Lipodystrophies

Congenital Generalized Lipodystrophy (Berardinelli–Seip Congenital Lipodystrophy, Berardinelli–Seip Syndrome)

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder with four known genetic subtypes. The two major forms, types 1 and 2, are due to mutations in AGPAT2 , which encodes 1-acylglycerol-3-phosphate O -acyltransferase 2, and BSCL2 / seipin , respectively (see Table 101.1 ). It has been postulated that these genetic mutations cause lipodystrophy primarily by affecting adipocyte differentiation or lipid droplet formation in adipose tissue. In type 1, aberrant AGPAT2 enzyme activity causes a marked reduction in triglyceride and phospholipid synthesis, resulting in abnormal adipocyte function . In type 2, BSCL2 mutations affect the endoplasmic reticulum membrane protein seipin which is critical for lipid droplet morphology.

In types 3 and 4 CGL, genetic mutations have been detected that affect the function of caveolae, which are invaginations of the plasma membrane involved in signal transduction and endocytosis, including internalization of the insulin receptor. Patients with type 3 CGL have mutations in CAV1 which encodes caveolin 1 ; caveolins are essential components of caveolae and caveolin 1 binds fatty acids and translocates them to lipid droplets. Type 4 CGL is due to mutations in CAVIN1/PTRF , whose protein product is involved in the biogenesis of caveolae and the expression of caveolins 1 and 3 .

Differences in the molecular basis of CGL may account for the phenotypic heterogeneity . AGPAT2 has been found to be highly expressed in human omental adipose tissue, which may explain the preferential loss of metabolically active intra-abdominal adipose tissue but preservation of mechanical palmoplantar adipose tissue in patients with type 1 CGL. BSCL2 has been found to also be highly expressed in the brain , which may account for the higher prevalence of intellectual disability in type 2 patients.

Familial Partial Lipodystrophy

Familial partial lipodystrophy (FPLD) is a heterogeneous group of autosomal dominantly and rarely autosomal recessively inherited disorders (see Table 101.1 ). The most prevalent subtype is the FPLD2, which is due to mutations in LMNA . LMNA encodes lamins A and C, with lamins belonging to the intermediate filament family of structural proteins that compose the nuclear lamina. LMNA mutations lead to disruption of nuclear function, resulting in apoptosis and premature cell death of adipocytes. These mutations also alter plasma levels of leptin, with heterozygotes (mutation in one copy of LMNA ) having decreased plasma leptin and increased fasting plasma insulin and C-peptide levels . Of note, LMNA mutations are also responsible for a group of laminopathies that includes muscular dystrophy, cardiomyopathy, neuropathies, and syndromes of premature aging (see Tables 63.9 & 63.10 ). The clinical phenotype/syndrome is determined by the site and type of LMNA mutations .

The genetic basis of FPLD1 is unknown, but FPLD3 results from heterozygous missense mutations of the gene that encodes peroxisome proliferator-activated receptor-γ ( PPARG ) . The PPAR-γ protein plays an essential role in adipogenesis (see Fig. 101.14 ), but the entire pathogenesis remains unclear. Although this subtype has a milder clinical phenotype than FPLD2, with a later age of onset and involvement confined to the distal extremities, metabolic disturbances are more severe, suggesting that PPARG mutations may have additional direct effects on metabolism.

In patients with FPLD4, heterozygous loss-of-function mutations have been described in the gene that encodes perilipin 1 ( PLIN1 ) . Perilipin is responsible for the formation, maturation, and function of lipid droplets within adipocytes. Lipoatrophy of the lower extremities is accompanied by marked hypertriglyceridemia and severe insulin resistance with type 2 diabetes.

To date, FPLD5 and FPLD6 are based on a single patient and two siblings, respectively, and because of homozygous missense mutations (FPLD5) and consanguinity (FPLD6), an autosomal recessive pattern is favored. The associated genes encode a member of the cell death-inducing DNA fragmentation factor-like effector family ( CIDEC ) that is thought to play a role in adipocyte apoptosis and lipase, hormone sensitive ( LIPE ).

Partial lipodystrophy may also be seen in association with mandibuloacral dysplasia (MAD), an autosomal recessive syndrome associated with mutations in LMNA (type A), or with mutations in ZMPSTE24 , which encodes a zinc metalloproteinase involved in post-translational proteolytic processing of prelamin A (type B) . The latter has been associated with severe mandibuloacral dysplasia, premature aging, and generalized lipodystrophy.

Mesangiocapillary glomerulonephritis type 2 (MCGN II) has been reported in a case of partial lipodystrophy due to a mutation in the LMNA gene, suggesting that partial lipodystrophy of both the sporadic and familial subtypes may predispose to this condition and the observed renal and complement abnormalities may be secondary to other factors associated with lipodystrophy .

Acquired Generalized Lipodystrophy (Lawrence Syndrome)

There is no known genetic defect. A third of patients have an antecedent autoimmune disease or viral or bacterial infection, but a causal relationship with the latter has not been established. Twenty-five percent of cases of acquired generalized lipodystrophy are heralded by panniculitis (see Table 101.1 ) .

The preceding panniculitis and the frequent association of autoimmune disease imply immunologically mediated fat cell lysis. Autoantibodies against the adipocyte membrane have been reported in one patient with this condition . As with the other forms of lipodystrophy, most patients have low serum levels of leptin and adiponectin.

Acquired Partial Lipodystrophy Syndrome (Barraquer–Simons Syndrome)

Acquired partial lipodystrophy syndrome occurs sporadically or may be autosomal dominant, with mutations in LMNB2 reported in some patients . Subcutaneous fat is often lost acutely after a viral illness. The exact pathogenesis is not known, but it may be related to adipsin, a protein produced by adipocytes which is identical to factor D (a component of the alternative complement pathway; see Ch. 60 ), as well as C3 nephritic factor (C3NeF), an IgG autoantibody against an alternative pathway enzyme. There is dysregulated activation of the alternative pathway, associated with C3NeF binding to the rate-limiting C3 convertase enzyme (C3bBb). This results in unopposed activation of the alternative complement pathway, excessive consumption of C3, and complement-dependent lysis of adipocytes.

Regional differences in factor D expression parallel the regional distribution of adipocyte loss in partial lipodystrophy, which may explain the cephalocaudal distribution of fat. Renal cells also express complement components, and a similar mechanism of complement-mediated injury may be responsible for the MCGN II seen in these patients .

Localized Lipoatrophy

The pathogenesis of localized lipoatrophy is heterogeneous. Circumscribed areas of lipoatrophy may follow inflammation from pyogenic abscesses, various lobular panniculitides (especially lupus profundus and panniculitic dermatomyositis), localized autoimmune connective tissue diseases (e.g. morphea), or subcutaneous panniculitis-like T-cell lymphoma. Iatrogenic causes include traumatic and inflammatory responses to injected medications ( Table 101.2 ).

In the case of insulin lipoatrophy, it may be induced by impurities and is significantly associated with the presence of anti-insulin antibodies ; mononuclear infiltrates near insulin injections suggest a localized immune response. Because repeated use of the same injection site increases the risk of lipoatrophy, the latter can be largely prevented by regular rotation of injection sites. Of note, lipoatrophy is fairly rare with the use of human insulin and insulin pump therapy. Lipoatrophy may also occur at injection sites of growth hormone and glatiramer acetate due to a direct lipolytic effect and panniculitis, respectively.

Lipoatrophia semicircularis may represent repetitive trauma or pressure-induced changes ( Fig. 101.2 ), due to constant or intermittent pressure from leaning against a desk or chair edge, basin, bathtub or counter, or from tight-fitting jeans or girdles. Both resolution of the lesions when trauma is avoided and the occurrence of similar lesions in multiple employees in the same workplace provide support for microtrauma as the etiology . Local hyperproduction of TNF-α by macrophages has also been implicated . Localized lipoatrophy of the upper and lateral calf due to pressure is commonly observed in women who cross their legs when seated ( Fig. 101.3 ).

Up to 60% of involutional lipoatrophy (see below) may be associated with prior local injections, suggesting a trauma-related phenomenon . Lipophagocytizing macrophages seen by electron microscopy suggest an initial stimulation by injectable material; typically, an active foreign body reaction is absent.

Lipodystrophia centrifugalis abdominalis infantilis is usually idiopathic, but has been reported to be associated with mechanical trauma or focal infection. Predominance of this condition in East Asia is notable and reports in twins and siblings point to the possibility of an HLA predisposition. In one patient with lipodystrophia centrifugalis abdominalis infantilis, positive immunohistochemical staining for Fas, bcl-2 and p53 as well as terminal transferase-mediated dUTP nick end-labeling (TUNEL) in degenerating fatty tissue suggested apoptosis as a possible factor .

Congenital Generalized Lipodystrophy (CGL)

CGL is rare, with an estimated prevalence of less than 1 case in 10 million . As an autosomal recessive disorder, there is often consanguinity. All subtypes are characterized by generalized loss or absence of metabolically active subcutaneous fat from birth, resulting in a cadaveric facies and distinctive muscular-appearing body habitus ( Fig. 101.4A ). Anabolic features are evident in early childhood ( Table 101.3 ). There is also a deficiency of bone marrow fat (types 1,2) and visceral fat (types 1,3,4). Type 2 CGL also lacks mechanical fat, in addition to metabolically active fat.

The inability to store sufficient fat in the adipocytes results in the metabolic syndrome (see Ch. 53 ), which becomes more profound during puberty . Diabetes mellitus is evident by adolescence, but hyperinsulinemia can be detected as early as infancy. Enlarged genitalia are seen, especially in women, and may be associated with polycystic ovarian syndrome and infertility. Hepatosplenomegaly is typical and may be associated with umbilical herniation. Dermatologic sequelae (see Table 101.3 ) include acanthosis nigricans, which is noted by adolescence and may be extensive ( Fig. 101.4B ). Serious medical complications and metabolic derangements include cirrhosis from fatty liver, premature atherosclerosis, sequelae of diabetes, pancreatitis from hypertriglyceridemia, and a high mortality rate from hypertrophic cardiomyopathy. The mean age of death is 32 years. Type 2 appears to be a more severe disorder that is associated with intellectual disability, hypertrophic cardiomyopathy and a higher incidence of premature death while type 4 patients have cardiac arrhythmias and pyloric stenosis.

Familial Partial Lipodystrophy

Familial partial lipodystrophy (FPLD) was first described by Dunnigan and Köbberling , who outlined the clinical characteristics of large Scottish and German pedigrees with familial syndromes of partial lipodystrophy. FPLD is classified based upon genetic mutations and clinical phenotype (see Table 101.1 ). This group of disorders differs from other forms of inherited lipodystrophy by a later onset (after puberty) and fat loss predominantly affecting the extremities, with sparing of the face . FPLD is a rare disorder, with a prevalence of less than 1 in 15 million .

In FPLD2, a normal childhood is followed by a progressive, symmetric loss of subcutaneous fat; the latter uniformly involves the extremities and variably extends to the trunk (anterior > posterior). Compensatory accumulation of excess fat occurs and results in a fat head and neck, with a round face, as well as increased supraclavicular fat (see Fig. 101.1 ). Acromegalic facies with a double chin is characteristic. As a result of the loss of fat in the limbs, there is an accentuation of subcutaneous veins and muscular prominence ( Fig. 101.5 ). Although FPLD3 has milder clinical features and an onset after the second decade of life, the metabolic disturbances may be more severe .

Metabolic disturbances in FPLD are similar to those in the generalized lipodystrophy syndromes. Glucose intolerance, ranging from mild to severe, develops during young adulthood. Acute pancreatitis and hepatic steatosis and cirrhosis may occur, with complications from diabetes mellitus, atherosclerotic cardiovascular disease, or hypertrophic cardiomyopathy leading to premature death. When compared to men, affected women have been reported to have more severe triglyceride elevations. Dermatologic manifestations include tuberous xanthomas, acanthosis nigricans and hirsutism, while gynecologic findings include menstrual irregularities, polycystic ovaries, and fat hypertrophy within the labia majora.

Familial partial lipodystrophy with mandibuloacral dysplasia is a rare variant of partial lipodystrophy characterized by mandibular and clavicular hypoplasia, short stature, a high-pitched voice, and ectodermal abnormalities of the skin, teeth, nails and hair . There are multiple craniofacial defects, including dental overcrowding and a bird-like facies with prominent eyes and a beaked nose. Skeletal abnormalities include osteolysis of the clavicles, acro-osteolysis, delayed closure of cranial sutures, and joint contractures. Mottled hyperpigmentation, alopecia, atrophy of extremity skin, and nail dysplasia are the characteristic cutaneous findings. Less common clinical features include sensorineural hearing loss, delayed puberty, a high-arched palate, and cutaneous calcinosis. Features of the metabolic syndrome may be present (see Ch. 53 ).