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The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice GuidelineEndorsing Societies (tentative):Pediatric Endocrine SocietyAmerican Diabetes AssociationAmerican Association of Clinical EndocrinologistsEndocrine SocietyJapanese Society for Pediatric EndocrinologyAustralasian Paediatric Endocrine GroupEuropean Society for Paediatric EndocrinologyAsia Pacific Paediatric Endocrine SocietyAfrican Society for Paediatric and Adolescent?EndocrinologyAuthor names and institutions:Rebecca J. Brown1,2, David Araujo-Vilar3, Pik To Cheung4, David Dunger5, Abhimanyu Garg6, Michelle Jack7, Lucy Mungai8, Elif A. Oral9, Nivedita Patni10, Kristina Rother2, Julia von Schnurbein11, Ekaterina Sorkina12, Takara Stanley13, Corinne Vigouroux14,15,16, Martin Wabitsch11, Rachel Williams17, Tohru Yorifuji181 Committee Chair; all other authors appear in alphabetical order2 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA3 Department of Medicine, University of Santiago de Compostela, Spain4 Department of Paediatrics and Adolescent Medicine, The University of Hong Kong5 Department of Paediatrics, University of Cambridge Box 116 Level 8, Cambridge Biomedical Campus, Cambridge CB2 0QQ), MRL Wellcome Trust MRC Institute of Metabolic Science, NIHR Cambridge Comprehensive Biomedical Research Centre, UK, MRC Epidemiology Unit, University of Cambridge6 Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, UT Southwestern Medical Center, Dallas, Texas, USA7 Royal North Shore Hospital, Northern Clinical School, University of Sydney St Leonards NSW 21268 Department of Paediatrics and Child Health, University of Nairobi, Kenya9 Brehm Center for Diabetes and Division of Metabolism, Endocrinology, and Diabetes; Department of Internal Medicine; University of Michigan Medical School and Health Systems, Ann Arbor, USA10 Division of Pediatric Endocrinology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA11 Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Eythstr. 24 / 89075 Ulm, Germany12 Clamp technologies laboratory, Endocrinology Research Center, Moscow, Russia13 Pediatric Endocrine Unit and Program in Nutritional Metabolism, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA14 Sorbonne Universities, UPMC Univ Paris 6,?Inserm UMRS 938, Saint-Antoine Research Center, and?Institute of Cardiometabolism and Nutrition (ICAN), Paris, France15 AP-HP, Saint-Antoine Hospital, Molecular Biology and Genetics Department, Paris, France16 Institute of Cardiometabolism and Nutrition, Paris, France17Department of Paediatric Endocrinology, Cambridge University Hospitals NHS Trust, Hills Road, Cambridge, United Kingdom18Division of Pediatric Endocrinology and Metabolism, Children’s Medical Center, Osaka City General Hospital, JapanAbbreviated title: Diagnosis and Management of LipodystrophyKeywords: Lipodystrophy, lipoatrophy, lipoatrophic diabetes, metabolic syndrome, insulin resistanceWord count: 3594Tables: 4Figures: 2References: 120Supplemental Tables: 3Corresponding Author and Reprint Requests:Rebecca J. Brown, MD, MHScNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBuilding 10-CRC, Room 6-594210 Center DriveBethesda, MD, 20892Phone: 301-594-0609Fax: 301-480-3675Email: brownrebecca@niddk.Grant and Fellowship Support: This practice guideline was sponsored and organized by the Pediatric Endocrine Society via an unrestricted education grant from AstraZeneca. Individual authors were supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH grants RO1-DK088114, RO1-DK105448, RO1-DK101941, the Sopha Fund for Lipodystrophy Research at the University of Michigan, and ?grant 14-35-0026 of the Russian Science Foundation.Disclosures: RJB, PTC, MJ, LM, NP, KR, JvS, ES, TS, MW, and TY have nothing to declare. AG consults for Aegerion Pharmaceuticals, Ionis, and Amgen, previously consulted for Biomedical Insights, Clearview Healthcare, Gerson Lehrman, and Smithsolve, and received grant support from Aegerion Pharmaceuticals, Pfizer (2013-2016), and Ionis Pharmaceuticals (2015-2017).??? DA-V has consulted for Bristol-Myers Squibb and AstraZeneca. EAO received past grant/drug support from Bristol-Myers Squibb,?AstraZeneca, and Amylin Pharmaceuticals, current research/drug support from Aegerion Pharmaceuticals, and Ionis Pharmaceuticals, previously consulted for all of the previously listed companies, and is a current consultant to AstraZeneca, Aegerion and Ionis Pharmaceuticals. CV is a member of the Aegerion “Metreleptin Expanded Access Review Board.”AbstractObjective: Lipodystrophy syndromes are extremely rare disorders of deficient body fat complicated by potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes diagnosis and management of lipodystrophy syndromes. Participants: Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via unrestricted educational grant (Astra Zeneca) to the Pediatric Endocrine Society. Meetings were not open to the general public. Evidence: Literature review was conducted by the committee. Recommendations of the committee were graded using the system of the American Heart Association. Expert opinion was used when published data were not available or scarce. Consensus Process: The guideline was drafted by committee members, and reviewed, revised, and approved by the entire committee during group meetings. Contributing societies reviewed the document and provided approval.Conclusions: Lipodystrophy syndromes are heterogeneous, and are diagnosed by clinical phenotype, supplemented by genetic testing in certain forms. Patients with most lipodystrophy syndromes should be screened for diabetes, dyslipidemia, and liver, kidney, and heart disease annually. Diet is essential for management of metabolic complications of lipodystrophy. Metreleptin therapy is effective for metabolic complications in hypoleptinemic patients with generalized lipodystrophy, and selected patients with partial lipodystrophy. Other treatments not specific for lipodystrophy may be helpful as well (e.g. metformin for diabetes, statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated.INTRODUCTIONThe lipodystrophy syndromes are a heterogeneous group of rare disorders that have in common selective deficiency of adipose tissue in the absence of nutritional deprivation or catabolic state (Figure 1). Lipodystrophies are categorized based on etiology (genetic or acquired) and distribution of lost adipose tissue, affecting the entire body (generalized) or only regions (partial). This yields four major categories: congenital generalized lipodystrophy (CGL), familial partial lipodystrophy (FPLD), acquired generalized lipodystrophy (AGL), and acquired partial lipodystrophy (APL) (Figure 1). Additional subtypes include progeroid disorders, autoinflammatory disorders, and others (Table 1). This practice guideline will not discuss lipodystrophy in HIV infected patients or localized lipodystrophy (e.g. from injectable drugs). Lipodystrophy syndromes are frequently associated with hormonal and metabolic derangements resulting in severe comorbidities (Table 2) that depend on the subtype, extent of fat loss, age, and gender. Many complications of lipodystrophy are secondary to deficient adipose mass, resulting in ectopic lipid storage in the liver, muscle, and other organs, causing insulin resistance. Insulin resistance leads to diabetes, hypertriglyceridemia, polycystic ovarian syndrome (PCOS), and non-alcoholic fatty liver disease (NAFLD) ADDIN EN.CITE <EndNote><Cite><Author>Brown</Author><Year>2015</Year><RecNum>774</RecNum><DisplayText>(1)</DisplayText><record><rec-number>774</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">774</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Brown, R. J.</author><author>Gorden, P.</author></authors><secondary-authors><author>Dagogo-Jack, S.</author></secondary-authors></contributors><titles><title>Leptin Therapy in Patients with Lipodystrophy and Syndromic Insulin Resistance</title><secondary-title>Leptin: Regulation and Clinical Applications</secondary-title></titles><dates><year>2015</year></dates><pub-location>Switzerland</pub-location><publisher>Springer International Publishing</publisher><urls></urls></record></Cite></EndNote>(1). Major causes of mortality in patients with lipodystrophy include heart disease (cardiomyopathy, heart failure, myocardial infarction, arrhythmia) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cam9ybnN0YWQ8L0F1dGhvcj48WWVhcj4xOTg1PC9ZZWFy
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ADDIN EN.CITE.DATA (6,7), kidney failure ADDIN EN.CITE <EndNote><Cite><Author>Seip</Author><Year>1971</Year><RecNum>29</RecNum><DisplayText>(6)</DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="e0e9v50ertwddoepww0vzdvw9pr99eexp2v2">29</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Seip, M.</author></authors><secondary-authors><author>Frick P, von Harnack GA, Miller AF, Prader A, Schoen R, Wolf HP (eds)</author></secondary-authors></contributors><titles><title>Generalized lipodystrophy</title><secondary-title>Ergeb Inn Med Kinderheilkd</secondary-title></titles><pages>59-95</pages><num-vols>31</num-vols><dates><year>1971</year></dates><publisher>Springer Berlin</publisher><urls></urls></record></Cite></EndNote>(6), acute pancreatitis ADDIN EN.CITE <EndNote><Cite><Author>Garg</Author><Year>2011</Year><RecNum>308</RecNum><DisplayText>(7)</DisplayText><record><rec-number>308</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">308</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garg, A.</author></authors></contributors><auth-address>Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8537, USA. abhimanyu.garg@utsouthwestern.edu</auth-address><titles><title>Clinical review#: Lipodystrophies: genetic and acquired body fat disorders</title><secondary-title>J Clin Endocrinol Metab</secondary-title><alt-title>The Journal of clinical endocrinology and metabolism</alt-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><alt-periodical><full-title>J Clin Endocrinol Metab</full-title><abbr-1>The Journal of clinical endocrinology and metabolism</abbr-1></alt-periodical><pages>3313-25</pages><volume>96</volume><number>11</number><keywords><keyword>Adipose Tissue/*metabolism</keyword><keyword>Humans</keyword><keyword>Insulin Resistance/genetics</keyword><keyword>Lipodystrophy/*genetics/metabolism/therapy</keyword><keyword>Mutation</keyword><keyword>Prognosis</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1945-7197 (Electronic)
0021-972X (Linking)</isbn><accession-num>21865368</accession-num><urls><related-urls><url>;(7), and sepsis.Due to the rarity of lipodystrophy syndromes, most clinicians are unfamiliar with their diagnosis and management. In December 2015, an expert panel including representatives from endocrine societies around the world convened to generate this practice guideline. The panel used the evidence rating system of the American Heart Association (Supplemental Table 1) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaWJib25zPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48
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ADDIN EN.CITE.DATA (8).Overview of lipodystrophy syndromes:This section reviews major categories of lipodystrophy. Detailed phenotypic information on individual subtypes is in Table 3. Congenital Generalized Lipodystrophy (CGL, Berardinelli-Seip Syndrome)CGL is an autosomal recessive disorder characterized by near-complete lack of fat starting at birth or infancy, prominent muscles, phlebomegaly, acanthosis nigricans, hepatomegaly, umbilical prominence, and voracious appetite in childhood PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2Fyd2FsPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48
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ADDIN EN.CITE.DATA (11-13). Metabolic complications are frequent and may be severe. Cardiomyopathy or rhythm disturbances may occur. Familial Partial Lipodystrophy (FPLD)FPLD is a group of usually autosomal dominant disorders characterized by loss of fat affecting the limbs, buttocks, and hips ADDIN EN.CITE <EndNote><Cite><Author>Garg</Author><Year>2004</Year><RecNum>3411</RecNum><DisplayText>(10)</DisplayText><record><rec-number>3411</rec-number><foreign-keys><key app="EN" db-id="2ft2re2d59da9ue2p9u5ww56de5eswxe5txe">3411</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garg, A.</author></authors></contributors><auth-address>Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, and the Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9052, USA. abhimanyu.garg@utsouthwestern.edu</auth-address><titles><title>Acquired and inherited lipodystrophies</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>1220-34</pages><volume>350</volume><number>12</number><keywords><keyword>Acyltransferases/genetics</keyword><keyword>Female</keyword><keyword>HIV-Associated Lipodystrophy Syndrome/therapy</keyword><keyword>Humans</keyword><keyword>Hyperglycemia/complications/drug therapy</keyword><keyword>Insulin Resistance</keyword><keyword>*Lipodystrophy/complications/genetics/physiopathology/therapy</keyword><keyword>Male</keyword><keyword>Mutation</keyword><keyword>Nuclear Envelope/ultrastructure</keyword><keyword>Phospholipids/biosynthesis</keyword><keyword>Receptors, Cytoplasmic and Nuclear/genetics</keyword><keyword>Research Support, Non-U.S. Gov't</keyword><keyword>Research Support, U.S. Gov't, P.H.S.</keyword><keyword>Transcription Factors/genetics</keyword><keyword>Triglycerides/biosynthesis</keyword></keywords><dates><year>2004</year><pub-dates><date>Mar 18</date></pub-dates></dates><accession-num>15028826</accession-num><urls><related-urls><url>;(10). Regional excess fat accumulation is frequent, varies by subtype, and may result in a Cushingoid appearance. Fat distribution is typically normal in early childhood, with loss of fat occurring around puberty. Muscular hypertrophy is common. Metabolic complications are common in adulthood PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW50eWdoZW08L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFy
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ADDIN EN.CITE.DATA (4,16). Acquired Partial Lipodystrophy (APL, Barraquer-Simons syndrome):APL is more frequent in females (F:M; 4:1) and usually begins in childhood or adolescence. Loss of fat follows a cranio-caudal trend, progressively affecting the face, neck, shoulders, arms, and trunk. Fat accumulation can appear in the hips, buttocks and legs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXNyYTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXNyYTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (17). APL is associated with autoimmune diseases, especially membranoproliferative glomerulonephritis (MPGN) in ~20% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXNyYTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (17).DIAGNOSIS OF LIPODYSTROPHYDiagnosis of lipodystrophy is based on history, physical examination, body composition, and metabolic status. (Class I, Level B)There are no defined serum leptin levels that establish or rule out the diagnosis of lipodystrophy. (Class IIa, Level C)Confirmatory genetic testing is helpful in suspected familial lipodystrophies. (Class I, Level A)Genetic testing should be considered in at-risk family members. (Class IIa, Level C)Serum complement levels and autoantibodies may support diagnosis of acquired lipodystrophy syndromes. (Class IIa, Level B)Firm diagnostic criteria for lipodystrophy have not been established. Figure 2 shows a suggested diagnostic approach.Establishing the presence of lipodystrophyLipodystrophy should be suspected in patients with regional or generalized lack of adipose tissue outside of the normal range by physical examination, which can be supported by anthropometry, dual energy X-ray absorptiometry (DXA), and whole-body magnetic resonance imaging (MRI) ADDIN EN.CITE <EndNote><Cite><Author>Handelsman</Author><Year>2013</Year><RecNum>326</RecNum><DisplayText>(18)</DisplayText><record><rec-number>326</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">326</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Handelsman, Y.</author><author>Oral, E. A.</author><author>Bloomgarden, Z. T.</author><author>Brown, R. J.</author><author>Chan, J. L.</author><author>Einhorn, D.</author><author>Garber, A. J.</author><author>Garg, A.</author><author>Garvey, W. T.</author><author>Grunberger, G.</author><author>Henry, R. R.</author><author>Lavin, N.</author><author>Tapiador, C. D.</author><author>Weyer, C.</author></authors></contributors><auth-address>Metabolic Institute of America, Tarzana, California.</auth-address><titles><title>The clinical approach to the detection of lipodystrophy - an aace consensus statement</title><secondary-title>Endocr Pract</secondary-title><alt-title>Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists</alt-title></titles><periodical><full-title>Endocr Pract</full-title><abbr-1>Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists</abbr-1></periodical><alt-periodical><full-title>Endocr Pract</full-title><abbr-1>Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists</abbr-1></alt-periodical><pages>107-16</pages><volume>19</volume><number>1</number><dates><year>2013</year><pub-dates><date>Jan 1</date></pub-dates></dates><isbn>1934-2403 (Electronic)
1530-891X (Linking)</isbn><accession-num>23435042</accession-num><urls><related-urls><url>;(18). Recognizing loss of subcutaneous fat is particularly challenging in partial lipodystrophy and especially in men, in whom low body fat overlaps with normal variation, and metabolic manifestations of lipodystrophy are less severe. In both genetic and acquired lipodystrophies, loss of fat may be gradual, delaying diagnosis.Physical, historical, and comorbid features that increase the suspicion of lipodystrophy ADDIN EN.CITE <EndNote><Cite><Author>Handelsman</Author><Year>2013</Year><RecNum>326</RecNum><DisplayText>(18)</DisplayText><record><rec-number>326</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">326</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Handelsman, Y.</author><author>Oral, E. A.</author><author>Bloomgarden, Z. T.</author><author>Brown, R. J.</author><author>Chan, J. L.</author><author>Einhorn, D.</author><author>Garber, A. J.</author><author>Garg, A.</author><author>Garvey, W. T.</author><author>Grunberger, G.</author><author>Henry, R. R.</author><author>Lavin, N.</author><author>Tapiador, C. D.</author><author>Weyer, C.</author></authors></contributors><auth-address>Metabolic Institute of America, Tarzana, California.</auth-address><titles><title>The clinical approach to the detection of lipodystrophy - an aace consensus statement</title><secondary-title>Endocr Pract</secondary-title><alt-title>Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists</alt-title></titles><periodical><full-title>Endocr Pract</full-title><abbr-1>Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists</abbr-1></periodical><alt-periodical><full-title>Endocr Pract</full-title><abbr-1>Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists</abbr-1></alt-periodical><pages>107-16</pages><volume>19</volume><number>1</number><dates><year>2013</year><pub-dates><date>Jan 1</date></pub-dates></dates><isbn>1934-2403 (Electronic)
1530-891X (Linking)</isbn><accession-num>23435042</accession-num><urls><related-urls><url>;(18) are in Table 4. Because serum leptin assays are not standardized and leptin concentrations in patients with lipodystrophy (especially partial forms) overlap the general population, leptin levels do not help in diagnosis, but may help with choice of therapies. Differential Diagnosis:Differential diagnosis should include conditions presenting with severe weight loss (malnutrition, anorexia nervosa, uncontrolled diabetes mellitus, thyrotoxicosis, adrenocortical insufficiency, cancer cachexia, HIV-associated wasting, chronic infections). Especially difficult is differentiating lipodystrophy from uncontrolled diabetes, as both may present with extreme hypertriglyceridemia. However, restoring glycemic control in patients with non-lipodystrophic diabetes leads to regain of body fat. Generalized lipodystrophies can be confused with Donohue or Rabson Mendenhall syndromes (mutations of the insulin receptor) or acromegaly/gigantism, and FPLD with Cushing’s syndrome, truncal obesity, and multiple symmetric lipomatosis. Establishing the subtype of lipodystrophyPattern of fat loss: Although the pattern of body fat loss in patients with a particular subtype of genetic lipodystrophy is quite characteristic, heterogeneity occurs in the onset, severity, and pattern of fat loss, even within a single family. Distinguishing genetic from acquired lipodystrophy: Pedigree analysis can suggest genetic versus acquired lipodystrophy. Review of photographs from infancy may distinguish CGL from AGL, as infants typically show absent fat in CGL, and normal fat in AGL. However, there have been cases of AGL with loss of fat during the first few months of life PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXNyYTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (4,10,16,17,19,20) increases the suspicion of acquired lipodystrophy. In APL, low serum C3, presence of C3NeF, proteinuria or biopsy-proven MPGN support the diagnosis. Genetic testing:Genotyping may include limited candidate gene sequencing, a panel of candidate genes, or whole exome/whole genome sequencing. The website, , lists clinical and research laboratories conducting genetic testing for lipodystrophy syndromes. Since there is strong evidence for additional loci for genetic lipodystrophies, negative tests do not rule out a genetic condition. Genetic counseling and screening of family members:Genetic counseling must take into consideration that current understanding of the natural history of genetic lipodystrophies and their complications is incomplete. In affected pedigrees, premarital counseling with genetic testing to detect carrier status can be considered.Clinical diagnosis of lipodystrophy may be difficult in men PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYXJnPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (22,23). Genetic screening of family members may help identify individuals with subtle phenotypes. Genetic screening may be particularly important for families with specific LMNA mutations associated with cardiomyopathy and arrhythmia. SCREENING FOR COMORBIDITIESAll patients should be screened for diabetes, dyslipidemia, NAFLD, cardiovascular, and reproductive dysfunction. Because patients with APL are at low risk for metabolic complications, clinical judgment should guide follow-up screening. Screening for comorbidities specific to individual lipodystrophy subtypes is not extensively discussed here. Diabetes mellitusDiabetes screening should be performed annually. (Class IIa, Level C) Diabetes screening should follow the guidelines of the American Diabetes Association (fasting plasma glucose, oral glucose tolerance test, or hemoglobin A1c). Children with CGL may manifest diabetes in the first years of life PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2Fyd2FsPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48
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ADDIN EN.CITE.DATA (24); measurement of auto-antibodies may clarify the diagnosis. DyslipidemiaTriglycerides should be measured at least annually, and with occurrence of abdominal pain or xanthomata. (Class I, Level C)Fasting lipid panel (total cholesterol, low density lipoprotein [LDL]-cholesterol, high density lipoprotein [HDL]-cholesterol, triglycerides) should be measured at diagnosis and annually after age 10 years. (Class IIa, Level C)Liver diseaseAlanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be measured annually. (Class IIa, Level C)Liver ultrasound should be performed at diagnosis, then as clinically indicated. (Class IIa, Level C)Liver biopsy should be performed as clinically indicated. (Class IIa, Level C)In addition to physical examination, ultrasound and elastography are useful to estimate liver and spleen size, severity of steatosis and fibrosis, and existence of portal hypertension. Patients with CGL2 are at high risk for early cirrhosis, and those with AGL may have autoimmune hepatitis in addition to NAFLD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWZhciBaYWRlaDwvQXV0aG9yPjxZZWFyPjIwMTM8L1ll
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ADDIN EN.CITE.DATA (19). Reproductive dysfunction Gonadal steroids, gonadotropins, and pelvic ultrasonography should be performed as clinically indicated. (Class IIa, Level C)Pubertal staging should be performed annually in children. (Class IIa, Level C)Early adrenarche, true precocious puberty, or central hypogonadism may occur in children with generalized lipodystrophy. Oligo/amenorrhea, decreased fertility, and PCOS are common in women. Cardiac diseaseBlood pressure should be measured at least annually. (Class I, Level C)ECG and echocardiogram should be performed annually in CGL and progeroid disorders, and at diagnosis and as clinically indicated in FPLD and AGL. (Class IIa, Level C)Evaluation for ischemia and rhythm monitoring should be considered in patients with progeroid disorders and FPLD2 with cardiomyopathy. (Class IIa, Level C)Hypertension is common ADDIN EN.CITE <EndNote><Cite><Author>Brown</Author><Year>2015</Year><RecNum>675</RecNum><DisplayText>(25)</DisplayText><record><rec-number>675</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">675</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brown, R. J.</author><author>Meehan, C. A.</author><author>Gorden, P.</author></authors></contributors><auth-address>Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: phillipg@intra.niddk..</auth-address><titles><title>Leptin Does Not Mediate Hypertension Associated With Human Obesity</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></periodical><alt-periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></alt-periodical><pages>465-6</pages><volume>162</volume><number>3</number><keywords><keyword>Animals</keyword><keyword>Hypertension/*metabolism</keyword><keyword>Leptin/*metabolism</keyword><keyword>Obesity/*metabolism</keyword></keywords><dates><year>2015</year><pub-dates><date>Jul 30</date></pub-dates></dates><isbn>1097-4172 (Electronic)
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ADDIN EN.CITE.DATA (34). Kidney biopsy should be performed as clinically indicated, and pathology may include diabetic nephropathy, focal segmental glomerulosclerosis (especially in CGL) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYXZvcjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYXZvcjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (34) or MPGN (especially in APL) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXNyYTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (4,35). Appropriate screening has not been established, but would reasonably include annual skin and lymph node examination. Generalized lipodystrophy has been reported as a paraneoplastic manifestation of pilocytic astrocytoma in three children who regained body fat following cancer therapy ADDIN EN.CITE <EndNote><Cite><Author>Patni</Author><Year>2015</Year><RecNum>9174</RecNum><DisplayText>(36)</DisplayText><record><rec-number>9174</rec-number><foreign-keys><key app="EN" db-id="2ft2re2d59da9ue2p9u5ww56de5eswxe5txe">9174</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Patni, N.</author><author>Alves, C.</author><author>von Schnurbein, J.</author><author>Wabitsch, M.</author><author>Tannin, G.</author><author>Rakheja, D.</author><author>Garg, A.</author></authors></contributors><auth-address>Division of Pediatric Endocrinology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA.
Hospital Universitario Prof. Edgard Santos, Pediatric Endocrinology Unit, Faculty of Medicine Federal University of Bahia, Salvador, Bahia, Brazil.
Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany.
Departments of Pathology and Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA.
Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.</auth-address><titles><title>A novel syndrome of generalized lipodystrophy associated with pilocytic astrocytoma</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>jc20152476</pages><edition>2015/08/08</edition><dates><year>2015</year><pub-dates><date>Aug 7</date></pub-dates></dates><isbn>1945-7197 (Electronic)
0021-972X (Linking)</isbn><accession-num>26252356</accession-num><urls><related-urls><url>;(36). Clinicians should consider screening for brain tumors in children who present with idiopathic AGL or atypical CGL. Specific progeroid syndromes (e.g. Bloom and Werner syndrome) are associated with increased malignancy risk (Table 3).TREATMENT OF LIPODYSTROPHY SYNDROMESCurrent therapies prevent or ameliorate the comorbidities of lipodystrophy syndromes. There is no cure for lipodystrophy, and no treatment that can regrow adipose tissue. DietMost patients should follow diets with balanced macronutrient composition. (Class IIa, Level C)Energy restricted diets improve metabolic abnormalities, and may be appropriate in adults. (Class I, Level C)Very low fat diets should be used in chylomicronemia-induced acute pancreatitis. (Class I, Level C)A dietician should be consulted for specialized dietary needs, especially in infants and young children. Overfeeding should be avoided. (Class IIa, Level C)Medium chain triglyceride (MCT) oil formulas can provide energy and reduce triglycerides in infants. (Class IIa, Level C)The cornerstone of therapy for metabolic complications of lipodystrophy is diet. Studies of specific diets in lipodystrophy are lacking, and recommendations rely on sparse literature and clinical experience.Patients with lipodystrophy, especially generalized forms, are typically hyperphagic due to leptin deficiency. Energy-restricted diets in adolescents and adults lower triglycerides and glucose ADDIN EN.CITE <EndNote><Cite><Author>Robbins</Author><Year>1979</Year><RecNum>726</RecNum><DisplayText>(37)</DisplayText><record><rec-number>726</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">726</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Robbins, D. C.</author><author>Danforth, E., Jr.</author><author>Horton, E. S.</author><author>Burse, R. L.</author><author>Goldman, R. F.</author><author>Sims, E. A.</author></authors></contributors><titles><title>The effect of diet on thermogenesis in acquired lipodystrophy</title><secondary-title>Metabolism</secondary-title><alt-title>Metabolism: clinical and experimental</alt-title></titles><periodical><full-title>Metabolism</full-title></periodical><alt-periodical><full-title>Metabolism</full-title><abbr-1>Metabolism: clinical and experimental</abbr-1></alt-periodical><pages>908-16</pages><volume>28</volume><number>9</number><keywords><keyword>Adolescent</keyword><keyword>*Basal Metabolism</keyword><keyword>Body Temperature Regulation</keyword><keyword>*Diet</keyword><keyword>Dietary Carbohydrates</keyword><keyword>Dietary Fats</keyword><keyword>Dietary Proteins</keyword><keyword>Energy Intake</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lipodystrophy/blood/*metabolism</keyword><keyword>Thyroid Gland/metabolism</keyword><keyword>Thyroxine/*blood</keyword><keyword>Triiodothyronine/*blood</keyword></keywords><dates><year>1979</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0026-0495 (Print)
0026-0495 (Linking)</isbn><accession-num>481216</accession-num><urls><related-urls><url>;(37), but dietary restriction is challenging to achieve.? Food restriction to control metabolic complications must be balanced by requirements for growth and development in children. Overfeeding to achieve normal weight may worsen metabolic complications and hepatic steatosis. Assessment of weight-for-length and body mass index (BMI) by comparison to reference growth data is not appropriate because body composition is atypical. Low weight-for-length or BMI is acceptable provided linear growth is maintained. Patients with lipodystrophy should not be labeled as having malnutrition.?Patients should follow a 50-60% carbohydrate, 20-30% fat, and ~20% protein diet. Simple sugars should be restricted in preference for high-fiber complex carbohydrates, distributed evenly among meals and snacks and consumed in combination with protein or fat. Dietary fat should be primarily cis-mono-unsaturated fats and long chain omega-3 fatty acids. In extremely hypertriglyceridemic infants, MCT-based formula may help PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HbHVlY2s8L0F1dGhvcj48WWVhcj4xOTc3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (38,39). During acute pancreatitis, parenteral nutrition followed by very low fat (<20 grams) diet should be used.ExercisePatients with lipodystrophy should be encouraged to exercise in the absence of specific contraindications. (Class IIa, Level C)Patients with subtypes of lipodystrophy predisposed to cardiomyopathy should undergo cardiac evaluation prior to initiating an exercise regimen. (Class III, Level C)Individuals with lipodystrophy engaged in intense exercise have amelioration of metabolic complications. Most patients should be encouraged to be physically active. However, strenuous exercise should be avoided in patients with cardiomyopathy. Contact sports should be avoided in patients with severe hepatosplenomegaly and CGL patients with lytic lesions in long bones. MetreleptinIn generalized lipodystrophy, metreleptin (with diet) is a first-line treatment for metabolic and endocrine abnormalities (Class I, Level B), and may be considered for prevention of these comorbidities in young children. (Class IIb, Level C)Metreleptin may be considered for hypoleptinemic (leptin < 4 ng/mL) patients with partial lipodystrophy and severe metabolic derangements (HbA1C > 8% and/or triglycerides > 500 mg/dL). (Class IIb, Level B)Currently, metreleptin (recombinant human methionyl leptin) is the only drug approved specifically for lipodystrophy. It is approved in the US as an adjunct to diet for treatment of metabolic complications in patients with generalized lipodystrophy. In Japan, it is approved for both generalized and partial lipodystrophy. It is available in other parts of the world (e.g. Europe) through compassionate use programs. There is no age limit for initiation of metreleptin; children as young as 15 months have been treated. A dosing algorithm is provided in Supplemental Table 2 ADDIN EN.CITE <EndNote><Cite><Author>Meehan</Author><Year>2016</Year><RecNum>768</RecNum><DisplayText>(40)</DisplayText><record><rec-number>768</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">768</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Meehan, C. A.</author><author>Cochran, E.</author><author>Kassai, A.</author><author>Brown, R. J.</author><author>Gorden, P.</author></authors></contributors><auth-address>a Diabetes, Endocrinology, and Obesity Branch , National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health , Bethesda , MD , USA.</auth-address><titles><title>Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy</title><secondary-title>Expert Rev Clin Pharmacol</secondary-title><alt-title>Expert review of clinical pharmacology</alt-title></titles><periodical><full-title>Expert Rev Clin Pharmacol</full-title><abbr-1>Expert review of clinical pharmacology</abbr-1></periodical><alt-periodical><full-title>Expert Rev Clin Pharmacol</full-title><abbr-1>Expert review of clinical pharmacology</abbr-1></alt-periodical><pages>59-68</pages><volume>9</volume><number>1</number><dates><year>2016</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1751-2441 (Electronic)
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ADDIN EN.CITE.DATA (41-45), frequently leading to weight loss. Reduced food intake is at least partially responsible for many of the metabolic improvements. If excessive weight loss occurs, the dose of metreleptin should be reduced (Supplemental Table 2) ADDIN EN.CITE <EndNote><Cite><Author>Meehan</Author><Year>2016</Year><RecNum>768</RecNum><DisplayText>(40)</DisplayText><record><rec-number>768</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">768</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Meehan, C. A.</author><author>Cochran, E.</author><author>Kassai, A.</author><author>Brown, R. J.</author><author>Gorden, P.</author></authors></contributors><auth-address>a Diabetes, Endocrinology, and Obesity Branch , National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health , Bethesda , MD , USA.</auth-address><titles><title>Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy</title><secondary-title>Expert Rev Clin Pharmacol</secondary-title><alt-title>Expert review of clinical pharmacology</alt-title></titles><periodical><full-title>Expert Rev Clin Pharmacol</full-title><abbr-1>Expert review of clinical pharmacology</abbr-1></periodical><alt-periodical><full-title>Expert Rev Clin Pharmacol</full-title><abbr-1>Expert review of clinical pharmacology</abbr-1></alt-periodical><pages>59-68</pages><volume>9</volume><number>1</number><dates><year>2016</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1751-2441 (Electronic)
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PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA (46). Metreleptin lowered triglycerides within one week PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FYmloYXJhPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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ZE5vdGU+
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FYmloYXJhPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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ZE5vdGU+
ADDIN EN.CITE.DATA (42), reaching 60% reduction at one year PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaWtlci1Db2hlbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1ll
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ADDIN EN.CITE.DATA (42,49-51). In one case, metreleptin ameliorated recurrence of severe hepatic steatosis after liver transplantation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXNleTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (52).Metreleptin decreased proteinuria in most patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYXZvcjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (42,45,53,54), and improved fertility ADDIN EN.CITE <EndNote><Cite><Author>Brown</Author><Year>2015</Year><RecNum>774</RecNum><DisplayText>(1)</DisplayText><record><rec-number>774</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">774</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Brown, R. J.</author><author>Gorden, P.</author></authors><secondary-authors><author>Dagogo-Jack, S.</author></secondary-authors></contributors><titles><title>Leptin Therapy in Patients with Lipodystrophy and Syndromic Insulin Resistance</title><secondary-title>Leptin: Regulation and Clinical Applications</secondary-title></titles><dates><year>2015</year></dates><pub-location>Switzerland</pub-location><publisher>Springer International Publishing</publisher><urls></urls></record></Cite></EndNote>(1). Metreleptin decreased testosterone in women, but did not alter ovarian morphology PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MdW5ndTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (45).Metreleptin in Partial LipodystrophyThe response to metreleptin in partial lipodystrophy is less robust than in generalized lipodystrophy. In one study, metreleptin reduced hypertriglyceridemia and improved glycemia in severely hypoleptinemic patients with partial lipodystrophy and severe metabolic derangements (baseline HbA1C > 8%, triglycerides > 500 mg/dL, leptin < 4 ng/mL) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaWtlci1Db2hlbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1ll
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ADDIN EN.CITE.DATA (46). In a second study, metreleptin improved triglycerides and indices of insulin sensitivity and secretion in FPLD2 patients with moderate to severe hypoleptinemia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYXRpZXI8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (57). Metreleptin is only available to patients with partial lipodystrophy through clinical trials, compassionate use programs, and in Japan.Side effects of metreleptinApproximately 30% of patients experience side effects PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFuPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (47). The most clinically important are hypoglycemia (in patients receiving concomitant insulin) and infrequent injection-site reactions (erythema, urticaria). In vivo neutralizing antibody activity to leptin has been reported PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWx0cmFuZDwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+
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ADDIN EN.CITE.DATA (58,59). The clinical implications remain unclear, but may include treatment failure and sepsis ADDIN EN.CITE <EndNote><Cite><Author>Chan</Author><Year>2015</Year><RecNum>734</RecNum><DisplayText>(59)</DisplayText><record><rec-number>734</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">734</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chan, J. L.</author><author>Koda, J.</author><author>Heilig, J. S.</author><author>Cochran, E. K.</author><author>Gorden, P.</author><author>Oral, E. A.</author><author>Brown, R. J.</author></authors></contributors><auth-address>Bristol-Myers Squibb, Princeton, New Jersey, USA.
Bristol-Myers Squibb, San Diego, California, USA.
AstraZeneca, San Diego, California, USA.
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Division of Metabolism, Endocrinology & Diabetes (MEND), University of Michigan, Ann Arbor, Michigan, USA.</auth-address><titles><title>Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy</title><secondary-title>Clin Endocrinol (Oxf)</secondary-title><alt-title>Clinical endocrinology</alt-title></titles><periodical><full-title>Clin Endocrinol (Oxf)</full-title></periodical><dates><year>2015</year><pub-dates><date>Nov 21</date></pub-dates></dates><isbn>1365-2265 (Electronic)
0300-0664 (Linking)</isbn><accession-num>26589105</accession-num><urls><related-urls><url>;(59). Additional serious adverse events occurring during metreleptin treatment are likely related to the underlying lipodystrophy syndrome, rather than metreleptin. These include T-cell lymphoma in patients with AGL ADDIN EN.CITE <EndNote><Cite><Author>Brown</Author><Year>2015</Year><RecNum>735</RecNum><DisplayText>(35)</DisplayText><record><rec-number>735</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">735</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brown, R. J.</author><author>Chan, J. L.</author><author>Jaffe, E. S.</author><author>Cochran, E.</author><author>DePaoli, A. M.</author><author>Gautier, J. F.</author><author>Goujard, C.</author><author>Vigouroux, C.</author><author>Gorden, P.</author></authors></contributors><auth-address>Diabetes, Endocrinology and Obesity Branch (DEOB), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) , Bethesda, MD , USA.</auth-address><titles><title>Lymphoma in acquired generalized lipodystrophy</title><secondary-title>Leuk Lymphoma</secondary-title><alt-title>Leukemia & lymphoma</alt-title></titles><periodical><full-title>Leuk Lymphoma</full-title><abbr-1>Leukemia & lymphoma</abbr-1></periodical><alt-periodical><full-title>Leuk Lymphoma</full-title><abbr-1>Leukemia & lymphoma</abbr-1></alt-periodical><pages>1-6</pages><dates><year>2015</year><pub-dates><date>May 12</date></pub-dates></dates><isbn>1029-2403 (Electronic)
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ADDIN EN.CITE.DATA (34) disease.Additional treatments for specific comorbiditiesDiabetesMetformin is a first-line agent for diabetes and insulin resistance (Class IIa, Level C)Insulin is effective for hyperglycemia. In some patients, concentrated preparations and high-doses may be required. (Class IIa, Level C)Thiazolidinediones may improve metabolic complications in patients with partial lipodystrophy, but should be used only with caution in generalized lipodystrophy. (Class IIb, Level B)Among the oral hypoglycemic agents, metformin is used most frequently. In patients with partial lipodystrophy, thiazolidinediones improved HbA1c, triglycerides, hepatic volume and steatosis, but may increase regional fat excess (Supplemental Table 3) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcmlvZ2x1PC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48
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ADDIN EN.CITE.DATA (65,66). Because cardiovascular risk may be enhanced in lipodystrophic syndromes independent of other risk factors, clinicians may consider applying stricter lipid targets (e.g. LDL-cholesterol < 100 mg/dl, triglycerides < 200 mg/dL) even in patients without diabetes.? In addition to diet, fibrates and long-chain omega-3-fatty acids (eicosapentaenoic and docosahexaenoic acid from fish oils) have wide clinical use to avoid acute complications of severe hypertriglyceridemia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaWtlci1Db2hlbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1ll
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ADDIN EN.CITE.DATA (46), but have not been formally studied. Plasmapheresis has been used in extreme hypertriglyceridemia, but must be repeated frequently PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2xhbjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (68). HypertensionAngiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARB) are first-line treatments for hypertension in patients with diabetes. (Class IIa, Level C)As in other patients with diabetes, ACE-inhibitors or ARBs should be used for hypertension ADDIN EN.CITE <EndNote><Cite><Author>King</Author><Year>1999</Year><RecNum>1405</RecNum><DisplayText>(69)</DisplayText><record><rec-number>1405</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">1405</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>King, P.</author><author>Peacock, I.</author><author>Donnelly, R.</author></authors></contributors><auth-address>Jenny O'Neill Diabetes Centre, Derbyshire Royal Infirmary, Derby, UK.</auth-address><titles><title>The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes</title><secondary-title>Br J Clin Pharmacol</secondary-title><alt-title>British journal of clinical pharmacology</alt-title></titles><periodical><full-title>Br J Clin Pharmacol</full-title><abbr-1>British journal of clinical pharmacology</abbr-1></periodical><alt-periodical><full-title>Br J Clin Pharmacol</full-title><abbr-1>British journal of clinical pharmacology</abbr-1></alt-periodical><pages>643-8</pages><volume>48</volume><number>5</number><keywords><keyword>Diabetes Mellitus, Type 2/complications/epidemiology/*therapy</keyword><keyword>Great Britain/epidemiology</keyword><keyword>Humans</keyword><keyword>Prospective Studies</keyword><keyword>Research Design</keyword></keywords><dates><year>1999</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0306-5251 (Print)
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ADDIN EN.CITE.DATA (70). In NAFLD not associated with lipodystrophy, diet and exercise are first-line treatments ADDIN EN.CITE <EndNote><Cite><Author>Mitchel</Author><Year>2014</Year><RecNum>818</RecNum><DisplayText>(71)</DisplayText><record><rec-number>818</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">818</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mitchel, E. B.</author><author>Lavine, J. E.</author></authors></contributors><auth-address>Division of Pediatric Gastroenterology, Hepatology and Nutrition, Columbia University, New York, NY, USA.</auth-address><titles><title>Review article: the management of paediatric nonalcoholic fatty liver disease</title><secondary-title>Aliment Pharmacol Ther</secondary-title><alt-title>Alimentary pharmacology & therapeutics</alt-title></titles><periodical><full-title>Aliment Pharmacol Ther</full-title><abbr-1>Alimentary pharmacology & therapeutics</abbr-1></periodical><alt-periodical><full-title>Aliment Pharmacol Ther</full-title><abbr-1>Alimentary pharmacology & therapeutics</abbr-1></alt-periodical><pages>1155-70</pages><volume>40</volume><number>10</number><keywords><keyword>Child</keyword><keyword>Diet</keyword><keyword>Humans</keyword><keyword>Life Style</keyword><keyword>Motor Activity</keyword><keyword>Non-alcoholic Fatty Liver Disease/*therapy</keyword><keyword>Vitamin E/therapeutic use</keyword><keyword>Weight Loss</keyword></keywords><dates><year>2014</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1365-2036 (Electronic)
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ADDIN EN.CITE.DATA (7,75), or muscle grafts ADDIN EN.CITE <EndNote><Cite><Author>Hurwitz</Author><Year>1982</Year><RecNum>448</RecNum><DisplayText>(76)</DisplayText><record><rec-number>448</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">448</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hurwitz, P. J.</author><author>Sarel, R.</author></authors></contributors><titles><title>Facial reconstruction in partial lipodystrophy</title><secondary-title>Ann Plast Surg</secondary-title><alt-title>Annals of plastic surgery</alt-title></titles><periodical><full-title>Ann Plast Surg</full-title></periodical><pages>253-7</pages><volume>8</volume><number>3</number><keywords><keyword>Adipose Tissue/transplantation</keyword><keyword>Adolescent</keyword><keyword>Face/*surgery</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lipodystrophy/*surgery</keyword><keyword>Surgery, Plastic</keyword></keywords><dates><year>1982</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0148-7043 (Print)
0148-7043 (Linking)</isbn><accession-num>7103380</accession-num><urls><related-urls><url>;(76) may be used. Excess fat from the head, neck, or vulva may be surgically reduced or ameliorated by liposuction ADDIN EN.CITE <EndNote><Cite><Author>Garg</Author><Year>2011</Year><RecNum>308</RecNum><DisplayText>(7)</DisplayText><record><rec-number>308</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">308</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garg, A.</author></authors></contributors><auth-address>Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8537, USA. abhimanyu.garg@utsouthwestern.edu</auth-address><titles><title>Clinical review#: Lipodystrophies: genetic and acquired body fat disorders</title><secondary-title>J Clin Endocrinol Metab</secondary-title><alt-title>The Journal of clinical endocrinology and metabolism</alt-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><alt-periodical><full-title>J Clin Endocrinol Metab</full-title><abbr-1>The Journal of clinical endocrinology and metabolism</abbr-1></alt-periodical><pages>3313-25</pages><volume>96</volume><number>11</number><keywords><keyword>Adipose Tissue/*metabolism</keyword><keyword>Humans</keyword><keyword>Insulin Resistance/genetics</keyword><keyword>Lipodystrophy/*genetics/metabolism/therapy</keyword><keyword>Mutation</keyword><keyword>Prognosis</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1945-7197 (Electronic)
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ADDIN EN.CITE.DATA (79,80). Management of hirsutism is reviewed elsewhere ADDIN EN.CITE <EndNote><Cite><Author>Loriaux</Author><Year>2012</Year><RecNum>472</RecNum><DisplayText>(81)</DisplayText><record><rec-number>472</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">472</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Loriaux, D. L.</author></authors></contributors><auth-address>Department of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. loriauxl@ohsu.edu</auth-address><titles><title>An approach to the patient with hirsutism</title><secondary-title>J Clin Endocrinol Metab</secondary-title><alt-title>The Journal of clinical endocrinology and metabolism</alt-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><alt-periodical><full-title>J Clin Endocrinol Metab</full-title><abbr-1>The Journal of clinical endocrinology and metabolism</abbr-1></alt-periodical><pages>2957-68</pages><volume>97</volume><number>9</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Androgen Antagonists/therapeutic use</keyword><keyword>Child</keyword><keyword>Cosmetic Techniques</keyword><keyword>Diagnosis, Differential</keyword><keyword>Electrolysis</keyword><keyword>Female</keyword><keyword>Hair/pathology</keyword><keyword>Hair Removal</keyword><keyword>Hirsutism/diagnosis/etiology/psychology/*therapy</keyword><keyword>Humans</keyword><keyword>Laser Therapy</keyword><keyword>Middle Aged</keyword><keyword>Ovary/physiopathology</keyword><keyword>Terminology as Topic</keyword><keyword>Women</keyword><keyword>Young Adult</keyword></keywords><dates><year>2012</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1945-7197 (Electronic)
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ADDIN EN.CITE.DATA (82,83). There is clinical experience in the safe use of oral progestins and progestin containing intrauterine devices. PregnancyPregnant patients should receive prenatal care from an obstetrician experienced in managing diabetes, and a physician experienced in managing lipodystrophy. (Class IIa, level C)Should a patient become pregnant while taking metreleptin, clinicians may consider continuing metreleptin if withdrawal would harm the mother and fetus, and the patient understands that effects of metreleptin in pregnancy are unknown, and wishes to continue. (Class IIc, level C)In patients with lipodystrophy who have extreme insulin resistance at baseline, worsening insulin resistance during pregnancy may make diabetes management difficult, with attendant fetal risks.? Furthermore, metreleptin withdrawal has been associated with rebound hypertriglyceridemia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcmFsPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (41), placing patients at risk for pancreatitis, endangering both mother and fetus.? ConclusionsLipodystrophy syndromes are a group of heterogeneous syndromes with diverse pathophysiology. For diagnosis, clinical recognition and physical examination are critical. In management efforts, attention should be paid to metabolic derangements, and to many other facets of these syndromes affecting multiple organs, and quality of life.AcknowledgmentsThis work was generously supported by an educational grant from AstraZeneca. We thank the staff of the Pediatric Endocrine Society for their help in sponsoring and organizing this practice guideline, the patients from around the world whose contributions to research allowed the development of these guidelines, and Elaine Cochran for providing the guideline for metreleptin dosing.?Table 1: Subtypes and inheritance of lipodystrophySubtype of lipodystrophyPathogenesis: gene involved, altered protein and functionInheritanceRefer-enceGeneralized lipodystrophiesCGL1AGPAT2?: AGPAT2, synthesis of triglycerides and glycerophospholipidsARPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2Fyd2FsPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48
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ADDIN EN.CITE.DATA (85)CGL3CAV1:caveolin-1, formation of membrane caveolae, lipid trafficAR (single case) ADDIN EN.CITE <EndNote><Cite><Author>Kim</Author><Year>2008</Year><RecNum>11803</RecNum><DisplayText>(86)</DisplayText><record><rec-number>11803</rec-number><foreign-keys><key app="EN" db-id="z29f0asse90rasexde5pzafbetswrdd0r5z9">11803</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim, C. A.</author><author>Delepine, M.</author><author>Boutet, E.</author><author>El Mourabit, H.</author><author>Le Lay, S.</author><author>Meier, M.</author><author>Nemani, M.</author><author>Bridel, E.</author><author>Leite, C. C.</author><author>Bertola, D. R.</author><author>Semple, R. K.</author><author>O'Rahilly, S.</author><author>Dugail, I.</author><author>Capeau, J.</author><author>Lathrop, M.</author><author>Magre, J.</author></authors></contributors><auth-address>Department of Pediatrics, Instituto da Crianca, University of Sao Paulo, 05403-900 Sao Paulo, Brazil.</auth-address><titles><title>Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy</title><secondary-title>J Clin Endocrinol Metab</secondary-title><alt-title>The Journal of clinical endocrinology and metabolism</alt-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>1129-34</pages><volume>93</volume><number>4</number><keywords><keyword>Adipocytes/physiology</keyword><keyword>Adipose Tissue/metabolism</keyword><keyword>Adult</keyword><keyword>Caveolin 1/*genetics/physiology</keyword><keyword>*Codon, Nonsense</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lipodystrophy, Congenital Generalized/*genetics</keyword></keywords><dates><year>2008</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0021-972X (Print)</isbn><accession-num>18211975</accession-num><urls><related-urls><url> </url></related-urls></urls><language>eng</language></record></Cite></EndNote>(86) CGL4PTRF?: cavin-1, formation of membrane caveolae, lipid trafficARPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXlhc2hpPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE.DATA (87)AGL (Lawrence syndrome)Frequently associated with autoimmune diseases and/or complement abnormalities- ADDIN EN.CITE <EndNote><Cite><Author>Misra</Author><Year>2003</Year><RecNum>2</RecNum><DisplayText>(4)</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="e0e9v50ertwddoepww0vzdvw9pr99eexp2v2">2</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Misra, A.</author><author>Garg, A.</author></authors></contributors><auth-address>Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 75390, USA.</auth-address><titles><title>Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature</title><secondary-title>Medicine (Baltimore)</secondary-title><alt-title>Medicine</alt-title></titles><pages>129-46</pages><volume>82</volume><number>2</number><keywords><keyword>Adipose Tissue/*metabolism/radiography/surgery</keyword><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Body Composition</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Diabetes Complications</keyword><keyword>Diabetes Mellitus/drug therapy</keyword><keyword>Female</keyword><keyword>Glucose Intolerance/etiology/therapy</keyword><keyword>Humans</keyword><keyword>Hypertriglyceridemia/drug therapy/etiology</keyword><keyword>Hypolipidemic Agents/therapeutic use</keyword><keyword>Leptin/metabolism/therapeutic use</keyword><keyword>Lipodystrophy/*diagnosis/*metabolism/therapy</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Reconstructive Surgical Procedures</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0025-7974 (Print)
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ADDIN EN.CITE.DATA (16)Partial lipodystrophiesFPLD1genetic cause unknownUsually AD ADDIN EN.CITE <EndNote><Cite><Author>Herbst</Author><Year>2003</Year><RecNum>1350</RecNum><DisplayText>(88)</DisplayText><record><rec-number>1350</rec-number><foreign-keys><key app="EN" db-id="z29f0asse90rasexde5pzafbetswrdd0r5z9">1350</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Herbst, K. L.</author><author>Tannock, L. R.</author><author>Deeb, S. S.</author><author>Purnell, J. Q.</author><author>Brunzell, J. D.</author><author>Chait, A.</author></authors></contributors><auth-address>Department of Medicine, University of Washington, Seattle, Washington, USA. kaherbst@cdrew.edu</auth-address><titles><title>Kobberling type of familial partial lipodystrophy: an underrecognized syndrome</title><secondary-title>Diabetes Care</secondary-title></titles><periodical><full-title>Diabetes Care</full-title></periodical><pages>1819-24</pages><volume>26</volume><number>6</number><keywords><keyword>Anthropometry</keyword><keyword>Body Composition</keyword><keyword>European Continental Ancestry Group</keyword><keyword>Exons</keyword><keyword>Female</keyword><keyword>Human</keyword><keyword>Lamin Type A/genetics</keyword><keyword>Leptin/blood</keyword><keyword>Lipodystrophy/*diagnosis/genetics</keyword><keyword>Obesity/*complications/genetics</keyword><keyword>Receptors, Cytoplasmic and Nuclear/genetics</keyword><keyword>Skinfold Thickness</keyword><keyword>Support, U.S. Gov't, P.H.S.</keyword><keyword>Syndrome</keyword><keyword>Transcription Factors/genetics</keyword><keyword>Washington</keyword></keywords><dates><year>2003</year><pub-dates><date>Jun</date></pub-dates></dates><accession-num>12766116</accession-num><urls><related-urls><url>;(88)FPLD2LMNA : lamin A/C, structure and functions of nuclear laminaAD ADDIN EN.CITE <EndNote><Cite><Author>Cao</Author><Year>2000</Year><RecNum>429</RecNum><DisplayText>(89)</DisplayText><record><rec-number>429</rec-number><foreign-keys><key app="EN" db-id="z29f0asse90rasexde5pzafbetswrdd0r5z9">429</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cao, H.</author><author>Hegele, R. A.</author></authors></contributors><titles><title>Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy</title><secondary-title>Hum Mol Genet</secondary-title></titles><periodical><full-title>Hum Mol Genet</full-title></periodical><pages>109-12</pages><volume>9</volume><number>1</number><keywords><keyword>Adipocytes/pa [Pathology]</keyword><keyword>Age Factors</keyword><keyword>Body Weight/ge [Genetics]</keyword><keyword>Canada</keyword><keyword>Codon</keyword><keyword>Female</keyword><keyword>Heterozygote</keyword><keyword>Human</keyword><keyword>*Laminin/ge [Genetics]</keyword><keyword>Laminin/me [Metabolism]</keyword><keyword>*Lipodystrophy/ge [Genetics]</keyword><keyword>Male</keyword><keyword>*Mutation</keyword><keyword>Mutation, Missense</keyword><keyword>*Nuclear Proteins/ge [Genetics]</keyword><keyword>Nuclear Proteins/me [Metabolism]</keyword><keyword>Pedigree</keyword><keyword>Support, Non-U.S. Gov't</keyword></keywords><dates><year>2000</year></dates><accession-num>20056129</accession-num><urls></urls></record></Cite></EndNote>(89) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFja2xldG9uPC9BdXRob3I+PFllYXI+MjAwMDwvWWVh
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ADDIN EN.CITE.DATA (97) ADDIN EN.CITE <EndNote><Cite><Author>De Sandre-Giovannoli</Author><Year>2003</Year><RecNum>685</RecNum><DisplayText>(98)</DisplayText><record><rec-number>685</rec-number><foreign-keys><key app="EN" db-id="z29f0asse90rasexde5pzafbetswrdd0r5z9">685</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>De Sandre-Giovannoli, A.</author><author>Bernard, R.</author><author>Cau, P.</author><author>Navarro, C.</author><author>Amiel, J.</author><author>Boccaccio, I.</author><author>Lyonnet, S.</author><author>Stewart, C. L.</author><author>Munnich, A.</author><author>Le Merrer, M.</author><author>Levy, N.</author></authors></contributors><auth-address>Inserm U491: Genetique Medicale et Developpement, Faculte de Medecine Timone, Marseille, France.</auth-address><titles><title>Lamin a truncation in Hutchinson-Gilford progeria</title><secondary-title>Science</secondary-title></titles><periodical><full-title>Science</full-title></periodical><pages>2055</pages><volume>300</volume><number>5628</number><keywords><keyword>Alleles</keyword><keyword>Cell Nucleus/ultrastructure</keyword><keyword>Child</keyword><keyword>Exons</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lamin Type A/analysis/*chemistry/*genetics</keyword><keyword>Lymphocytes/chemistry/ultrastructure</keyword><keyword>Mutation</keyword><keyword>Polymorphism, Genetic</keyword><keyword>Progeria/blood/*genetics</keyword><keyword>RNA Splicing</keyword><keyword>RNA, Messenger/genetics</keyword><keyword>Research Support, Non-U.S. Gov't</keyword><keyword>Sequence Deletion</keyword><keyword>Transcription, Genetic</keyword></keywords><dates><year>2003</year><pub-dates><date>Jun 27</date></pub-dates></dates><accession-num>12702809</accession-num><urls><related-urls><url>;(98)Progeroid laminopathiesLMNA : lamin A/C, structure and functions of nuclear laminaAD, de novoPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGVuPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (106)Ruijs-Aalfs syndromeSPRTN: SprT-like N-terminal domain protein, DNA repairARPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZXNzZWw8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (107)Neonatal progeroid syndromeCAV1: Caveolin-1, formation of membrane caveolae, lipid traffic de novo ADDIN EN.CITE <EndNote><Cite><Author>Garg</Author><Year>2015</Year><RecNum>18893</RecNum><DisplayText>(108)</DisplayText><record><rec-number>18893</rec-number><foreign-keys><key app="EN" db-id="z29f0asse90rasexde5pzafbetswrdd0r5z9">18893</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garg, A.</author><author>Kircher, M.</author><author>Del Campo, M.</author><author>Amato, R. S.</author><author>Agarwal, A. K.</author><author>University of Washington Center for Mendelian, Genomics</author></authors></contributors><auth-address>Department of Internal Medicine and the Center for Human Nutrition, Division of Nutrition and Metabolic Diseases, UT Southwestern Medical Center, Dallas, Texas.
Department of Genome Sciences, University of Washington, Seattle, Washington.
Division of Clinical and Molecular Genetics, Hospital Vall d'Hebron, Universitat Pompeu Fabra, CIBERER, Barcelona, Spain.
Department of Pediatrics, Division of Genetics and Metabolism, University of Kentucky, Lexington, Kentucky.</auth-address><titles><title>Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome</title><secondary-title>Am J Med Genet A</secondary-title><alt-title>American journal of medical genetics. Part A</alt-title></titles><periodical><full-title>Am J Med Genet A</full-title></periodical><pages>1796-806</pages><volume>167</volume><number>8</number><dates><year>2015</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1552-4833 (Electronic)
1552-4825 (Linking)</isbn><accession-num>25898808</accession-num><urls><related-urls><url>;(108)Auto-inflammatory syndromes with lipodystrophyAuto-inflammatory lipodystrophy (JMP, CANDLE)PSMB8: Proteasome (prosome, macropain) subunit, beta type, 8; (PSMB8); immunoproteasome subunitARPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ2Fyd2FsPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
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ADDIN EN.CITE.DATA (111)AD, autosomal dominant; AGL, acquired generalized lipodystrophy; AGPAT2, acylglycerol-3-phosphate-O-acyltransferase 2; AKT2, v-akt murine thymoma viral oncogene homolog 2 ; APL, acquired partial lipodystrophy; AR, autosomal recessive; BANF1, barrier to autointegration factor 1; BSCL2, Berardinelli-Seip congenital lipodystrophy 2; CANDLE, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature syndrome; CAV1, caveolin 1; CGL, congenital generalized lipodystrophy; CIDEC, cell death inducing DFFA like effector c; FPLD, familial partial lipodystrophy; FBN1, fibrillin 1; ; JMP, joint contractures, muscle atrophy; KCNJ6, potassium voltage-gated channel subfamily J member 6; LIPE, lipase E, hormone sensitive type ; LMNA, lamin A/C; Microcytic anemia and Panniculitis induced lipodystrophy syndrome; MDP, mandibular hypoplasia, deafness and progeroid features; PCYT1A, phosphate cytidylyltransferase 1, choline, alpha ; PIK3R1, phosphoinositide-3-kinase regulatory subunit 1; PLIN1, perilipin 1; POLD1, polymerase, delta 1, catalytic subunit; PPARG, peroxisome proliferator activated receptor gamma; PSMB8, proteasome subunit beta 8; PTRF , polymerase I and transcript release factor; SPRTN, SprT-like N-terminal domain; WRN, Werner syndrome RecQ like helicase; ZMPSTE24, Zinc metalloproteinase Table 2: Major comorbidities and complications of lipodystrophyComplicationAffected subtypesReferenceHyperphagia AGL, CGL, ±FPLDPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bb3Rhbmk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA (4,5,7,9,13,17,20,21,67)Reproductive dysfunction (PCOS, oligomenorrhea, reduced fertility, hirsutism, preeclampsia, miscarriage, macrosomia)AGL, CGL, FPLD, APLPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYXJnPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (4,5,7,10,14,20,55,113)Non-alcoholic fatty liver disease (ranging from simple steatosis to cirrhosis)AGL, CGL, FPLD, ±APLPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2xhbjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (9,13)Psychological distress (fatigue, pain, depression, anxiety)AGL, CGL, FPLD, APLPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWNrc29uPC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48
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ADDIN EN.CITE.DATA (10,120)AGL, acquired generalized lipodystrophy; APL, acquired partial lipodystrophy; CAD, coronary artery disease; CGL, congenital generalized lipodystrophy; FPLD, familial partial lipodystrophy; MPGN, membranoproliferative glomerulonephritis; FSGS, focal segmental glomerulosclerosis; PCOS, polycystic ovary syndromeMany of these features are also found in other forms of lipodystrophy, including progeroid disorders.Table 3: Phenotypes of Lipodystrophy SyndromesCongenital Generalized LipodystrophySubtype (gene)Gene-ticsOnset↓Fat↑FatSkinAppendagesMuscleBoneMineralCardio-vascularMeta-bolicKidneyNer-vousGILiverSpleenGUEndocrineOtherCGL 1(AGPAT2)ARBirthChild-hoodAlmost all fat lostNormal mechanical↓MarrowNoneANHypertrichosisPhlebomegalyEruptive xanthomataAcromegaloidMuscle hypertrophyCystic bone lesionsHyper-trophic cardio-myopathy (25%)HTNIR/DM↑TG↓LeptinProteinuriaMR in-freq-uentHyperphagiaAcute pancreatitisNAFLDCirrhosisSplenomegalyPrecocious puberty (♀)Accelerated growth↓Fertility (♀)PCOSAfrican descent (58%)Umbilical prominence/herniaCGL 2(BSCL2)ARBirthAlmost all fat lost↓Mechanical↓Marrow NoneANHypertrichosisPhlebomegaly Eruptive xanthomataAcromegaloidMuscle hypertrophyHyper-trophic cardio-myopathy (33%)IR/DM↑TG↓LeptinProteinuriaMR(75%)HyperphagiaPancreatitisNAFLDCirrhosisSplenomegalyPrecocious puberty (♀)Accelerated growth↓Fertility (♀)PCOSUmbilical prominence/herniaCGL 3(CAV1)ARChild-hoodAlmost all fat lost↓MechanicalNormal marrowNoneANHirsutismMuscle hypertrophy HypocalcemiaVitamin D resistanceOsteopeniaNIR/DM↑TG↓LeptinNNMegaesophagusNAFLDSplenomegalyDelayed growthShort stature AmenorrheaHyper-androgenismCGL 4(PTRF)ARChild-hoodAlmost all fat lostNormal mechanicalMarrow fat unknownNoneHypertrichosisAcromegaloidPercussion-induced muscle moundingMuscle weakness & hypertrophySpinal rigidity↑LordosisOsteoporosisAtlanto-axial instabilityArthritisContracturesCardiac arrhyth-miaRisk of sudden cardiac deathIRMild ↑glucose↑TG↓LeptinNNHypertrophic pyloric stenosisEsophageal dysmotilityHepato-splenomegaly↑ALT/ASTNot reportedFailure to thriveUmbilical prominenceTransient immuno-deficiencyRecurrent infectionsCGLPPARG-associatedARChild-hoodAlmost all fat lostNoneANPhlebomegalyEruptive xanthomataMuscle hypertrophyIR/DM↑TG↓LeptinNNAcute pancreatitisHepato-splenomegalyIrregular mensesHyper-parathyroidismAcquired Generalized LipodystrophySubtypeGene-ticsOnset↓Fat↑FatSkinAppendagesMuscleBoneMineralCardio-vascularMeta-bolicKidneyNervousGILiverSpleenGUEndocrineOthern/an/aAfter birth, often before adolescenceAlmost all fat lost↓MechanicalNormal marrowNoneANHirsutismPhlebo-megalyMuscular appearanceIschemic cardio-myopathy± HTNIR/ DM↑ TG↓ LeptinNNHepato-splenomegalyPCOS3 variants: Panniculitis Autoimmune (complement abnormalities)IdiopathicFamilial Partial LipodystrophySubtypeGene-ticsOnset↓Fat↑FatSkinAppendagesMuscleBoneMineralCardio-vascularMeta-bolicKidneyNervousGILiverSpleenGUEndocrineOtherFPLD1UChild- orAdult-hoodButtocksLimbsFaceNeckAbd(sc + visc.)ANPhlebomegalyEruptive xanthomata HirsutismCalf hypertrophyCoronary artery disease HTNIR/DM↑TGNNHepatomegalyNOnly ♀ reported FPLD2 (LMNA)ADPubertyButtocksLimbsFaceNeckAbd(visc.)ANPhlebomegaly Eruptive xanthomata HirsutismMuscle hypertrophy MyalgiaCoronary artery disease HTNIR/DM↑TGMild ↓LeptinProteinuria in late stagesNerve entrapment syndromesPancreatitisHepatomegalyHepatic steatosisPCOSLabial pseudo-hypertrophy Breast hypoplasiaPreeclampsiaMiscarriagesLipomasFPLD3 (PPAR?)ADAdult-hoodTrunk ButtocksLimbs±AbdomenANPhlebomegaly HirsutismMuscular appearance HTNIR/DM↑TGMild ↓LeptinNNHepatomegalyHepatic steatosisPCOSPreeclampsiaFPLD4 (PLIN1)ADChild- or adult-hoodButtocksLimbs±FaceANMuscle hypertrophy HTNIR/DM↑TGNNHepatomegalyHepatic steatosisPCOSCushingoid appearance occasionalFPLD5(CIDEC)ARChild-hoodButtocksLower limbsNoneANMuscle hypertrophyHTNIR/DM↑TG↓LeptinProteinuriaNPancreatitisHepatomegalyHepatic steatosisIrregular mensesDiabetic ketoacidosisFPLD6(LIPE)ARAdult-hoodLower limbsNeckAxilla±Back Supra-clavicular Below tricepsNMuscle weaknessNIR/DM↑TGNNHepatic steatosisNMild muscular dystrophyHigh CK↑adiponectinAkt2-linked lipodys-trophyADAdult-hoodLower limbsAbd(visc.)IR/DM↑TG↓LeptinNNHepatic steatosisNAcquired Partial LipodystrophySubtypeGene-ticsOnset↓Fat↑FatSkinAppendagesMuscleBoneMineralCardio-vascularMeta-bolicKidneyNervousGILiverSpleenGUEndocrineOthern/an/aChild-hood, adolescence, adulthoodFace, trunk, upper limbs, Lower limbs-Muscular appearance-Infrequent IR/ DM↑ TG-Membranoproliferative GlomerulonephritisNHepato-splenomegalyPCOSAssociation with auto-immune diseasesLow C3 complement levels, presence of C3NeF (C3 nephritic factor)Progeroid and Autoinflammatory disordersSubtypeGene-ticsOnset↓Fat↑FatSkin &AppendagesMuscleBoneMineralCardio-vascularMeta-bolicKidneyNervousGILiverSpleenGUEndocrineOtherHGPS(LMNA)AD de novo<1 yearAlmost all fat lost(intra-abdominal fat spared)NoneSkin dimpling & mottlingSclerotic skin changesProminent cutaneous vasculatureAlopeciaDysplastic nailsOgival palate Abnormal dentitionStooped shouldersAcroosteolysisCoxa valgaOsteoporosisSubluxed finger jointsJoint stiffness↓muscle massEKG & Echo abnormalitiesAnginaHTNPremature athero-sclerosisMild IRMild ↑glucose↑TGNTIAStrokeNPubertal delayMammary aplasiaDysmorphic faciesAged appearance Growth failureShort statureNasal voiceDeath in 2nd decadeType A MAD(LMNA)ARChild-hoodUpper and Lower limbsFaceNeckTrunkPigmentary skin changesAlopeciaSoft tissue calcinosisPhlebo-megalyMandibular hypoplasiaAcroosteolysis Dental crowding Hypoplastic teeth Wide cranial sutures Wormian bonesJoint stiffnessBulbous fingertipsValvular calcificationPremature athero-sclerosisIR/DM↑TGNNNNDysmorphic faciesAged appearance Growth failureShort statureType B MAD(ZMPSTE24)AR<1 yearAlmost all fat lostNoneMottled pigmentation Skin atrophyAlopeciaMandible & clavicle hypoplasia Acroosteolysis Joint contracturesDelayed closure of cranial suturesSC calcificationsNIR/DM↑TGNNNProgressive glomerulopathyDysmorphic faciesNéstor-Guillermo Progeria Syndrome(BANF1)AR1-2 yearsAlmost all fat lostNoneSkin atrophyPigmented skin lesionsAlopeciaPhlebo-megalySevere osteoporosisOsteolysisMicrognathiaScoliosisDental crowdingOpen cranial suturesStiff joints Sinus tachycardia Right bundle branch blockPulmonary hypertensionNNNNNGrowth failureShort statureAtypical Progeria(LMNA)AD de novoChild-hoodPub-ertyPartial or generalized fat lossNormal mechanical fatNoneAlopecia Mottled skin pigmentSclero-dermatous skin changesSmall mandibleDental crowdingHigh arched palate Mild clavicular resorptionAcroosteolysisMild flexion contracturesValvular calcificationIR/DM↑TGNNHepatomegaly Mammary hypoplasiaDysmorphic faciesAged appearance Short statureWerner syndrome(RECQL2)AR2nd decadeLimbsAbd-omenSclero-dermatous skin changes Tissue calcification and ulcerationAlopeciaOsteoporosisAthero-sclerosisMyocardial infarctionIR/DM↑TGNNNDysmorphic faciesGrowth failureShort statureCataracts↑CancerBloom Syndrome (BLM)ARChild-hoodLimbsAbd-omenTelangiec-tasiaAltered skin pigmentPhoto-sensitivityHyper-trichosisPolydactylyDMMild MR in some patientsReduced fertilityDysmorphic faciesGrowth failure↑CancerPCYT1ALipo-dystrophyARChild-hoodLimbsLow HDL-CIR/DM↑TGLiver steatosisGrowth failureShort stature MDPL (POLD1)AD de novoChild-hoodAlmost all fat lost ↓ in soles of feetVisc.Telangiec-tasiaSkin atrophySclerodermaNormal hairHypoplasia of mandible & metatarsalsJoint contracturesFused carpal bonesDental crowdingOsteoporosis↓muscle massNIR/DM↑TGNSensori-neural deafnessHepato-megalyHypogonadism & cryptorchidism (♂)Hypoplastic breasts(♀)Dysmorphic faciesShort statureCataractsHigh-pitched voiceSHORT(PIK3R1)ADChild-hoodAlmost all fat lost (most cases)NoneThin, wrinkled skinDelayed dental eruption ±Joint laxity MicrognathiaHeart mal-formationsIR/DMNormal TGNephro-calcinosisSensori-neural hearing loss Speech delayNInguinal herniaDysmorphic faciesAged appearanceIUGRShort statureGlaucomaRieger anomalyCataractsMarfan syndrome with neonatal progeroid syndrome-like lipo-dystrophy(FBN1)ADde novoBirthAlmost all fat lostNoneAlopeciaAtrophic skinArthrogryposisArachno-dactylyHyperlaxity Large fontanelsAortic root dilatationNNRelative macro-cephalyNNDysmorphic faciesAged appearanceMyopiaCockayne syndrome(ERCC6, ERCC8)ARBirthChild-hoodAlmost all fat lostNoneDry skinPhoto-sensitivitySkin atrophyAlopeciaPrognathismLong limbsLarge hands/feetJoint contracturesKyphosisEarly athero-sclerosisHTNNRenal diseaseMicrocephalySevere MRSensorineural hearing lossSeizuresAtaxia Tremor WeaknessDementiaNIrregular mensesHypogonadismDysmorphic faciesFTTShort statureCongenital cataractsPigmentary retinopathyDeath before 15yNeonatal Progeroid SyndromeARBirthFaceDistal extremities±para-vertebral ±gluteal↓ in palmsButt-ocks Ano-geni-talAlopeciaThin wrinkled skinHypoplastic nailsPhlebomegalyLarge fontanelsThin long bones with enlarged metaphysesLoss of teethJoint contractures ↓muscle massProminent scalp veins↑TGPelvi-calyceal ectasiaMacrocephalyMRHypotonia Truncal ataxiaN↑T4Irregular mensesDysmorphic faciesFTTShort statureAged appearance EctropionDeath in childhoodKeppen-Lubinsky syndrome(KCNJ6)ADde novoChild-hoodAlmost all fat lostNoneTightly adherent facial skinJoint contracturesScoliosisMicrognathiaNNNMicrocephalyMRHypertonia Hyperreflexia Spastic tetraparesis SeizuresNNDysmorphic faciesFTTShort statureAged appearanceRuijs-Aalfs syndrome(SPRTN)ARChild-hoodAlmost all fat lostNonePalmar creasesPremature graying of scalp hairPectus excavatumSloping shouldersDelayed bone ageJoint contractures KyphoscoliosisClinodactylyPes planus↓ muscle mass MicrognathiaNNNNHepato-cellular carcinomaNDysmorphic faciesFTTShort statureCataractsSensitivity to genotoxinsNakajo-Nishimura,JMP,CANDLE syndromes(PSMB8)ARChild-hoodFaceHandsFeet± ChestNoneErythematous nodular skin lesions Panniculitis Dry, stiff skinJoint contracturesMuscle weakness↓ muscle massHypertrophic pulmonary osteo-arthropathyLong and thick fingersCardiac insufficiency Arrhythmias ↑ TGNMR± Seizures Basal ganglia calcification Hepato-spleno-megalyAb-normal liver enzymesNDysmorphic faciesFTTShort statureRecurrent feverMicrocytic anemia↑ ESRHypergamma-globulinemia1 Palms, soles, orbits, scalp, and periarticular regionsAD, autosomal dominant; AN, acanthosis nigricans; AR, autosomal recessive; BM, bone marrow fat; CANDLE, chronic neutrophilic dermatosis with lipodystrophy and elevated temperature; DM, diabetes mellitus; ESR, erythrocyte sedimentation rate ; FTT, failure to thrive; HTN, hypertension; IR, insulin resistance; IUGR, intrauterine growth restriction; JMP, joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy; MAD, Mandibuloacral dysplasia; MDPL, mandibular hypoplasia, deafness, progeroid features, and lipodystrophy; MR, mental retardation ; N, No alterations reported; NAFLD, non-alcoholic fatty liver disease; PCOS, polycystic ovarian syndrome; SC, subcutaneous; SHORT, short stature, hyperestensibility, hernia, ocular depression, Rieger anomaly, and teething delay; TG, triglyceride; TIA, transient ischemic attack; U, unknown; Visc, visceralTable 4: Clinical Features that Increase the Suspicion of Lipodystrophy1Essential feature Generalized or regional absence of body fatPhysical FeaturesFailure to thrive (infants and children)Prominent musclesProminent veins (phlebomegaly)Severe acanthosis nigricansEruptive xanthomataCushingoid appearanceAcromegaloid appearanceProgeroid (premature aging) appearanceComorbid ConditionsDiabetes mellitus with high insulin requirements≥200 units/day≥2 units/kg/dayRequiring U-500 insulinSevere hypertriglyceridemia≥500 mg/dL with or without therapy≥250 mg/dL despite diet and medical therapyHistory of acute pancreatitis secondary to hypertriglyceridemiaNon-alcoholic steatohepatitis in a non-obese individualEarly-onset cardiomyopathyPolycystic Ovarian SyndromeOther Historical CluesAutosomal dominant or recessive pattern of similar physical features or metabolic complicationsSignificant hyperphagia (may manifest as irritability/aggression in infants/children)1Adapted from ADDIN EN.CITE <EndNote><Cite><Author>Handelsman</Author><Year>2013</Year><RecNum>326</RecNum><DisplayText>(18)</DisplayText><record><rec-number>326</rec-number><foreign-keys><key app="EN" db-id="devt2w5ai500swev5zpvxv9efxtttsae5paf">326</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Handelsman, Y.</author><author>Oral, E. A.</author><author>Bloomgarden, Z. T.</author><author>Brown, R. J.</author><author>Chan, J. L.</author><author>Einhorn, D.</author><author>Garber, A. J.</author><author>Garg, A.</author><author>Garvey, W. T.</author><author>Grunberger, G.</author><author>Henry, R. R.</author><author>Lavin, N.</author><author>Tapiador, C. D.</author><author>Weyer, C.</author></authors></contributors><auth-address>Metabolic Institute of America, Tarzana, California.</auth-address><titles><title>The clinical approach to the detection of lipodystrophy - an aace consensus statement</title><secondary-title>Endocr Pract</secondary-title><alt-title>Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists</alt-title></titles><periodical><full-title>Endocr Pract</full-title><abbr-1>Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists</abbr-1></periodical><alt-periodical><full-title>Endocr Pract</full-title><abbr-1>Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists</abbr-1></alt-periodical><pages>107-16</pages><volume>19</volume><number>1</number><dates><year>2013</year><pub-dates><date>Jan 1</date></pub-dates></dates><isbn>1934-2403 (Electronic)
1530-891X (Linking)</isbn><accession-num>23435042</accession-num><urls><related-urls><url>;(18)Figure LegendsFigure 1: Physical appearance of patients with the four main subtypes of lipodystrophy syndromesA. Lateral 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 subcutaneous 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 40-year-old Caucasian female with familial partial lipodystrophy of the Dunnigan variety due to heterozygous p.Arg482Gln mutation in LMNA gene. She had marked loss of subcutaneous fat from the limbs and anterior truncal region. The breasts were atrophic. She had increased subcutaneous 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 subcutaneous fat with marked acanthosis nigricans in the neck, axillae and groin. D. Anterior view of a 45-year-old Caucasian female with acquired partial lipodystrophy (Barraquer-Simons syndrome). She had marked loss of subcutaneous fat from the face, neck, upper extremities, and chest and but had lipodystrophy on localized regions on anterior thighs. She had increased subcutaneous fat deposition in the lower extremities.Figure 2: Diagnostic approach to lipodystrophy syndromesLipodystrophy should be suspected in patients with regional or generalized lack of adipose tissue. History should assess age of onset of fat loss and comorbidities. Physical examination should determine distribution of subcutaneous fat loss and presence of prominent muscles, phlebomegaly, acanthosis nigricans, hepatomegaly, xanthomas, and acromegaloid or progeroid appearance. All patients should undergo metabolic work up for insulin resistance, diabetes, dyslipidemia and fatty liver disease. Conventional anthropometry including skinfold thickness measurements, ± DXA and whole body MRI (if available) should be performed to confirm the pattern of fat loss. Common genetic lipodystrophies include congenital generalized lipodystrophy (CGL), familial partial lipodystrophy (FPLD) and progeroid lipodystrophies. They require genotyping to confirm the diagnosis followed by genetic counseling and screening of family members. Patients with progeroid lipodystrophies have progeroid features like bird like facies, high-pitched voice, skin atrophy and pigmentation, alopecia and nail dysplasia. Patients with FPLD have fat loss of the extremities typically occurring around puberty and can have positive family history. Patients with CGL have near-complete lack of fat starting at birth or infancy. Acquired lipodystrophies have fat loss typically in late childhood. 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J Clin Endocrinol Metab 2014:jc20141353 Supplemental TablesSupplemental Table 1: Evidence rating systemClassification????I: Intervention is useful and effective????IIa: Weight of evidence/opinion is in favor of usefulness/efficacy????IIb: Usefulness/efficacy less well-established by evidence/opinion????III: Intervention is not useful/effective and may be harmfulLevel of Evidence????A: Sufficient evidence from multiple randomized trials????B: Limited evidence from single, randomized trial or other nonrandomized studies????C: Based on expert opinion, case studies, or standard of care ................
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