Lipodystrophy



Lipodystrophy: Introduction




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Lipodystrophy at a Glance





  • Lipodystrophies are genetic or acquired disorders characterized by selective loss of body fat. The extent of fat loss determines the severity of associated metabolic complications such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, and acanthosis nigricans.
  • Four loci have been identified for the autosomal recessive congenital generalized lipodystrophy (CGL), namely, (1) AGPAT2, (2) BSCL2, (3) CAV1, and (4) PTRF.
  • Four loci have been identified for autosomal dominant familial partial lipodystrophy (FPL), namely, (1) LMNA, (2) PPARG, (3) AKT2, and (4) PLIN1.
  • CIDEC is the locus for autosomal recessive FPL, and LMNA and ZMPSTE24 are loci for autosomal recessive mandibuloacral dysplasia-associated lipodystrophy.
  • Molecular basis of many rare forms of genetic lipodystrophies remains to be elucidated.
  • The most prevalent variety of lipodystrophy develops after prolonged duration of protease inhibitor containing highly active antiretroviral therapy in HIV-infected patients.
  • The acquired generalized lipodystrophy and acquired partial lipodystrophy are mainly autoimmune in origin.
  • Localized lipodystrophies occur due to drug or vaccine injections, pressure, panniculitis, and other unknown reasons.
  • The current management includes cosmetic surgery and early identification and treatment of metabolic and other complications.





Lipodystrophies are a heterogeneous group of disorders characterized by selective loss of adipose tissue.1 The extent of fat loss varies, with some patients losing fat from small areas (localized lipodystrophy), whereas others may have more extensive fat loss, for example, involving the extremities (partial lipodystrophy) or the entire body (generalized lipodystrophy). Depending upon the extent of fat loss, patients may be predisposed to develop complications associated with insulin resistance such as, diabetes mellitus, dyslipidemia, hepatic steatosis, acanthosis nigricans, polycystic ovarian disease, and coronary heart disease.2,3 There are two main types of lipodystrophies: (1) genetic and (2) acquired. A detailed classification of various types of lipodystrophies is given in Table 71-1.







Table 71-1 Classification of Lipodystrophies 






Genetic Lipodystrophies





In the last decade or so, considerable progress has been made in elucidation of the molecular basis of many types of genetic lipodystrophies. In general, mutations in genes involved in adipocyte differentiation, triglyceride synthesis, lipid droplet formation, and adipocyte survival have been reported to cause lipodystrophies.






Epidemiology



Although the genetic lipodystrophies are rare, recent advances such as improved definition of the phenotypes and elucidation of the molecular defects, have led to increased recognition of these syndromes. Overall, based on literature reports of less than 1,000 patients, the estimated prevalence of genetic lipodystrophies may be less than 1 in a million. The autosomal recessive, congenital generalized lipodystrophy (CGL) has been reported in fewer than 300 patients, with clustering of patients reported from Lebanon and Brazil where there is increased prevalence of consanguinity. The autosomal dominant, familial partial lipodystrophy (FPL) of the Dunnigan variety due to LMNA mutations is the most common with ∼500 patients being reported; autosomal dominant, FPL due to PPARG mutations with ∼30 patients; autosomal recessive, mandibuloacral dysplasia (MAD) due to LMNA mutations in ∼30 patients and due to ZMPSTE24 mutations in eight patients. Affected females are recognized easily and thus are reported more often than males.






Congenital Generalized Lipodystrophy (CGL, Berardinelli–Seip Syndrome)



Etiology and Pathogenesis



This autosomal recessive disorder can be recognized at birth or soon thereafter due to near total lack of body fat. Genome-wide linkage analysis with positional cloning strategy and candidate gene approach have led to the identification of four genetic loci for CGL: (1) 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) gene on chromosome 9q34,4,5 (2) Berardinelli–Seip congenital lipodystrophy 2 (BSCL2) gene on chromosome 11q13,6 (3) caveolin 1 (CAV1) gene on chromosome 7q31,7 and (4) polymerase I and transcript release factor (PTRF) on chromosome 17q21.8 AGPAT2 is a critical enzyme involved in the biosynthesis of triglycerides and phospholipids from glycerol-3-phosphate and is expressed highly in the adipose tissue.9 The BSCL2-encoded protein, seipin, plays a role in lipid droplet formation and may also be involved in adipocyte differentiation.1012 Caveolin 1 is an integral component of caveolae, specialized microdomains seen in abundance on adipocyte membranes. Caveolin 1 binds fatty acids and translocates them to lipid droplets. PTRF is involved in biogenesis of caveolae and regulates expression of caveolins 1 and 3.8



Clinical Findings



Patients with CGL present with near total loss of body fat, marked muscularity, prominent subcutaneous veins, acromegaloid features, acanthosis nigricans, hepatomegaly, and umbilical prominence or hernia (Fig. 71-1A, Table 71-2). During childhood, they have a voracious appetite, and accelerated linear growth. Females usually have hirsutism, clitoromegaly, oligoamenorrhea, and polycystic ovaries. Only a few women have had successful pregnancies. Fertility is normal in men. Some of them develop hypertrophic cardiomyopathy, mild mental retardation, and focal lytic lesions in the appendicular bones after puberty.1315 Metabolic abnormalities related to insulin resistance, such as diabetes mellitus, hyperlipidemia, and hepatic steatosis, may manifest at a young age and are often difficult to control. Patients with BSCL2 mutations lack mechanical fat located in the retro-orbital region, palm, sole, and in periarticular regions as well as metabolically active adipose tissue located in the subcutaneous (sc), intra-abdominal, intrathoracic, and other areas as compared to those with AGPAT2, CAV1, and PTRF mutations where mechanical fat is preserved.7,16 The only reported patient with CAV1 mutation also had short stature and presumed vitamin D resistance.7 Only 21 patients with PTRF mutations have been reported and they have congenital myopathy, increased creatine kinase levels, percussion-induced myoedema, pyloric stenosis, cardiac rhythm disturbances including prolonged QT interval, exercise-induced ventricular tachycardia, and atlantoaxial instability.8,17,18 Patients of Lebanese origin harbor homozygous c.659delGTATC mutation in BSCL2, whereas those of African origin nearly always have either homozygous or compound heterozygous c.IVS4–2A>G mutation in AGPAT2 gene.5,6,13




Figure 71-1



Clinical features of patients with various types of lipodystrophies. A. Anterior view of a 33-year-old Hispanic female with congenital generalized lipodystrophy (also known as Berardinelli–Seip congenital lipodystrophy), type 1 due to homozygous c.IVS4–2A>G mutation in AGPAT2 gene. The patient had generalized loss of sc fat with acanthosis nigricans in the axillae and neck. She has umbilical prominence and acromegaloid features (enlarged mandible, hands, and feet). B. Anterior view of a 27-year-old Native American Hispanic female with familial partial lipodystrophy of the Dunnigan variety due to heterozygous p.Arg482Trp mutation in LMNA gene. She had marked loss of sc fat from the limbs and anterior truncal region. The breasts were atrophic. She had increased sc fat deposits in the face, anterior neck, and vulvar regions. C. Anterior view of an 8-year-old German boy with acquired generalized lipodystrophy. He had severe generalized loss of sc fat with marked acanthosis nigricans in the neck, axillae, and groin. D. Anterior view of a 39-year-old Caucasian female with acquired partial lipodystrophy (Barraquer–Simons syndrome). She had marked loss of sc fat from the face, neck, upper extremities, and chest, but had lipodystrophy on localized regions on anterior thighs. She had increased sc fat deposition in the lower extremities. E. Lateral view of a 53-year-old Caucasian male infected with human immunodeficiency (HIV) virus with highly active antiretroviral therapy-induced lipodystrophy. He had marked loss of sc fat from the face and limbs, but had increased sc fat deposition in the neck region anteriorly and posteriorly showing buffalo hump. Abdomen was protuberant due to excess intra-abdominal fat. He had been on protease inhibitor-containing antiretroviral therapy for more than 8 years.





Table 71-2 Clinical Features of Various Types of Congenital Generalized Lipodystrophy (CGL) 






Familial Partial Lipodystrophy (FPL)



Etiology and Pathogenesis



FPL is an autosomal dominant disorder characterized by fat loss from the limbs with variable fat loss from the trunk and increased sc fat deposition in nonlipodystrophic regions (Fig. 71-1B). It results from heterozygous missense mutations in one of the four genes: (1) lamin A/C (LMNA) on chromosome 1q21–22,1922 an integral component of nuclear lamina; (2) peroxisome proliferator-activated receptor γ (PPARG) on chromosome 3p25,2325 a key transcription factor involved in adipocyte differentiation; (3) v-AKT murine thymoma oncogene homolog 2 (AKT2) on chromosome 19q13,26 involved in downstream insulin signaling; and (4) perilipin 1 (PLIN1) on chromosome 15q26, a key component of lipid droplets.27 Adipocyte loss in patients with LMNA mutations may be due to disruption of nuclear envelope function and integrity resulting in premature cell death.



Clinical Findings



Patients with FPL have normal body fat distribution during early childhood, but around the time of puberty, sc fat from the extremities and trunk is progressively lost (Fig. 71-1B). The face, neck, and intra-abdominal region are spared, and often excess fat accumulates there.28,29 Affected men are often more difficult to diagnose clinically, as many normal men are also quite muscular. Women are more severely affected metabolically.30 Some patients with mutations in amino-terminal region of lamin A/C also develop myopathy, cardiomyopathy, and conduction system abnormalities indicative of a multisystem dystrophy.31 On the other hand, others with mutations in the extreme C-terminal region of lamin A may have mild lipodystrophy.32



Nearly 30 patients with FPL due to heterozygous mutations in PPARG gene have been reported so far. They have more marked fat loss from the extremities, especially from distal regions, but the fat from the face, neck, and truncal area is spared. There is increased prevalence of hypertension among the affected subjects. Four subjects from a single family with diabetes and insulin resistance were reported to harbor a heterozygous mutation in AKT2 gene. The female proband had lipodystrophy of the limbs although detailed studies of body fat distribution were not performed. Recently, five FPL patients were reported to harbor PLIN1 mutations.27






Mandibuloacral Dysplasia (MAD) Associated Lipodystrophy



Etiology and Pathogenesis



Mutations in LMNA and zinc metalloproteinase (ZMPSTE24) on chromosome 1p34 also result in autosomal recessive, MAD-associated lipodystrophies.33,34ZMPSTE24 is involved in posttranslational proteolytic processing of prelamin A to mature lamin A and its deficiency can result in accumulation of prelamin A in cells which is supposed to cause toxicity.



Clinical Findings



Patients with MAD have characteristic skeletal abnormalities including hypoplasia of the mandible and clavicles, acroosteolysis, cutaneous atrophy, progeroid features such as thin beaked nose, hair loss, thin skin with prominent superficial vasculature and mottled hyperpigmentation, delayed dentition and closure of cranial sutures, joint stiffness, and lipodystrophy.35,36 Those with ZMPSTE24 mutations develop clinical manifestations earlier in life, are premature at birth, and can develop focal segmental glomerulosclerosis and calcified skin nodules.37,38




Jun 11, 2016 | Posted by in Dermatology | Comments Off on Lipodystrophy

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