Version July 2025
INTRODUCTION —
The lipodystrophy syndromes are a heterogeneous group of disorders characterized by either complete or partial (regional) lack of adipose tissue (lipoatrophy) [1-3]. In some of these disorders, abnormal accumulation of fat occurs in other regions of the body, which are not affected by adipose tissue loss. Although generalized forms of lipodystrophy are exceedingly rare, some partial lipodystrophy syndromes are relatively common but remain highly underrecognized.
Clinically, features of severe lipodystrophy include severe insulin resistance, hyperglycemia, severe hypertriglyceridemia, progressive liver disease, and increased metabolic rate (table 1). The extent of fat loss correlates with the severity of the metabolic abnormalities. Acquired and congenital lipodystrophies may also be associated with proteinuric kidney diseases and cardiovascular disease. This topic will review the clinical manifestations, classification, and diagnostic evaluation of lipodystrophy syndromes. The management of lipodystrophy is reviewed separately. (See "Lipodystrophy syndromes: Management".)
Lipodystrophy that occurs in patients with human immunodeficiency virus (HIV) infection is the most prevalent form and is likely related to antiretroviral therapy. HIV-related lipodystrophy is discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy" and "Treatment of HIV-associated lipodystrophy".)
COMMON CLINICAL MANIFESTATIONS
Physical findings — All lipodystrophy syndromes are characterized by the loss or absence of adipose tissue. Other, less specific findings may be present and reflect lipodystrophy-associated complications.
●Specific findings – The prototypical feature of lipodystrophy is the absence of adipose tissue. The pattern of adipose tissue loss may be generalized or confined to specific depots. (See 'Classification' below.)
Prominent musculature and veins in the regions affected by adipose tissue loss are also apparent on examination. The appearance of prominent, well-defined musculature may be due solely to absence of overlying adipose tissue or, in certain forms of lipodystrophy, true muscle hypertrophy [4]. Veins also are prominent due to absence of overlying adipose tissue.
●Nonspecific findings – Other, nonspecific physical findings reflect complications associated with lipodystrophy syndromes and include the following (table 1):
•Acanthosis nigricans (due to insulin resistance and resulting hyperinsulinemia)
•Eruptive xanthomas (due to severe hypertriglyceridemia)
•Hepatomegaly (due to metabolic dysfunction-associated steatotic liver disease [MASLD])
•Hirsutism and other signs of hyperandrogenism, including infertility (females)
Rare forms of lipodystrophy also are associated with progeroid features. (See 'Progeria-associated lipodystrophy' below.)
Laboratory findings — In individuals with lipodystrophy, common laboratory findings reflect associated complications and comorbidities and include hyperglycemia, hypertriglyceridemia, and elevated liver biochemical tests.
Leptin levels are typically low or undetectable, particularly in generalized lipodystrophies, but this is not a specific finding for lipodystrophy; low leptin levels reflect lower total body fat mass and can be found in other causes of low fat mass such as extreme leanness. Levels of the endogenous insulin sensitizer adiponectin are usually also low, reflecting abnormal "ectopic" intraabdominal fat accumulation, and contribute to manifestations of cardiorenal metabolic syndrome.
Complications and comorbidities — In lipodystrophy syndromes, the severity of complications generally correlates with the degree of adipose tissue loss [3]. Common complications and comorbidities include the following:
●Insulin resistance and diabetes – Most forms of lipodystrophy confer high risk of type 2 diabetes that is often treatment resistant. Many patients require high doses of insulin (eg, ≥200 units daily). Despite this relative insulin deficiency, diabetic ketoacidosis is generally rare.
●Kidney disease – Acquired and congenital lipodystrophies may also be associated with proteinuric kidney diseases. This may be due to diabetes-related kidney disease, focal segmental glomerulosclerosis, or membranoproliferative glomerulonephritis [5,6].
●Liver disease – MASLD (also known as nonalcoholic fatty liver disease) is common. MASLD can progress to steatohepatitis and cirrhosis.
●Hypertriglyceridemia – Hypertriglyceridemia can be severe and present with eruptive xanthomas, lipemia retinalis, abdominal pain, and acute pancreatitis.
●Hypertension – Early-onset hypertension is common in lipodystrophy syndromes and contributes to cardiovascular risk.
●Reproductive dysfunction – In females with lipodystrophy, hyperandrogenism, menstrual irregularity, reduced fertility, and polycystic ovary syndrome are common.
●Cardiovascular disease – Some forms of lipodystrophy are associated with increased risk of premature atherosclerotic cardiovascular disease, cardiomyopathy, and/or cardiac arrhythmias.
●Other – Intellectual disability, hyperphagia, and other associated features are less common and specific to certain forms of lipodystrophy. These are reviewed under discussion of specific lipodystrophy syndromes immediately below.
The approach to evaluating and managing lipodystrophy-related complications is presented separately. (See "Lipodystrophy syndromes: Management".)
CLASSIFICATION
Types of lipodystrophy — A widely accepted classification of the various types of lipodystrophies is presented in the table (table 2). Lipodystrophies are classified as congenital or acquired and as having a partial or generalized pattern of absence of adipose tissue [3]. Knowledge of the molecular basis for these disorders is growing, and multiple molecular defects are responsible (figure 1). In addition to the general features described above, discrete forms of lipodystrophy also have unique clinical manifestations (figure 2).
Congenital lipodystrophies
Congenital generalized lipodystrophy — Congenital generalized lipodystrophy (CGL) is also known as Seip-Berardinelli syndrome [7,8] and is inherited as an autosomal recessive trait with frequent parental consanguinity. At least four molecularly distinct forms of congenital lipodystrophy have been defined, and pathogenic variants of AGPAT2 and BSCL2 (type 1 and type 2 CGL, respectively) are responsible for 95 percent of reported cases (figure 1) [9-11]. The prevalence of CGL is estimated at less than one case per one million people.
Clinical features — Absence of subcutaneous fat is noted within the first two years of life, often at birth or soon thereafter. Adipose tissue is almost completely absent from most subcutaneous areas, the abdomen, thorax, and bone marrow. Mechanical fat depots (eg, palms, soles) are preserved in some forms.
During childhood, these patients have a voracious appetite, accelerated linear growth, increased metabolic rate, and advanced bone age. Adult height is usually normal. Insulin resistance evolves at an early age. Type 2 diabetes usually develops in the early teens, and hypertriglyceridemia, which may be severe and lead to acute pancreatitis, is common. Serum leptin concentrations are low, consistent with near total absence of body fat [12]. Precocious secondary sexual development also may occur, and adult females may present with signs of hyperandrogenism and polycystic ovary syndrome. Some patients have intellectual disability (figure 3).
Major forms — Among the molecularly distinct forms of CGL, the clinical phenotype varies [11,13]. Some individuals with CGL do not have any of the known pathogenic gene variants, indicating the existence of other, yet unidentified CGL genes.
●Type 1 CGL (CGL1) is due to pathogenic variants in AGPAT2. APGAT2 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 triglycerides and glycerophospholipids. AGPAT2 variants are found predominantly in patients of African ancestry.
In CGL1, normal adipose tissue deposition is limited to mechanical fat (orbital regions, palms, soles, and joints), the mouth and tongue, scalp, and perineum [14].
●Type 2 CGL (CGL2) is due to pathogenic variants in BSCL2, the gene that encodes the protein seipin. BSCL2 expression is critical for normal adipogenesis in vitro, as cells lacking BSCL2 fail to express key lipogenic transcription factors. CGL2 is more severe than CGL1, with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Patients with CGL2 also have more pronounced absence of body fat, with loss of both metabolically active fat (subcutaneous and intermuscular regions, bone marrow, intraabdominal and intrathoracic regions) and mechanical fat (orbital regions, palms, soles, and joints). Patients with CGL2 also have a higher prevalence of intellectual disability and cardiomyopathy than those with CGL1.
●Type 3 CGL (CGL3) is due to a homozygous nonsense variant in CAV1 [15], which encodes the protein caveolin-1. Caveolin-1 is a fatty acid-binding protein found on the plasma membrane in microdomains called caveolae. Abnormal function of caveolin-1 may lead to lipodystrophy through disordered lipid handling, lipid droplet formation, and/or adipocyte differentiation. Patients with CGL3 have an intermediate phenotype between CGL1 and CGL2. In CGL3, mechanical fat is preserved and intellectual disability is absent. Key associated features include short stature, vitamin D resistance, hypocalcemia, and hypomagnesemia.
Heterozygous variants in CAV1 also have been associated with partial lipodystrophy. (See 'Partial lipodystrophy due to CAV1 variant' below.)
●Type 4 CGL (CGL4) is due to pathogenic variants in PTRF [16], which encodes cavin. Cavin is a polymerase I and transcript release factor involved in the biogenesis of caveolae. Only 21 patients with PTRF pathogenic variants have been reported [1]. Clinical features include moderate lipodystrophy in association with congenital myopathy, esophageal dysfunction, pyloric stenosis, atlantoaxial instability, and QT interval prolongation with exercise-induced ventricular tachycardia and sudden death.
Congenital partial lipodystrophy
Familial partial lipodystrophy — Familial partial lipodystrophy (FPLD) syndromes are characterized by variable loss of adipose tissue that occurs during childhood, puberty, or young adulthood. They are associated with metabolic complications and, in some cases, cardiomyopathy, conduction disturbances, and congestive heart failure. Syndromes of regional lipoatrophy may be associated with simultaneous hypertrophy of adipose tissue in nonatrophic areas. Clinical partial lipodystrophy syndromes were once considered rare; however, some data suggest a prevalence of approximately 1 in 20,000 [17]. Such findings underscore the widespread lack of recognition and underdiagnosis of these syndromes.
●FPLD type 1 – FPLD type 1 (Kobberling lipodystrophy) is characterized by loss of adipose tissue in the extremities and normal adipose tissue elsewhere. Affected individuals may have excess subcutaneous truncal fat, creating well-demarcated "ledges" between regions of fat loss and increased fat deposition. FPLD type 1 is predominantly diagnosed in females [18]. The genetic basis of Kobberling-type lipodystrophy is unknown, and it may be a polygenic disorder in some individuals [19]. No LMNA or PPARG variants have been identified. Although this syndrome is predominantly familial, it may also occur spontaneously.
The age of onset, mode of inheritance, and characteristic features are not completely defined. Lipodystrophy and prominent, well-defined muscles (without increased muscularity) are the most frequently described clinical characteristics. Most reported patients have diabetes and hypertriglyceridemia, which is often severe and may lead to acute pancreatitis [20].
●FPLD type 2 – FPLD type 2 (Dunnigan lipodystrophy) is associated with fat loss from the extremities, abdomen, and thorax and excess subcutaneous fat in the chin and supraclavicular area [1,21-23].
•Pathogenesis – This disorder may be transmitted as an X-linked dominant or autosomal dominant trait [24-28]. The pathogenic variants appear to involve the LMNA gene, which encodes nuclear lamins A and C, nuclear envelope proteins that organize nuclear architecture through structural attachments that vary during the cell cycle and cell differentiation (figure 1) [29]. A less severe phenotype has been described in two sisters whose variant involved lamin A only [30].
Most pathogenic variants in LMNA are missense variants within the 3' end of the gene [31]. The aberrant gene products may disrupt interaction with chromatin or other nuclear lamin proteins, resulting in apoptosis and premature death of adipocytes. The accumulation of prelamin A may also impair adipogenesis.
•Clinical features – Loss of subcutaneous adipose tissue from the extremities usually occurs with the onset of puberty. The syndrome is associated with increased muscularity, rather than merely the appearance of increased muscularity that occurs with loss of subcutaneous fat. As a result, this syndrome is relatively easier to recognize in females. Muscle biopsies from affected individuals reveal hypertrophy of type 1 and 2 muscle fibers [32]. Patients may develop excess supraclavicular fat and round facies later in life. They also may have acanthosis nigricans, hirsutism, and menstrual abnormalities (ovarian hyperandrogenism) (figure 4).
Diabetes and hepatic steatosis may develop prior to the age of 20 years [20,33] and are accompanied by hypertriglyceridemia (hyperchylomicronemia) and low serum high-density lipoprotein cholesterol (HDL-C) concentrations [24,34], contributing to increased cardiovascular risk. Such patients also have increased risk of cardiac arrhythmias [35].
●FPLD type 3 – FPLD type 3 is associated with heterozygous PPARG gene pathogenic variants (figure 1) [31]. Heterozygous variants may cause loss of function by directly interfering with normal gene function (dominant negative) or by reducing gene expression (haploinsufficiency). The phenotype is similar to FPLD2 (Dunnigan lipodystrophy), with the exception that fat deposition in the head and neck may appear normal. Patients with FPLD3 appear to have more severe metabolic abnormalities than those with FPLD2.
●FPLD type 4 – FPLD type 4 is associated with a variant in the PLIN1 gene, which encodes perilipin 1. Perilipin 1 is a required component of lipid droplet membranes and is essential for lipolysis and lipid storage [36]. FPLD type 4 is characterized phenotypically by loss of subcutaneous fat from the extremities. Histologically, adipose tissue analyses from the six patients identified with this genetic variant show small adipocytes with increased macrophage infiltration and abundant fibrosis.
●FPLD type 5 – FPLD type 5 is due to an autosomal recessive pathogenic variant in the CIDEC gene, which encodes the cell death-inducing DFFA like effector c (CIDEC). CIDEC contributes to the regulation of adipocyte differentiation and lipid droplet formation. Variant(s) in the CIDEC gene result in low levels of functional CIDEC protein, leading to inability of lipid droplets to store fat. Reported features include partial lipodystrophy, severe insulin resistance, steatotic liver disease, acanthosis nigricans, and diabetes.
●FPLD type 6 – FPLD type 6 is due to an autosomal recessive pathogenic variant in the LIPE gene, which encodes lipase E, hormone sensitive type. This form of lipodystrophy is characterized by abnormal subcutaneous fat distribution. Affected individuals may have increased visceral fat, impaired lipolysis, dyslipidemia, hepatic steatosis, systemic insulin resistance, and diabetes. Some patients manifest muscular dystrophy and elevated serum creatine phosphokinase.
●Other – FPLD can also be due to a pathogenic variant in AKT2 (protein kinase B), a serine/threonine-protein kinase that plays multiple roles in cell signaling, cell growth, glycogen synthesis, and insulin-stimulated glucose transport. Lipodystrophy in patients with AKT2 variants has been ascribed to impaired insulin signaling and adipocyte differentiation [37].
Partial lipodystrophy due to CAV1 variant — A pathogenic variant in CAV1 was identified as a rare cause of sporadic partial lipodystrophy [38]. Two cases with different frameshift CAV1 variants have been reported 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.
Progeria-associated lipodystrophy
Mandibuloacral dysplasia — Mandibuloacral dysplasia (MAD) is an extremely rare, autosomal recessive, premature aging (progeroid) syndrome, which has been reported in approximately 40 case reports [39]. There are two distinctive phenotypes.
●Pathogenesis – MAD type A is due to pathogenic variants of the LMNA gene and involves the loss of subcutaneous fat from the arms and legs but normal or excessive deposition of fat in the face and neck. MAD type B is characterized by more generalized loss of subcutaneous fat. These patients carry compound heterozygous variants in the gene encoding an endoprotease, zinc metalloprotease (ZMPSTE24) [40-42]. The enzyme is important in posttranslational processing of prelamin A to mature lamin A.
●Clinical features – Lipoatrophy is first noted in childhood or early adolescence and is more marked in females [40]. In addition to lipodystrophy, this disorder is characterized by postnatal growth delay, craniofacial and skeletal abnormalities (mandibular and clavicular hypoplasia, delayed closure of the cranial sutures, acro-osteolysis, joint contractures, bird-like face, dental abnormalities), and cutaneous changes (restrictive dermatopathy, skin atrophy, alopecia, and mottled cutaneous pigmentation). 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. Focal segmental glomerulosclerosis has been reported in patients with ZMPSTE24 deficiency (type B MAD) [43].
Hyperinsulinemia, insulin resistance, impaired glucose tolerance, type 2 diabetes, and hyperlipidemia have been reported in some patients. Serum leptin concentration can be low or normal. In one study, individuals with FPLD due to pathogenic variants in the PPARG gene had less prominent fat loss and relatively higher levels of leptin than those with pathogenic variants in the LMNA gene [44].
Mandibular hypoplasia, deafness, and progeroid features syndrome — Mandibular hypoplasia, deafness, and progeroid features syndrome (MDP) is also characterized by progressive lipodystrophy and severe insulin resistance. It is caused by pathogenic variants in the POLD1 gene, which encodes a subunit of DNA polymerase delta [45].
Autoinflammatory syndromes — JMP (joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy) syndrome of childhood is a rare, autosomal recessive, autoinflammatory syndrome that has been reported in three individual patients from Japan and two families from Mexico and Portugal [1]. Clinical features include hepatosplenomegaly, intermittent fever, calcification of the basal ganglia, and hypergammaglobulinemia. Sequencing of candidate genes demonstrated a loss-of-function variant in the proteasome subunit, beta-type, (PSMB)-8 gene on chromosome 6. PSMB8 encodes b5i, a catalytic subunit of immunoproteasomes that mediate proteolysis and generate major histocompatibility complex (MHC) class 1 molecules. Pathogenic variants may result in adipose tissue lymphocytic infiltrations and loss of surrounding fat tissue.
CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) is another syndrome causing partial lipodystrophy. It has been reported in six patients and is likely characterized by autosomal recessive inheritance [1]. Infants present with annular violaceous plaques and recurrent fevers, with eventual loss of adipose tissue from the upper limbs and face. Associated clinical characteristics include hepatosplenomegaly, anemia, eyelid swelling, and calcifications of the basal ganglia. The molecular mechanism of this syndrome remains unknown.
Other syndromes with a component of lipodystrophy — 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, progeria-associated arthropathy, and atypical progeroid syndrome [46]. Most of these syndromes are associated with de novo LMNA variants, yielding a lipodystrophy syndrome similar to MAD type A. (See 'Mandibuloacral dysplasia' above and "Hutchinson-Gilford progeria syndrome".)
Werner syndrome (short stature, bird-like appearance of the face, and early onset of aging processes) has been linked to homozygous pathogenic variants in RECQL2, which encodes a DNA helicase [47], as well as null variants in the WRN gene. (See "Werner syndrome".)
SHORT syndrome (short stature, hyperextensibility of joints and/or hernia [inguinal], ocular depression, Rieger anomaly, and teething delay) is associated with autosomal dominant inheritance of variants in the PIK3R1 gene, which encodes phosphatidylinositol 3-kinase, regulatory 85a subunit (PIK3R1) [3]. PI3K heterodimers that include the p85 subunit are immediately downstream of the insulin receptor and function as key mediators of insulin-induced effects on energy metabolism and growth.
In contrast, the molecular genetic basis and inheritance patterns have yet to be clarified for the following syndromes:
●Cockayne syndrome (short stature, photosensitivity, hearing loss, premature aging).
●Carbohydrate-deficient glycoprotein syndrome (nonprogressive ataxia associated with cerebellar hypoplasia, stable developmental delay, variable peripheral neuropathy, and strabismus).
●Ectodermal dysplasia in association with generalized lipodystrophy acral renal ectodermal dysplasia lipoatrophic diabetes (AREDYLD) syndrome [1].
Acquired lipodystrophies
Acquired generalized lipodystrophy — Acquired generalized lipodystrophy is also called Lawrence syndrome (figure 5) [48]. Possible etiologies include previous viral infection or autoimmunity [49,50], and an association with panniculitis is evident in approximately 25 percent of patients. The syndrome may coexist with other autoimmune diseases, such as Hashimoto's thyroiditis, rheumatoid arthritis, hemolytic anemia, and chronic, active hepatitis.
●Pathogenesis – A previous infection has been causally linked to this syndrome because histologic analysis of subcutaneous tissue reveals panniculitis [49]. Antibodies against adipocyte-membrane antigens have been detected in a few patients [51]. In one cohort of 40 patients with autoimmune- or panniculitis-associated acquired generalized lipodystrophy, anti-perilipin (anti-PLIN1) antibodies were detected in 50 percent of patients, and a pathogenic role for anti-PLIN1 antibodies has been proposed [50,52].
●Clinical features – The clinical characteristics of acquired generalized lipodystrophy are similar to those of the congenital disorder, except that the former develops in a previously healthy individual [53]. The syndrome can develop in children, adolescents, or adults and predominately occurs in females. In most patients, the loss of fat begins in adolescence and occurs variably over a period of weeks, months, or years. Only a few dozen cases have been reported. Metabolic complications are often severe and include type 2 diabetes, MASLD, and hypertriglyceridemia. These severe complications may be associated with low leptin levels and very low levels of adiponectin.
Acquired partial lipodystrophy
Barraquer-Simons syndrome — Approximately 250 patients have been reported with this syndrome (also known as partial acquired cephalothoracic lipodystrophy or acquired partial lipodystrophy). It is characterized by the loss of adipose tissue from the face and upper trunk, with sparing or increased adiposity in the rest of the body (figure 5) [54,55]. Intramuscular, intraperitoneal, and perirenal fat, as well as bone marrow, orbital, and mediastinal fat deposition are normal.
●Pathogenesis – Autoimmune disorders such as dermatomyositis, hypothyroidism, pernicious anemia, rheumatoid arthritis, temporal arteritis, or mesangiocapillary glomerulonephritis have been reported in these patients [20,56,57]. Most patients with Barraquer-Simons syndrome have accelerated complement activation with low complement component 3 (C3) levels in association with a serum immunoglobulin G called C3 nephritic factor [58,59], which is thought to cause lysis of adipose tissue expressing adipsin. The heterogeneity in adipsin expression in different sites of adipose tissue may explain selective adipose tissue loss. Nonetheless, some individuals develop partial lipodystrophy without any evidence of autoimmunity.
●Clinical features – This disorder begins in childhood or adolescence, usually in females and often after a febrile illness. Fat loss usually occurs over a period of months or years. Several patients have had serum antinuclear and anti-double stranded DNA antibodies. As many as 20 percent of patients develop membranoproliferative glomerulonephritis (MPGN), occurring on average 8 to 10 years after initial diagnosis [55]. Presence of kidney impairment due to MPGN is an important prognostic factor.
Patients may have hyperinsulinemia but not severe insulin resistance, and the prevalence of diabetes (approximately 7 percent) is much lower when compared with other types of lipodystrophy (over 50 percent) [55].
Lipodystrophy associated with HIV therapy — Patients with human immunodeficiency virus (HIV) infection who are treated with antiretroviral therapy, and especially HIV-1 protease inhibitors, can develop lipodystrophy, and these drugs are probably the cause (figure 5). HIV-associated lipodystrophy is reviewed separately. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy" and "Treatment of HIV-associated lipodystrophy".)
DIAGNOSIS
Evaluation — Lipodystrophy is a clinical diagnosis based on clinical and family history and physical examination (algorithm 1 and algorithm 2). Imaging and laboratory testing can support the diagnosis but are not required. The approach to diagnostic evaluation below is consistent with the Endocrine Society clinical practice guidelines [60].
History and examination
●Clinical history – Patients should be queried about a personal and/or family history of known lipodystrophy, diabetes, hypertriglyceridemia, polycystic ovary syndrome (females), and acute pancreatitis. Diabetes and/or hypertriglyceridemia are often treatment resistant. If patients are unaware of a family history of lipodystrophy, we ask whether other individuals in the family have a similar body habitus (ie, preferential adipose deposition and loss in specific regions). Patients also should be queried about the timing of adipose tissue loss, both the age of onset and rapidity of change.
The following elements of clinical history can suggest a specific form of lipodystrophy:
•Adipose tissue loss in infancy or early childhood – In congenital generalized lipodystrophy (CGL), adipose tissue loss is evident before age two years. (See 'Congenital generalized lipodystrophy' above.)
•Proteinuric kidney disease – Severe kidney disease may be seen in most forms of lipodystrophy but is particularly prominent in acquired partial lipodystrophy. (See 'Barraquer-Simons syndrome' above.)
•Cardiomyopathy and/or intellectual disability – Cardiomyopathy and intellectual disability are common features of type 2 CGL. (See 'Major forms' above.)
•History of human immunodeficiency virus infection (HIV) and anti-retroviral therapy – HIV treatment is associated with acquired partial lipodystrophy. (See 'Lipodystrophy associated with HIV therapy' above and "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy".)
•Autoimmunity – Autoimmune conditions are associated with acquired generalized and acquired partial lipodystrophy. (See 'Acquired generalized lipodystrophy' above and 'Barraquer-Simons syndrome' above.)
●Physical examination – Physical examination should include assessment of regions with either adipose tissue loss or increased deposition, including face, neck, extremities, mechanical depots (eg, palms, soles), and abdomen (figure 2). Adipose tissue loss may be generalized or partial. With partial lipodystrophy, absence of adipose tissue is confined to specific depots or regions. Absence of subcutaneous fat may be apparent as the appearance of prominent musculature and veins.
Physical examination also should include assessment of other common physical findings associated with lipodystrophy-related complications, although these additional findings are not specific for lipodystrophy. (See 'Physical findings' above.)
•Suspected generalized lipodystrophy – In patients with suspected generalized lipodystrophy, the absence of adipose tissue in mechanical depots (eg, soles, palms) can help distinguish between type 1 and type 2 CGL, the most common forms of CGL (algorithm 2). Short stature suggests type 3 CGL. (See 'Major forms' above.)
•Suspected partial lipodystrophy – In patients with suspected familial partial lipodystrophy (FPLD), adipose tissue loss that is confined to the extremities suggests FPLD type 1 (Kobberling lipodystrophy), whereas more extensive fat loss is consistent with FPLD type 2 or type 3 (algorithm 1). (See 'Familial partial lipodystrophy' above.)
Unusual associated features can suggest a rarer underlying cause. Such features include progeroid features, muscle atrophy, joint contractures, and/or deafness. (See 'Progeria-associated lipodystrophy' above and 'Autoinflammatory syndromes' above and 'Other syndromes with a component of lipodystrophy' above.)
Laboratory testing — No laboratory tests are required for diagnosis. A low leptin level supports the diagnosis of lipodystrophy and could be helpful to identify candidates for metreleptin therapy; however, a low leptin level is not a specific finding and can be found in other conditions (eg, anorexia nervosa, relative energy deficiency in sport [RED-S]). (See "Lipodystrophy syndromes: Management", section on 'Generalized lipodystrophy (metreleptin)'.)
Low serum complement levels can support the diagnosis of acquired partial lipodystrophy but are not usually measured in practice. (See 'Barraquer-Simons syndrome' above.)
Although laboratory testing is not required for diagnosis, all patients with lipodystrophy should undergo laboratory evaluation to identify associated complications and comorbidities. This evaluation is reviewed separately. (See "Lipodystrophy syndromes: Management", section on 'Clinical and laboratory assessments'.)
Imaging (rarely needed) — If the diagnosis of lipodystrophy remains equivocal based on history and examination, imaging with dual-energy x-ray absorptiometry (DXA) or magnetic resonance imaging (MRI) can quantitatively establish the distribution of adipose tissue. However, this is rarely needed for diagnosis, which usually can be made based on clinical and family history and physical examination.
Genetic testing — Genetic testing is not a standard component of the diagnostic evaluation. However, genetic testing may help guide the approach to monitoring for complications and comorbid conditions, and it may be offered to family members at risk for developing the disorder. Further, it may be helpful for preconception counseling in individuals who seek fertility. Genetic testing is available clinically and/or through research studies for many forms of congenital lipodystrophy, and medical geneticists and genetic counselors can facilitate testing. Importantly, as not all pathogenic variants have been identified for partial or generalized lipodystrophies, negative genetic testing does not exclude the presence of congenital lipodystrophy.
Differential diagnosis — Other disorders that need to be differentiated from primary lipodystrophies are shown in the table (table 3). The differential diagnosis also includes localized lipodystrophies, in which adipose tissue loss is confined to a small area and does not cause metabolic sequelae.
●Non-lipodystrophy conditions – Conditions that lead to severe weight loss can mimic generalized lipodystrophy. These include cancer- or infection-related cachexia, anorexia nervosa, or thyrotoxicosis. Therefore, patients with acquired generalized lipodystrophy should undergo additional evaluation that may include a careful dietary history, assessment of thyroid function, and/or age-appropriate cancer screening. (See "Diagnosis of hyperthyroidism" and "Overview of preventive care in adults", section on 'Cancer screening'.)
The differential diagnosis for partial lipodystrophy includes Cushing syndrome and other forms of severe, insulin-resistant diabetes, particularly in association with a central pattern of adipose tissue deposition (ie, truncal obesity). Patients with acquired partial lipodystrophy should be assessed for signs and symptoms that suggest underlying Cushing syndrome and undergo additional testing if indicated. (See "Epidemiology and clinical manifestations of Cushing syndrome" and "Establishing the diagnosis of Cushing syndrome".)
Rare conditions that should be distinguished from partial lipodystrophy include progeroid syndromes and multiple symmetric lipomatosis.
●Localized lipodystrophy/lipoatrophy – Localized lipodystrophies are characterized by a loss of subcutaneous fat from small areas of the body and do not cause insulin resistance or other metabolic abnormalities. Drug-induced lipoatrophy at the site of injection was a complication of insulin therapy before the availability of purified human insulin but is rare now. Other medications, such as glucocorticoids and antibiotics, can also cause localized lipoatrophy [20].
Other rare causes of localized lipoatrophy include repeated pressure against any body part and lipoatrophy occurring as part of a rare syndrome called lipodystrophia centrifugalis abdominalis infantilis. This is characterized by a centrifugal loss of adipose tissue in the abdomen with erythematous and scaly changes at the periphery, and it usually occurs before the age of three years. More than 50 percent of patients recover spontaneously later in life. Finally, some patients have localized lipoatrophy, ie, lack of adipose tissue in small areas of the trunk or parts of a limb, as an isolated abnormality [20].
SUMMARY AND RECOMMENDATIONS
●Lipodystrophy syndromes – Lipodystrophy syndromes are a heterogeneous group of congenital or acquired disorders characterized by either complete or partial lack of adipose tissue (lipoatrophy) (table 2). In some of these disorders, accumulation of fat occurs in other regions of the body. The extent of fat loss correlates with the severity of the metabolic abnormalities. Clinically, patients with severe lipodystrophy have severe insulin resistance, severe hyperlipidemia, and progressive steatotic liver disease (table 1). (See 'Introduction' above.)
●Congenital lipodystrophy
•Congenital generalized lipodystrophy – In patients with congenital generalized lipodystrophy (CGL), an absence of subcutaneous fat is noted within the first two years of life, often at birth or soon thereafter. At least four molecularly distinct forms of CGL have been defined. (See 'Congenital generalized lipodystrophy' above.)
•Congenital partial lipodystrophy – Familial partial lipodystrophy (FPLD) syndromes are characterized by variable loss of adipose tissue that occurs during childhood, puberty, or young adulthood. The molecular basis for these disorders has been incompletely elucidated, and multiple molecular defects may underlie some forms (figure 1). (See 'Congenital partial lipodystrophy' above.)
●Acquired lipodystrophy
•Acquired generalized lipodystrophy – Acquired generalized lipodystrophy presents later in life (ie, after two years of age) and may be associated with autoimmune conditions or prior infection. (See 'Acquired generalized lipodystrophy' above.)
•Acquired partial lipodystrophy – Acquired partial lipodystrophy (Barraquer-Simons syndrome) is characterized by the loss of adipose tissue from the face and upper trunk, with sparing or increased adiposity in the rest of the body (figure 5). It is often associated with autoimmune disorders. (See 'Barraquer-Simons syndrome' above.)
Patients with human immunodeficiency virus (HIV) infection who are treated with antiretroviral therapy, and especially HIV-1 protease inhibitors, can develop partial lipodystrophy (figure 5). (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy" and "Treatment of HIV-associated lipodystrophy".)
●Diagnosis – Lipodystrophy is a clinical diagnosis based on clinical and family history and physical examination (algorithm 1 and algorithm 2). Imaging and laboratory testing can support the diagnosis but are not required. (See 'Evaluation' above.)
•Clinical history – Patients should be queried about a personal and/or family history of known lipodystrophy, diabetes, hypertriglyceridemia, polycystic ovary syndrome (females), and acute pancreatitis. Diabetes and/or hypertriglyceridemia are often treatment resistant. Patients also should be queried about the timing of adipose tissue loss, both the age of onset and rapidity of change. (See 'History and examination' above.)
•Physical examination – Physical examination should include assessment of regions with either adipose tissue loss or increased deposition, including face, neck, extremities, mechanical depots, and abdomen (figure 2). (See 'History and examination' above.)
Physical examination also should include assessment of other common physical findings associated with lipodystrophy-related complications, although these additional findings are not specific for lipodystrophy. (See 'Physical findings' above.)
•Genetic testing – Genetic testing is not a standard component of the diagnostic evaluation. However, genetic testing may help guide the approach to monitoring for complications and comorbid conditions, and it may be offered to family members at risk for developing the disorder. Further, it may be helpful for preconception counseling in individuals who seek fertility. It is available clinically and/or through research studies for many forms of congenital lipodystrophy. (See 'Genetic testing' above.)
●Differential diagnosis – Other disorders that need to be differentiated from primary lipodystrophies are shown in the table (table 3). The differential diagnosis also includes localized lipodystrophies, in which adipose tissue loss is confined to a small area and does not cause metabolic sequelae. (See 'Differential diagnosis' above.)
