Dermatologic Manifestations of Generalized Lipodystrophy

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.[7]  Type 2 congenital generalized lipodystrophy has been described with a heterozygous missense NOTCH2 mutation.[8]

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. In a patient with juvenile-onset generalized lipodystrophy due to a novel heterozygous missense LMNA mutation affecting lamin C, the generalized lipodystrophy was postulated to be a result of mutant lamin C disrupting its interaction with other cellular proteins.[9]

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.[10]

In one patient with congenital generalized lipodystrophy (Berardinelli–Seip congenital lipodystrophy), a homozygous de novo point mutation was described in the c-fos promoter.[11] Several candidate genes (BSCL1, BSCL2, BSCL3, BSCL4) have been linked with this syndrome, but not all carry mutations in these genes. A survey of 150 patients with a genetically confirmed BSCL1 syndrome found 42 different mutations, most of which caused frame-shifts or alter mRNA splicing leading to the synthesis of a nonfunctional enzyme, while rarer pathogenic variants cause amino acid substitutions.[12]

This may be an altered acylated ghrelin response to food intake in patients with congenital generalized lipodystrophy.[13]

Race

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

Autosomal recessive congenital generalized lipodystrophy has a worldwide prevalence of around 1 in every 12 million people, but it was found to be much more prevalent in part of Peru in 2017 at 0.86 per 100,000 population.[14]

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.[15] 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.[16] A survey of 54 patients with Berardinelli-Seip congenital lipodystrophy found the mean age was 21.3 ± 13.7 years.[15]

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. Asymmetric hypertrophic cardiomyopathy has been described.[17]  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.[18]

The presence of dental abnormalities such as talon cusps, macrodontia, and aberrant tooth morphology has been described.[19]

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. Acquired generalized lipodystrophy has been described after use of an immune checkpoint inhibitor for metastatic melanoma.[20]

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.

Successful treatment of acanthosis nigricans (AN) in association with generalized lipodystrophy was accomplished in 1 patient with etretinate beginning at 75 mg/d.[21] Therapy for AN was undertaken in this patient for cosmetic reasons. After 4 weeks, the cutaneous eruption had disappeared, with only modest elevation of the preexisting hyperlipemia.

Substitution of eucaloric medium-chain triglycerides for long-chain fatty acids in the diet of 1 patient led to improvement of chylomicronemia, xanthomatosis, hypertriglyceridemia, hepatomegaly, carbohydrate tolerance, and hyperinsulinemia, but not lipoatrophy. Dietary fish oil also may be useful in improving AN.

Because conventional lipid-lowering and antihyperglycemic medications may be insufficient to control severe metabolic abnormalities, leptin has been used for severe lipodystrophy and found to significantly improve metabolic abnormalities.[22] This new option for therapy is leptin, an adipocyte hormone, which may improve insulin resistance, hyperglycemia, dyslipidemia, and hepatic steatosis.[23] Leptin is the first of a group of adipocyte-secreted hormones to be used clinically.[24] Its long-term efficacy in 15 patients with generalized lipodystrophy was evaluated.[25]

Leptin has been judged the first novel, effective, long-term treatment for severe forms of lipodystrophy. Treating severe lipodystrophy as a leptin deficiency syndrome has been shown to improve the metabolic outcomes in those affected patients.[26]

In February 2014, the FDA approved metreleptin (Myalept), a recombinant leptin analog, for congenital or acquired generalized lipodystrophy in children and adults.[27] The approval was based on results from an NIH open-label, single-arm study that included 48 patients with congenital or acquired generalized lipodystrophy who also had diabetes mellitus, hypertriglyceridemia, and/or elevated levels of fasting insulin. The trial showed reductions in fasting glucose and triglycerides.[17]

Metreleptin is not indicated for the following:

• Treatment of complications of partial lipodystrophy

• Treatment of liver disease, including nonalcoholic steatohepatitis (NASH)

• HIV-related lipodystrophy

• Use in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of generalized lipodystrophy

Class Summary

Metreleptin may improve complications associated with leptin deficiency in patients with generalized lipodystrophy including hyperglycemia, hyperlipidemia, insulin resistance, and fatty infiltration of the liver.

Metreleptin (Myalept)

Metreleptin is a recombinant leptin analog. It binds to and activates the human leptin receptor (ObR), which belongs to the class I cytokine family of receptors that signals through the JAK/STAT transduction pathway. It is indicated as replacement therapy (in addition to diet) for the complications of leptin deficiency in patients with congenital generalized or acquired generalized lipodystrophy.