Other somatic abnormalities that contribute to the abnormal appearance are acanthosis nigricans, a protuberant abdomen associated with hepatomegaly and/or splenomegaly, and prominent musculature. Congenital muscular weakness and cervical spine instability has also been reported in occasional cases.¹³ Females may present with enlarged clitoris, increased body hair, absence of or irregular menstrual cycles, and polycystic ovaries. Only a few affected women have had successful pregnancies, whereas affected men have normal fertility. The patients with CGL tend to have voracious appetite. The basal metabolic rate of their body may also be increased. Although patients may have accelerated linear growth and advanced bone age during their childhood, they normally have normal or reduced heights as adults.

Although both boys and girls are affected at similar rates, the metabolic features tend to be more severe and develop earlier in girls. Hypertriglyceridemia is characterized by increased concentrations of very low–density lipoproteins (VLDLs) and chylomicrons, whereas serum high-density lipoprotein (HDL) is usually low. Severely elevated triglycerides may provoke acute pancreatitis and is frequently related to fatty liver. This commonly progresses to cirrhosis, which in many cases may be fatal. Insulin resistance has been noted at an early age and may be present even at birth. Clinical diabetes usually develops in the early teens, is rarely ketotic, and is usually refractory to insulin therapy. Serum adipocytokines, the hormones produced by adipose tissue (e.g., leptin and adiponectin), circulate in extremely low levels in CGL.¹⁴ CGL may also be associated with focal lytic lesions in the long bones,^15–17 mild mental retardation,¹⁸ cardiomyopathy,^19–21 generalized muscle weakness, and cervical spine instability.¹³

At least three molecularly distinct forms of congenital lipodystrophy have been defined, with mutations of AGPAT2 and BSCL2 responsible for 95% of reported cases of CGLs.

Type 1 CGL (CGL1) is due to AGPAT2 gene mutations. This gene has been mapped to chromosome 9q34.22,23 It encodes the enzyme acyltransferase 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) which catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglyceride and glycerophospholipids. AGPAT2 mutations are found predominantly in patients of African ancestry.

Type 2 CGL (CGL2) is due to BSCL2 gene mutations. This gene is located in chromosome 11q13 and encodes a 398-amino-acid protein called seipin.²⁴ The BSCL2 gene mutation has been found in patients of European and Middle Eastern origins but has also been reported as a causative gene in Japanese patients with CGL. Seipin is expressed diffusely in many tissues but predominantly in testis and brain; its function in humans is largely unknown. A recent study in yeast suggests that seipin is important for lipid droplet morphology and perhaps assembly.⁹ Another study in cultured murine and human adipocytes also indicates that BSCL2 expression is critical for normal adipogenesis in vitro, as cells lacking BSCL2 failed to induce expression of key lipogenic transcription factors (peroxisome proliferator–activated receptor gamma [PPARG] and CCAAT/enhancer binding protein alpha [C/EBP-α]), as well as enzymes (AGPAT2, DGAT2, and lipin 1). BSCL2 mutations are usually related to more severe adipose tissue loss than in CGL1.⁹

The CGL due to seipin mutation appears to have a more severe disease phenotype than that due to AGPAT2 mutation, with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Furthermore, patients with seipin mutations have a higher prevalence of intellectual impairment than those with the AGPAT2 mutations.

Compared to CGL1, CGL2 patients have more pronounced absence of body fat. In addition to the loss of metabolically active fat (subcutaneous regions, intermuscular regions, bone marrow, intraabdominal and intrathoracic regions), CGL2 patients also lack mechanical fat (orbital regions, palms, soles, and joints), Mild mental retardation and cardiomyopathy are also reported to be of higher prevalence in patients with CGL2.

Recently a third gene mutation has been identified in one individual with CGL 25–27 who had a homozygous nonsense mutation of CAV1, probably as a result of a consanguineous union. CAV1 is located on chromosome 7q31. Its end product, caveolin 1, is a highly conserved 22-KD protein and a crucial component of plasma membrane microdomains known as caveolae. These plasma membrane domains have important roles in regulating signaling pathways and processes such as cell migration, polarization, and proliferation. Caveolin 1 has also been identified as a major fatty acid binder on the plasma membranes. Mutated function of CAV1 may induce lipodystrophy by interfering with lipid handling, lipid droplet formation, and adipocyte differentiation.^9,28

The patient with CAV1 mutation reportedly has clinical features similar to those of patients with CGL1 and CGL2, with the degree of her lipodystrophy being intermediate between these two phenotypes. This patient also presented with some distinctive features, including well-preserved bone marrow fat, short stature, hypocalcemia, hypomagnesemia, and decreased bone density. However, because there is only one patient who has been identified as having this mutation, it is difficult to fully ascertain the exact relationship between the mutation and the associated clinical features.

Acquired Generalized Lipodystrophy (Lawrence Syndrome)

The acquired syndrome of total lipoatrophy is similar to that of the congenital disorder, except that it develops in a previously healthy individual over days to weeks, often after a nonspecific febrile illness. The syndrome is very rare. It commonly develops during childhood and aldolence in patients who are predominantly white, with a male-to-female ratio of 1 : 3.26,29

In addition to the generalized loss of fat that has an active metabolic function, as seen in CGL, fat loss in acquired generalized lipodystrophy (AGL) also occurs in palms, soles, and genital areas. However, retroorbital and bone marrow fat may be preserved.²⁷

The median time to develop diabetes after loss of fat tissue is approximately 4 years.²⁷ Diabetic ketoacidosis has been reported, and hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, menstrual irregularities, and polycystic ovary syndrome (PCOS) are also common findings. Patients with AGL also have markedly reduced adiponectin levels and moderately reduced leptin levels.¹⁴

Several autoimmune diseases and inflammatory conditions have shown a temporal relationship to AGL. These include juvenile-onset dermatomyositis (JDM), rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, Sjögren syndrome, and panniculitis.27,30 JDM shows a particularly strong correlation with lipodystrophy; 8% to 40% of patients with JDM develop acquired lipodystrophy.^31–35 The chronicity and severity of JDM, as well as the high frequency of calcinosis, have been shown to predict the onset of lipodystrophy.³¹ AGL following autoimmune diseases is also termed AGL type 2 or the autoimmune disease variety. Panniculitis is another inflammatory condition that frequently heralds the onset of acquired generalized lipodystrophy. It is estimated to be present in approximately 25% of affected patients.^27,36 Panniculitis manifests as subcutaneous inflammatory nodules which show a mixed infiltrate of lymphocytes and mononucleated macrophages in adipose tissue. The course of AGL is frequently protracted in patients with panniculitis and linked to less fat loss and less severe metabolic disorders.^32,33 The panniculitis variety is also known as AGL type 1. Up to 50% of AGL patients have no clear history of autoimmune disease or panniculitis, however. These lipodystrophies are known as AGL type 3 or the idiopathic type.

The pathogenesis of AGL is unknown. The autoimmune-mediated destruction of adipocytes or preadipocytes has been hypothesized to be the underlying mechanism. Autoantibodies against adipocyte membranes may also impair fat uptake and adipocyte differentiation.30,31,37 Several antibodies have been found to be present in AGL, but no causative relationship has been established.³¹ Cytokines, including tumor necrosis factor alpha (TNF-α) and interleukin 1 (IL-1), are also likely to play important roles in the immunopathogenesis of lipodystrophy. They can potentially lead to lipodystrophy by inhibiting adipogenesis³⁸ or increasing receptor-mediated apoptosis of adipocytes and preadipocytes.³⁹

The gene for Dunnigan variety, LMNA, is located on chromosome 1q21-22. It encodes for lamins A and C, which are essential components of nuclear lamina and provide structural integrity of the nuclear envelope. Most FPLD2 mutations in LMNA are missense mutations within the 3′ end of the gene.⁴¹ The mutant gene products may disrupt interaction with chromatin or other nuclear lamina proteins, resulting in apoptosis and premature death of adipocytes.⁴² The accumulation of prelamin A may also impair adipogenesis by interfering with the key adipocyte transcription factors/regulators, including sterol response element–binding protein 1 (SREBP-1) and PPARG.^42–45 It is interesting to note that there is a lack of difference in the levels of lamin A and lamin C expression in different adipose depots even though the fat loss of FPLD2 is regionally selective, suggesting that the downstream effects of LMNA mutations are differentially regulated in different areas of the body.⁴⁰

Köbberling-Type Lipodystrophy

Also known as FPLD type 1 (FPLD1), Köbberling-type lipodystrophy was first reported by Köbberling et al. in 1971. In comparison to Dunnigan variety, the loss of adipose tissue is restricted to the extremities. The distribution of fat on the face and neck is normal or increased in association to frequently observed significant central obesity. The hallmark anthropomorphic feature of this syndrome includes a palpable “ledge” formed between the normal and lipodystrophic areas and high triceps-to-forearm and abdomen-to-thigh skinfold ratios.⁴⁶ Only women have been diagnosed with Köbberling-type lipodystrophy to date. It is hypothesized that males have a very gentle clinical presentation that does not allow early detection, but this remains to be proven. FPLD1 tends to have a childhood onset.

Metabolic syndrome, especially hypertriglyceridemia, is common in Köbberling-type lipodystrophy. This correlates with high incidence of pancreatitis and premature coronary artery disease. Leptin concentrations are low and correspond to the BMI and the level of fat loss of individual patients.⁴⁶

The genetic defect associated with Köbberling-type lipodystrophy is currently unknown, and no LMNA or PPARG mutations have been identified. It appears that this syndrome may be familial for some subjects but may also occur spontaneously.

Familial Partial Lipodystrophy Due to PPARG Mutations

Also referred as FPLD3, familial partial lipodystrophy due to PPARG mutations is associated with heterozygous PPARG gene mutations. The phenotype is similar to the Dunnigan variety, with the exception that fat accumulation in the head and neck may be spared.47–50 Patients with FPLD3 appear to have more severe metabolic abnormalities than those with FDLP2.⁴⁵

PPARG encodes the peroxisome proliferator–activator receptor, which belongs to the superfamily of nuclear hormone receptors. It has a higher expression in adipocytes and plays an essential role in adipogenesis. Heterozygous mutations may cause loss of function by directly interfering with normal gene function (dominant negative) or by reducing gene expression (haploinsufficiency).

Familial Partial Lipodystrophy Due to AKT2 Mutation

Familial partial lipodystrophy due to AKT2 mutation has been reported in a single family by George et al.⁵¹ It is inherited in an autosomal dominant fashion and manifests as severe insulin resistance and partial lipodystrophy confined to extremities.⁵¹

AKT, also known as protein kinase B, is a serine/threonine protein kinase and plays multiple roles in cell signaling, cell growth, and glycogen synthesis, as well as insulin-stimulated glucose transport.⁵² Lipodystrophy in patients with AKT2 mutations is thought to be due to reduced adipocyte differentiation and dysfunctional postreceptor insulin signaling.

Partial Lipodystrophy Due to CAV1 Mutation

Partial lipodystrophy due to CAV1 mutation was recently identified as a rare cause for partial lipodystrophy.⁵³ Two cases with different frameshift CAV1 mutations have been reported. Both patients were described to have partial lipodystrophy with subcutaneous fat loss in the face and upper body, micrognathia, and congenital cataracts. One case was also associated with abnormal neurologic findings. Diabetes, hypertriglyceridemia, and recurrent pancreatitis were reported in both cases.⁵³

Other Syndromes With a Component of Lipodystrophy

Mandibuloacral dysplasia (MAD) is an extremely rare autosomal recessive progeroid syndrome which has been reported in approximately 40 case reports. MAD is characterized by postnatal growth retardation, craniofacial and skeletal abnormalities (mandibular and clavicular hypoplasia, delayed closure of the cranial sutures, acroosteolysis, joint contractures, birdlike face, dental abnormalities), cutaneous changes (restrictive dermatopathy, skin atrophy, alopecia, and mottled cutaneous pigmentation), and lipodystrophy. Although MAD is present at birth, dysmorphic manifestations and progeroid features become more prominent with time, and the full clinical phenotype is recognizable during the early school years. The patients have normal intelligence,⁵⁴ and their serum leptin concentration can be low or normal. Hyperinsulinemia, insulin resistance, impaired glucose tolerance, diabetes mellitus, and hyperlipidemia have been reported in some patients.

There are two distinctive phenotypes of MAD: type A involves the loss of subcutaneous fat from the arms and legs but normal or excessive deposition of fat in the face and neck, and type B is characterized by more generalized loss of subcutaneous fat. Mandibular dysplasia type A (MADA) is also considered to be due to mutations of the LMNA gene which result in accumulation of prelamin A and lead to alterations of nuclear architecture and chromatin defects. It remains unclear how different mutations in the same gene lead to a variety of phenotypes. Patients with mandibular dysplasia type B have been reported to carry compound heterozygous mutations in the gene encoding an endoprotease, zinc metalloprotease (ZMPSTE24), on chromosome 1q34. The enzyme is important in posttranslational processing of prelamin A to mature lamin A. As in MADA, the accumulation of farnesylated prelamin A is proposed to be responsible for the phenotype.⁵⁴ Focal segmental glomerulosclerosis has been reported in patients with ZMPSTE24 deficiency.⁵⁵

Multiple other syndromes are also linked to lipodystrophy. Several of them have also been identified as laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS, a very rare and uniformly fatal segmental progeroid syndrome with progressive and generalized fat loss), restrictive dermopathy (RD), progeria-associated arthropathy, and atypical progeroid syndrome (also referred to as atypical Werner’s syndrome).⁵⁴

Werner’s syndrome (short stature, birdlike appearance of the face, and early onset of aging processes) has been linked to homozygous mutations in RECQL2, which encodes a DNA helicase. In contrast, the molecular genetic basis and inheritance patterns have yet to be clarified for the following syndromes: Cockayne’s syndrome (short stature, photosensitivity, hearing loss, premature aging), carbohydrate-deficient glycoprotein syndrome (nonprogressive ataxia associated with cerebellar hypoplasia, stable mental retardation, variable peripheral neuropathy, and strabismus), SHORT syndrome (S–short stature; H–hyperextensibility of joints and/or hernia (inguinal); O–ocular depression; R–Rieger anomaly; T–teething delay), and ectodermal dysplasia in association with generalized lipodystrophy acral renal ectodermal dysplasia lipoatrophic diabetes (AREDYLD) syndrome.

Acquired Partial Lipodystrophy (Barraquer-Simons Syndrome)

First reported in 1885 by Mitchell, acquired partial lipodystrophy (APL) was further characterized by Barraquer-Roviralta in 1907. There have been approximately 250 cases reported in the English-language literature.²⁶

Patients with APL are primarily of European descent; however, cases have also been reported in Asian Indian, Vietnamese, and Samoan populations. The disease shows a female dominance, and most patients have clinical manifestations in early puberty or early adulthood. The characteristic fat loss progresses in a “cephalocaudal” fashion, with fat loss appearing first in the face and spreading to the upper part of the body. Fat under the umbilicus is rarely affected. Excess fat accumulation is seen over the lower abdomen, gluteal region, thighs, and calves. Breasts may lose fat and consist of firm glandular tissue only.²⁷ Hepatomegaly is common among patients with APL.

In contrast to other types of lipodystrophies, acanthosis nigricans, hirsutism, and hypertrichosis are rare. Female patients normally have regular menses and intact fertility. The prevalence of the metabolic syndrome is also significantly lower in patients with APL. Insulin resistance is uncommon, and the prevalence of diabetes is much reduced compared to other types of lipodystrophies. In the series of case reports by Misra and Garg,²⁷ 35% of APL patients had hypertriglyceridemia, and a third had low concentrations of HDL. Serum leptin levels were normal in the majority of patients.¹⁴

A strong association has been proposed to exist between acquired partial lipodystrophy and membranoproliferative glomerulonephritis (MPGN) type 2. The spectrum of presentations range from acute glomerulonephritis, hematuria, nocturia, urinary casts, albuminuria, and nephritic syndrome to chronic glomerulonephritis and uremia.53,56 The serum C3 complement levels are usually low with the presence of C3 nephritic factor.⁵³ Patients with low C3 levels tend to have an earlier onset of lipodystrophy than those with normal serum C3 levels. The median time interval between the onset of lipodystrophy and the development of MPGN is approximately 5 to 10 years but could be as long as 20 years.^53,57

Similar to acquired generalized lipodystrophy, APL is also frequently seen in the context of autoimmunity or infections.³⁰ The most frequently cited infection preceding APL is measles. The low C3 levels may also render APL patients susceptible to recurrent pyogenic infections, particularly due to Neisseria.⁵⁸ Systemic lupus erythematosus and dermatomyositis/polymyositis are autoimmune diseases most frequently associated with acquired partial lipodystrophy.²⁷

The precise mechanisms leading to adipose-tissue atrophy in APL remain unclear. The C3 nephritic factor has been shown to induce lysis of adipocytes expressing factor D (adipsin).²⁷ Lamin B gene mutations have also been reported in some cases of APL.⁵⁹ In a recent study by Guallar et al., PPARG gene down-regulation and mitochondrial toxicity were observed in a patient with APL, suggesting that impaired adipogenesis and adipocyte metabolism may also underlie the pathogenesis of APL.⁶⁰