fat. Fat cells are present but are reduced in number and size and contain little fat. Anabolic features are observed at birth, with enlarged visceral organs. Toddlers may have a potentially dangerous hyperplasia of pharyngeal tonsils and adenoids. Lipodystrophy produces 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 AN, eruptive xanthomas, hirsutism, and thick, tightly curled scalp hair that extends nearly to the eyebrows. Hirsutism of the face, neck arms, and legs may be observed at birth in some patients and tends to increase. No special growth of the pubic or axillary hair occurs.
  • All patients with Lawrence-Seip syndrome and lipodystrophy have AN to some degree. AN can diminish and disappear with puberty and is said to be prominent on the elbows, knees, and waist, as well as the more typical sites of the neck and axillae.
  • Acromegalic gigantism with advanced bone age and advanced dentition is an early and constant feature. The growth rate is most marked in the first 4 years, and these children may attain more than 90% of their adult growth within the first 10 years of life. Growth subsequently slows, and normal or short stature as adults usually is observed. Lipoatrophy does not affect female breast development at puberty, although females with this congenital lipodystrophy syndrome have a masculine habitus with marked muscularity.
  • Liver disease with fatty metamorphosis and cirrhosis is another constant feature, and hepatosplenomegaly tends to produce a markedly protuberant abdomen.
  • Childhood death due to massive GI bleeding has been reported frequently.
  • Diabetes mellitus usually begins in the teenage years. The diabetes is insulin resistant, and despite poor control of the diabetes, ketosis tends to be absent. Hyperlipemia usually precedes the diabetes.
  • An increased basal metabolic rate is a frequent finding.
  • Dilatation of the cerebral ventricular system has been described in most patients with generalized lipodystrophy.
  • Intelligence may range from normal to subnormal.
  • Kidneys may be enlarged without apparent histologic cause, and renal failure may ensue.
  • Cardiomegaly frequently is observed with muscle hypertrophy and ventricular disfunction. Increased chamber size may be demonstrated on echocardiogram with a systolic ejection murmur. Peripheral artery stenosis may be associated with reduced exercise tolerance, cardiac murmurs, and, possibly, pulmonary hypertension. Occasionally, congenital anomalies of the heart, bones, and kidneys also are found. These patients have abnormal autonomic modulation, reflected by an increased heart rate and a pronounced reduction in heart rate variability.²
  • The presence of dental abnormalities such as talon cusps, macrodontia, and aberrant tooth morphology has been described.³
• Acquired generalized lipodystrophy
  • Generalized lipodystrophy often is preceded by an illness and, in many instances, an infection. The fat loss becomes apparent either focally or diffusely, usually beginning in adolescence or early adult life.
  • Most of the features of the congenital form may occur, but in the acquired form, neurologic, cardiac, and renal abnormalities usually are absent.
  • Bone age is normal and genital hypertrophy is absent.
  • AN to varying degrees probably is a constant finding in acquired and congenital forms.
  • Autoimmune disorders also may be common, including Coombs-positive hemolytic anemia and chronic nephritis; however, great variability exists in the immunologic abnormalities in patients with the acquired form. Patients with the acquired form of generalized lipodystrophy also are prone to infection.

• Search for CME/CE on This Topic »

• Lipodystrophy, Progressive (Dermatology)
• Lipodystrophy, Generalized (Endocrinology)
• Lipodystrophy, Localized (Endocrinology)
• Lipodystrophy, Acquired Partial (Endocrinology)

• FDA Approves Duloxetine for Maintenance Treatment of Generalized Anxiety Disorder
• FDA Approves Extended-Release Lamotrigine for Primary Generalized Tonic-Clonic Seizures
• Levetiracetam Not Effective for Generalized Social Anxiety Disorder

• Improved Measures of Quality of Life, Lipid Profile, and Lipoatrophy After Treatment Interruption in HIV-Infected Patients With Immune Preservation
• Adult Combination Antiretroviral Therapy in Sub-Saharan Africa: Lessons from Botswana and Future Challenges
• Insulin Resistance and Lipid Disorders

• Fibromyalgia Resource Center
• Hypothyroidism Resource Center
• Anxiety Disorders Resource Center