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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline</title><author><name sortKey="Brown, Rebecca J" sort="Brown, Rebecca J" uniqKey="Brown R" first="Rebecca J." last="Brown">Rebecca J. Brown</name></author><author><name sortKey="Araujo Vilar, David" sort="Araujo Vilar, David" uniqKey="Araujo Vilar D" first="David" last="Araujo-Vilar">David Araujo-Vilar</name></author><author><name sortKey="Cheung, Pik To" sort="Cheung, Pik To" uniqKey="Cheung P" first="Pik To" last="Cheung">Pik To Cheung</name></author><author><name sortKey="Dunger, David" sort="Dunger, David" uniqKey="Dunger D" first="David" last="Dunger">David Dunger</name></author><author><name sortKey="Garg, Abhimanyu" sort="Garg, Abhimanyu" uniqKey="Garg A" first="Abhimanyu" last="Garg">Abhimanyu Garg</name></author><author><name sortKey="Jack, Michelle" sort="Jack, Michelle" uniqKey="Jack M" first="Michelle" last="Jack">Michelle Jack</name></author><author><name sortKey="Mungai, Lucy" sort="Mungai, Lucy" uniqKey="Mungai L" first="Lucy" last="Mungai">Lucy Mungai</name></author><author><name sortKey="Oral, Elif A" sort="Oral, Elif A" uniqKey="Oral E" first="Elif A." last="Oral">Elif A. Oral</name></author><author><name sortKey="Patni, Nivedita" sort="Patni, Nivedita" uniqKey="Patni N" first="Nivedita" last="Patni">Nivedita Patni</name></author><author><name sortKey="Rother, Kristina I" sort="Rother, Kristina I" uniqKey="Rother K" first="Kristina I." last="Rother">Kristina I. Rother</name></author><author><name sortKey="Von Schnurbein, Julia" sort="Von Schnurbein, Julia" uniqKey="Von Schnurbein J" first="Julia" last="Von Schnurbein">Julia Von Schnurbein</name></author><author><name sortKey="Sorkina, Ekaterina" sort="Sorkina, Ekaterina" uniqKey="Sorkina E" first="Ekaterina" last="Sorkina">Ekaterina Sorkina</name></author><author><name sortKey="Stanley, Takara" sort="Stanley, Takara" uniqKey="Stanley T" first="Takara" last="Stanley">Takara Stanley</name></author><author><name sortKey="Vigouroux, Corinne" sort="Vigouroux, Corinne" uniqKey="Vigouroux C" first="Corinne" last="Vigouroux">Corinne Vigouroux</name></author><author><name sortKey="Wabitsch, Martin" sort="Wabitsch, Martin" uniqKey="Wabitsch M" first="Martin" last="Wabitsch">Martin Wabitsch</name></author><author><name sortKey="Williams, Rachel" sort="Williams, Rachel" uniqKey="Williams R" first="Rachel" last="Williams">Rachel Williams</name></author><author><name sortKey="Yorifuji, Tohru" sort="Yorifuji, Tohru" uniqKey="Yorifuji T" first="Tohru" last="Yorifuji">Tohru Yorifuji</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27710244</idno><idno type="pmc">5155679</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155679</idno><idno type="RBID">PMC:5155679</idno><idno type="doi">10.1210/jc.2016-2466</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">002643</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002643</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline</title><author><name sortKey="Brown, Rebecca J" sort="Brown, Rebecca J" uniqKey="Brown R" first="Rebecca J." last="Brown">Rebecca J. Brown</name></author><author><name sortKey="Araujo Vilar, David" sort="Araujo Vilar, David" uniqKey="Araujo Vilar D" first="David" last="Araujo-Vilar">David Araujo-Vilar</name></author><author><name sortKey="Cheung, Pik To" sort="Cheung, Pik To" uniqKey="Cheung P" first="Pik To" last="Cheung">Pik To Cheung</name></author><author><name sortKey="Dunger, David" sort="Dunger, David" uniqKey="Dunger D" first="David" last="Dunger">David Dunger</name></author><author><name sortKey="Garg, Abhimanyu" sort="Garg, Abhimanyu" uniqKey="Garg A" first="Abhimanyu" last="Garg">Abhimanyu Garg</name></author><author><name sortKey="Jack, Michelle" sort="Jack, Michelle" uniqKey="Jack M" first="Michelle" last="Jack">Michelle Jack</name></author><author><name sortKey="Mungai, Lucy" sort="Mungai, Lucy" uniqKey="Mungai L" first="Lucy" last="Mungai">Lucy Mungai</name></author><author><name sortKey="Oral, Elif A" sort="Oral, Elif A" uniqKey="Oral E" first="Elif A." last="Oral">Elif A. Oral</name></author><author><name sortKey="Patni, Nivedita" sort="Patni, Nivedita" uniqKey="Patni N" first="Nivedita" last="Patni">Nivedita Patni</name></author><author><name sortKey="Rother, Kristina I" sort="Rother, Kristina I" uniqKey="Rother K" first="Kristina I." last="Rother">Kristina I. Rother</name></author><author><name sortKey="Von Schnurbein, Julia" sort="Von Schnurbein, Julia" uniqKey="Von Schnurbein J" first="Julia" last="Von Schnurbein">Julia Von Schnurbein</name></author><author><name sortKey="Sorkina, Ekaterina" sort="Sorkina, Ekaterina" uniqKey="Sorkina E" first="Ekaterina" last="Sorkina">Ekaterina Sorkina</name></author><author><name sortKey="Stanley, Takara" sort="Stanley, Takara" uniqKey="Stanley T" first="Takara" last="Stanley">Takara Stanley</name></author><author><name sortKey="Vigouroux, Corinne" sort="Vigouroux, Corinne" uniqKey="Vigouroux C" first="Corinne" last="Vigouroux">Corinne Vigouroux</name></author><author><name sortKey="Wabitsch, Martin" sort="Wabitsch, Martin" uniqKey="Wabitsch M" first="Martin" last="Wabitsch">Martin Wabitsch</name></author><author><name sortKey="Williams, Rachel" sort="Williams, Rachel" uniqKey="Williams R" first="Rachel" last="Williams">Rachel Williams</name></author><author><name sortKey="Yorifuji, Tohru" sort="Yorifuji, Tohru" uniqKey="Yorifuji T" first="Tohru" last="Yorifuji">Tohru Yorifuji</name></author></analytic><series><title level="j">The Journal of Clinical Endocrinology and Metabolism</title><idno type="ISSN">0021-972X</idno><idno type="eISSN">1945-7197</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Objective:</title><p>Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with 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 the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs.</p></sec><sec><title>Participants:</title><p>Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public.</p></sec><sec><title>Evidence:</title><p>A 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 unavailable or scarce.</p></sec><sec><title>Consensus Process:</title><p>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.</p></sec><sec><title>Conclusions:</title><p>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 the 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 (eg, metformin for diabetes, and statins or fibrates for hyperlipidemia). 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Endocrinol Metab</journal-id><journal-id journal-id-type="iso-abbrev">J. Clin. Endocrinol. Metab</journal-id><journal-id journal-id-type="hwp">jcem</journal-id><journal-id journal-id-type="publisher-id">jceme</journal-id><journal-id journal-id-type="pmc">jcem</journal-id><journal-title-group><journal-title>The Journal of Clinical Endocrinology and Metabolism</journal-title></journal-title-group><issn pub-type="ppub">0021-972X</issn><issn pub-type="epub">1945-7197</issn><publisher><publisher-name>Endocrine Society</publisher-name><publisher-loc>Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27710244</article-id><article-id pub-id-type="pmc">5155679</article-id><article-id pub-id-type="publisher-id">16-2466</article-id><article-id pub-id-type="doi">10.1210/jc.2016-2466</article-id><article-categories><subj-group subj-group-type="heading"><subject>Special Features</subject></subj-group><series-title>Consensus Statement</series-title></article-categories><title-group><article-title>The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Brown</surname><given-names>Rebecca J.</given-names></name><role>Committee Chair</role></contrib><contrib contrib-type="author"><name><surname>Araujo-Vilar</surname><given-names>David</given-names></name></contrib><contrib contrib-type="author"><name><surname>Cheung</surname><given-names>Pik To</given-names></name></contrib><contrib contrib-type="author"><name><surname>Dunger</surname><given-names>David</given-names></name></contrib><contrib contrib-type="author"><name><surname>Garg</surname><given-names>Abhimanyu</given-names></name></contrib><contrib contrib-type="author"><name><surname>Jack</surname><given-names>Michelle</given-names></name></contrib><contrib contrib-type="author"><name><surname>Mungai</surname><given-names>Lucy</given-names></name></contrib><contrib contrib-type="author"><name><surname>Oral</surname><given-names>Elif A.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Patni</surname><given-names>Nivedita</given-names></name></contrib><contrib contrib-type="author"><name><surname>Rother</surname><given-names>Kristina I.</given-names></name></contrib><contrib contrib-type="author"><name><surname>von Schnurbein</surname><given-names>Julia</given-names></name></contrib><contrib contrib-type="author"><name><surname>Sorkina</surname><given-names>Ekaterina</given-names></name></contrib><contrib contrib-type="author"><name><surname>Stanley</surname><given-names>Takara</given-names></name></contrib><contrib contrib-type="author"><name><surname>Vigouroux</surname><given-names>Corinne</given-names></name></contrib><contrib contrib-type="author"><name><surname>Wabitsch</surname><given-names>Martin</given-names></name></contrib><contrib contrib-type="author"><name><surname>Williams</surname><given-names>Rachel</given-names></name></contrib><contrib contrib-type="author"><name><surname>Yorifuji</surname><given-names>Tohru</given-names></name></contrib><aff>National Institute of Diabetes and Digestive and Kidney Diseases (R.J.B., K.I.R.), National Institutes of Health, Bethesda, Maryland 20892; Department of Medicine (D.A.-V.), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; Department of Paediatrics and Adolescent Medicine (P.T.C.), The University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Paediatrics (D.D.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Metabolic Research Laboratories Wellcome Trust (D.D.), Medical Research Council (MRC) Institute of Metabolic Science, National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre, MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Division of Nutrition and Metabolic Diseases (A.G.), Department of Internal Medicine and the Center for Human Nutrition, UT Southwestern Medical Center, Dallas, Texas 75390; Royal North Shore Hospital (M.J.), Northern Clinical School, University of Sydney, St Leonards, NSW 2126, Australia; Department of Paediatrics and Child Health (L.M.), University of Nairobi, 00100 Nairobi, Kenya; Brehm Center for Diabetes and Division of Metabolism, Endocrinology, and Diabetes (E.A.O.), Department of Internal Medicine, University of Michigan Medical School and Health Systems, Ann Arbor, Michigan 48109; Division of Pediatric Endocrinology (N.P.), Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas 75390; Division of Pediatric Endocrinology and Diabetes (J.v.S., M.W.), Department of Pediatrics and Adolescent Medicine, University of Ulm, 89075 Ulm, Germany; Clamp Technologies Laboratory (E.S.), Endocrinology Research Center, and Laboratory of Molecular Endocrinology of Medical Scientific Educational Centre of Lomonosov, Moscow State University, Moscow 119991, Russia; Pediatric Endocrine Unit and Program in Nutritional Metabolism (T.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115; Sorbonne Universities (C.V.), l'université Pierre et Marie Curie, University of Paris VI, Inserm Unité Mixte de Recherche en Santé 938, St-Antoine Research Center, Institute of Cardiometabolism and Nutrition, Assistance Publique-Hôpitaux de Paris, St-Antoine Hospital, Molecular Biology and Genetics Department, 75012 Paris, France; Department of Paediatric Endocrinology (R.W.), Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, United Kingdom; and Division of Pediatric Endocrinology and Metabolism (T.Y.), Children's Medical Center, Osaka City General Hospital, Osaka City 534–0021, Japan</aff></contrib-group><author-notes><corresp>Address all correspondence and requests for reprints to: Rebecca J. Brown, MD, MHSc, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10-CRC, Room 6-5942, 10 Center Drive, Bethesda, MD 20892. E-mail: <email>brownrebecca@niddk.nih.gov</email>.</corresp></author-notes><pub-date pub-type="ppub"><month>12</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>6</day><month>10</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>6</day><month>10</month><year>2016</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>101</volume><issue>12</issue><fpage>4500</fpage><lpage>4511</lpage><history><date date-type="received"><day>23</day><month>6</month><year>2016</year></date><date date-type="accepted"><day>14</day><month>9</month><year>2016</year></date></history><permissions><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by-nc/4.0/"><license-p>This article is published under the terms of the Creative Commons Attribution-Non Commercial License (CC-BY-NC; <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by-nc/4.0/">https://creativecommons.org/licenses/by-nc/4.0/</ext-link>).</license-p></license></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zeg01216004500.pdf"></self-uri><abstract><sec><title>Objective:</title><p>Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with 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 the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs.</p></sec><sec><title>Participants:</title><p>Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public.</p></sec><sec><title>Evidence:</title><p>A 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 unavailable or scarce.</p></sec><sec><title>Consensus Process:</title><p>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.</p></sec><sec><title>Conclusions:</title><p>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 the 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 (eg, metformin for diabetes, and statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated.</p></sec></abstract><abstract abstract-type="precis"><p>Multiple worldwide endocrine societies developed practice guidelines for diagnosis and management of lipodystrophy syndromes based on current evidence.</p></abstract></article-meta></front><body><p>The 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 (<xref ref-type="fig" rid="F1">Figure 1</xref>). 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) (<xref ref-type="fig" rid="F1">Figure 1</xref>). Additional subtypes include progeroid disorders, autoinflammatory disorders, and others (<xref ref-type="table" rid="T1">Table 1</xref>). This practice guideline will not discuss lipodystrophy in HIV infected patients or localized lipodystrophy (eg, from injectable drugs).</p><fig id="F1" position="float"><label>Figure 1.</label><caption><p>Physical appearance of patients with the four main subtypes of lipodystrophy syndromes. A, 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.589–2A>G; p.(Val197Glufs*32) mutation in the <italic>AGPAT2</italic> gene. The patient had generalized loss of subcutaneous (sc) fat with acanthosis nigricans in the axillae and neck. She has umbilical prominence and acromegaloid features (enlarged mandible, hands, and feet). B, Lateral view of a 26-year-old female with familial partial lipodystrophy of the Dunnigan variety due to heterozygous c.575A>T; p.(Asp192Val) mutation in the <italic>LMNA</italic> gene. She had marked loss of sc fat from the upper and lower extremities and accumulation of sc fat in the face and chin. 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 45-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 the anterior thighs. She had increased sc fat deposition in the lower extremities.</p></caption><graphic xlink:href="zeg0111628730001"></graphic></fig><table-wrap id="T1" position="float"><label>Table 1.</label><caption><p>Subtypes and Inheritance of Lipodystrophy</p></caption><table frame="hsides" rules="groups"><thead valign="bottom"><tr><th align="left" rowspan="1" colspan="1">Inheritance Pattern</th><th align="left" rowspan="1" colspan="1">Subtype</th><th align="left" rowspan="1" colspan="1">Lipodystrophy Phenotype</th><th align="left" rowspan="1" colspan="1">Genes Involved</th><th align="left" rowspan="1" colspan="1">Refs.</th></tr></thead><tbody valign="top"><tr><td align="left" rowspan="1" colspan="1">Autosomal recessive</td><td align="left" rowspan="1" colspan="1">CGL</td><td align="left" rowspan="1" colspan="1">Near total absence of body fat, generalized muscularity, metabolic complications</td><td align="left" rowspan="1" colspan="1"><italic>AGPAT2</italic>, <italic>BSCL2</italic>, <italic>CAV1</italic>, <italic>PTRF</italic>, <italic>PCYT1A</italic>, <italic>PPAR</italic>γ</td><td align="left" rowspan="1" colspan="1"><xref rid="B11" ref-type="bibr">11</xref>, <xref rid="B84" ref-type="bibr">84</xref><xref ref-type="bibr" rid="B85">–</xref><xref rid="B88" ref-type="bibr">88</xref></td></tr><tr><td rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Progeroid syndromes</td><td align="left" rowspan="1" colspan="1">Partial or generalized absence of body fat, progeroid features, variable metabolic complications</td><td align="left" rowspan="1" colspan="1"><italic>LMNA</italic>, <italic>ZMPSTE24</italic>, <italic>SPRTN</italic>, <italic>WRN</italic>, <italic>BANF1</italic></td><td align="left" rowspan="1" colspan="1"><xref rid="B89" ref-type="bibr">89</xref><xref ref-type="bibr" rid="B90">–</xref><xref rid="B93" ref-type="bibr">93</xref></td></tr><tr><td rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">FPLD</td><td align="left" rowspan="1" colspan="1">Absence of fat in limbs, metabolic complications</td><td align="left" rowspan="1" colspan="1"><italic>CIDEC</italic>, <italic>LIPE</italic>, <italic>PCYT1A</italic></td><td align="left" rowspan="1" colspan="1"><xref rid="B87" ref-type="bibr">87</xref>, <xref rid="B92" ref-type="bibr">92</xref>, <xref rid="B94" ref-type="bibr">94</xref><xref ref-type="bibr" rid="B95">–</xref><xref rid="B96" ref-type="bibr">96</xref></td></tr><tr><td rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Autoinflammatory</td><td align="left" rowspan="1" colspan="1">Variable absence of fat, variable metabolic complications</td><td align="left" rowspan="1" colspan="1"><italic>PSMB8</italic></td><td align="left" rowspan="1" colspan="1"><xref rid="B97" ref-type="bibr">97</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Autosomal dominant</td><td align="left" rowspan="1" colspan="1">FPLD</td><td align="left" rowspan="1" colspan="1">Absence of fat from the limbs, metabolic complications</td><td align="left" rowspan="1" colspan="1"><italic>LMNA</italic>, <italic>PPARG</italic>, <italic>AKT2</italic>, <italic>PLIN1</italic></td><td align="left" rowspan="1" colspan="1"><xref rid="B98" ref-type="bibr">98</xref><xref ref-type="bibr" rid="B99">–</xref><xref rid="B103" ref-type="bibr">103</xref></td></tr><tr><td rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Progeroid syndromes</td><td align="left" rowspan="1" colspan="1">Partial or generalized absence of body fat, progeroid features, variable metabolic complications</td><td align="left" rowspan="1" colspan="1"><italic>LMNA</italic>, <italic>FBN1</italic>, <italic>CAV1</italic>, <italic>POLD1</italic>, <italic>KCNJ6</italic></td><td align="left" rowspan="1" colspan="1"><xref rid="B104" ref-type="bibr">104</xref><xref ref-type="bibr" rid="B105">–</xref><xref rid="B109" ref-type="bibr">109</xref></td></tr><tr><td rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">SHORT syndrome</td><td align="left" rowspan="1" colspan="1">Variable loss of body fat, metabolic complications</td><td align="left" rowspan="1" colspan="1"><italic>PIK3R1</italic></td><td align="left" rowspan="1" colspan="1"><xref rid="B110" ref-type="bibr">110</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Acquired</td><td align="left" rowspan="1" colspan="1">AGL</td><td align="left" rowspan="1" colspan="1">Near total absence of body fat, metabolic complications</td><td align="left" rowspan="1" colspan="1">None</td><td align="left" rowspan="1" colspan="1"><xref rid="B4" ref-type="bibr">4</xref></td></tr><tr><td rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">APL</td><td align="left" rowspan="1" colspan="1">Absence of fat in upper body with increased fat in lower body, mild or no metabolic complications</td><td align="left" rowspan="1" colspan="1">None</td><td align="left" rowspan="1" colspan="1"><xref rid="B17" ref-type="bibr">17</xref></td></tr></tbody></table></table-wrap><p>Lipodystrophy syndromes are frequently associated with hormonal and metabolic derangements resulting in severe comorbidities (<xref ref-type="table" rid="T2">Table 2</xref>) 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 and causing insulin resistance. Insulin resistance leads to diabetes, hypertriglyceridemia, polycystic ovarian syndrome (PCOS), and nonalcoholic fatty liver disease (NAFLD) (<xref rid="B1" ref-type="bibr">1</xref>).</p><table-wrap id="T2" position="float"><label>Table 2.</label><caption><p>Major Comorbidities and Complications of Lipodystrophy</p></caption><table frame="hsides" rules="groups"><thead valign="bottom"><tr><th align="left" rowspan="1" colspan="1">Complication</th><th align="left" rowspan="1" colspan="1">Affected Subtypes</th><th align="left" rowspan="1" colspan="1">Refs.</th></tr></thead><tbody valign="top"><tr><td align="left" rowspan="1" colspan="1">Hyperphagia</td><td align="left" rowspan="1" colspan="1">AGL, CGL, ±FPLD</td><td align="left" rowspan="1" colspan="1"><xref rid="B4" ref-type="bibr">4</xref>, <xref rid="B10" ref-type="bibr">10</xref>, <xref rid="B111" ref-type="bibr">111</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Dyslipidemia (high triglycerides, low HDL-cholesterol, acute pancreatitis, eruptive xanthomas)</td><td align="left" rowspan="1" colspan="1">AGL, CGL, FPLD</td><td align="left" rowspan="1" colspan="1"><xref rid="B4" ref-type="bibr">4</xref>, <xref rid="B5" ref-type="bibr">5</xref>, <xref rid="B7" ref-type="bibr">7</xref>, <xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B13" ref-type="bibr">13</xref>, <xref rid="B21" ref-type="bibr">21</xref>, <xref rid="B30" ref-type="bibr">30</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Insulin resistance/diabetes, acanthosis nigricans (and diabetes complications)</td><td align="left" rowspan="1" colspan="1">AGL, CGL, FPLD</td><td align="left" rowspan="1" colspan="1"><xref rid="B4" ref-type="bibr">4</xref>, <xref rid="B5" ref-type="bibr">5</xref>, <xref rid="B7" ref-type="bibr">7</xref>, <xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B13" ref-type="bibr">13</xref>, <xref rid="B17" ref-type="bibr">17</xref>, <xref rid="B20" ref-type="bibr">20</xref>, <xref rid="B21" ref-type="bibr">21</xref>, <xref rid="B69" ref-type="bibr">69</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Reproductive dysfunction (PCOS, oligomenorrhea, reduced fertility, hirsutism, preeclampsia, miscarriage, macrosomia)</td><td align="left" rowspan="1" colspan="1">AGL, CGL, FPLD</td><td align="left" rowspan="1" colspan="1"><xref rid="B4" ref-type="bibr">4</xref>, <xref rid="B5" ref-type="bibr">5</xref>, <xref rid="B7" ref-type="bibr">7</xref>, <xref rid="B10" ref-type="bibr">10</xref>, <xref rid="B14" ref-type="bibr">14</xref>, <xref rid="B20" ref-type="bibr">20</xref>, <xref rid="B55" ref-type="bibr">55</xref>, <xref rid="B112" ref-type="bibr">112</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">NAFLD (ranging from simple steatosis to cirrhosis)</td><td align="left" rowspan="1" colspan="1">AGL, CGL, FPLD, ±APL</td><td align="left" rowspan="1" colspan="1"><xref rid="B4" ref-type="bibr">4</xref>, <xref rid="B7" ref-type="bibr">7</xref>, <xref rid="B10" ref-type="bibr">10</xref>, <xref rid="B17" ref-type="bibr">17</xref>, <xref rid="B19" ref-type="bibr">19</xref>, <xref rid="B49" ref-type="bibr">49</xref>, <xref rid="B51" ref-type="bibr">51</xref>, <xref rid="B69" ref-type="bibr">69</xref>, <xref rid="B113" ref-type="bibr">113</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Renal dysfunction (proteinuria, MPGN, FSGS, diabetic nephropathy)</td><td align="left" rowspan="1" colspan="1">AGL, CGL, FPLD, APL</td><td align="left" rowspan="1" colspan="1"><xref rid="B17" ref-type="bibr">17</xref>, <xref rid="B34" ref-type="bibr">34</xref>, <xref rid="B114" ref-type="bibr">114</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Heart disease (hypertension, cardiomyopathy, arrhythmias, conduction abnormalities, CAD)</td><td align="left" rowspan="1" colspan="1">AGL, CGL, FPLD</td><td align="left" rowspan="1" colspan="1"><xref rid="B3" ref-type="bibr">3</xref><xref ref-type="bibr" rid="B4">–</xref><xref rid="B5" ref-type="bibr">5</xref>, <xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B13" ref-type="bibr">13</xref>, <xref rid="B15" ref-type="bibr">15</xref>, <xref rid="B25" ref-type="bibr">25</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Autoimmune disease</td><td align="left" rowspan="1" colspan="1">AGL, APL</td><td align="left" rowspan="1" colspan="1"><xref rid="B4" ref-type="bibr">4</xref>, <xref rid="B10" ref-type="bibr">10</xref>, <xref rid="B17" ref-type="bibr">17</xref>, <xref rid="B19" ref-type="bibr">19</xref>, <xref rid="B20" ref-type="bibr">20</xref></td></tr></tbody></table><table-wrap-foot><fn fn-type="abbr"><p>Abbreviations: CAD, coronary artery disease; FSGS, focal segmental glomerulosclerosis. Many of these features are also found in other forms of lipodystrophy, including progeroid disorders.</p></fn></table-wrap-foot></table-wrap><p>Major causes of mortality include heart disease (cardiomyopathy, heart failure, myocardial infarction, arrhythmia) (<xref rid="B2" ref-type="bibr">2</xref><xref ref-type="bibr" rid="B3">–</xref><xref rid="B5" ref-type="bibr">5</xref>), liver disease (liver failure, gastrointestinal hemorrhage, hepatocellular carcinoma) (<xref rid="B6" ref-type="bibr">6</xref>, <xref rid="B7" ref-type="bibr">7</xref>), kidney failure (<xref rid="B6" ref-type="bibr">6</xref>), acute pancreatitis (<xref rid="B7" ref-type="bibr">7</xref>), and sepsis.</p><p>Due to the rarity of lipodystrophy syndromes, many 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. Evidence was rated using the system of the American Heart Association (<ext-link ext-link-type="uri" xlink:href="http://press.endocrine.org/doi/suppl/10.1210/jc.2016-2466/suppl_file/jc-16-2466.pdf">Supplemental Table 1</ext-link>) (<xref rid="B8" ref-type="bibr">8</xref>). Details of the literature review, consensus, and endorsement process are provided in the <ext-link ext-link-type="uri" xlink:href="http://press.endocrine.org/doi/suppl/10.1210/jc.2016-2466/suppl_file/jc-16-2466.pdf">Supplemental Data</ext-link>.</p><sec><title>Overview of Lipodystrophy Syndromes</title><p>This section reviews major categories of lipodystrophy. Details on individual subtypes are in <ext-link ext-link-type="uri" xlink:href="http://press.endocrine.org/doi/suppl/10.1210/jc.2016-2466/suppl_file/jc-16-2466.pdf">Supplemental Table 2</ext-link>.</p><sec><title>Congenital generalized lipodystrophy (Berardinelli-Seip syndrome)</title><p>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 (<xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B10" ref-type="bibr">10</xref>). Multiple genetic causes have been identified, each with unique clinical features (<xref rid="B11" ref-type="bibr">11</xref><xref ref-type="bibr" rid="B12">–</xref><xref rid="B13" ref-type="bibr">13</xref>). Metabolic complications are frequent and may be severe. Cardiomyopathy or rhythm disturbances may occur.</p></sec><sec><title>Familial partial lipodystrophy</title><p>FPLD is a group of usually autosomal dominant disorders characterized by loss of fat affecting the limbs, buttocks, and hips (<xref rid="B10" ref-type="bibr">10</xref>). 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 (<xref rid="B14" ref-type="bibr">14</xref>), with increased risk of coronary heart disease (<xref rid="B15" ref-type="bibr">15</xref>) and occasionally early cardiomyopathy.</p></sec><sec><title>Acquired generalized lipodystrophy (Lawrence syndrome)</title><p>AGL is more common in females (females:males, 3:1) and appears usually before adolescence (but may develop at any time in life) with progressive loss of fat affecting the whole body including palms and soles (<xref rid="B4" ref-type="bibr">4</xref>). Some fat accumulation can appear in the face, neck, or axillae. Metabolic complications are frequent and may be severe. AGL is often associated with autoimmune diseases (<xref rid="B4" ref-type="bibr">4</xref>, <xref rid="B16" ref-type="bibr">16</xref>).</p></sec><sec><title>Acquired partial lipodystrophy (Barraquer-Simons syndrome)</title><p>APL is more frequent in females (females:males, 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 (<xref rid="B17" ref-type="bibr">17</xref>). APL is associated with autoimmune diseases, especially membranoproliferative glomerulonephritis (MPGN) in approximately 20% (<xref rid="B17" ref-type="bibr">17</xref>). Most patients have low serum complement 3 (C3) levels, and some have presence of C3 nephritic factor. Metabolic complications are uncommon (<xref rid="B17" ref-type="bibr">17</xref>).</p></sec></sec><sec><title>Diagnosis of Lipodystrophy</title><list list-type="bullet"><list-item><p>Diagnosis of lipodystrophy is based on history, physical examination, body composition, and metabolic status. (Class I, Level B)</p></list-item><list-item><p>There are no defined serum leptin levels that establish or rule out the diagnosis of lipodystrophy. (Class IIa, Level C)</p></list-item><list-item><p>Confirmatory genetic testing is helpful in suspected familial lipodystrophies. (Class I, Level A)</p></list-item><list-item><p>Genetic testing should be considered in at-risk family members. (Class IIa, Level C)</p></list-item><list-item><p>Serum complement levels and autoantibodies may support diagnosis of acquired lipodystrophy syndromes. (Class IIa, Level B)</p></list-item></list><p>Firm diagnostic criteria for lipodystrophy have not been established. <xref ref-type="fig" rid="F2">Figure 2</xref> shows a suggested diagnostic approach.</p><fig id="F2" position="float"><label>Figure 2.</label><caption><p>Diagnostic approach to lipodystrophy syndromes. Lipodystrophy 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 sc fat loss and presence of prominent muscles, phlebomegaly, acanthosis nigricans, hepatomegaly, xanthomas, and acromegaloid or progeroid appearance. All patients should undergo a metabolic workup for insulin resistance, diabetes, dyslipidemia, and fatty liver disease. Conventional anthropometry including skinfold thickness measurements, ± dual energy x-ray absorptiometry, and whole-body magnetic resonance imaging (if available) should be performed to confirm the pattern of fat loss. Common genetic lipodystrophies include CGL, 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 a 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. Patients with AGL have generalized loss of sc fat and often have associated autoimmune diseases. Patients with APL have cranio-caudal fat loss affecting the face, neck, shoulders, arms, and upper trunk, and most patients have low serum C3 levels.</p></caption><graphic xlink:href="zeg0111628730002"></graphic></fig><sec><title>Establishing the presence of lipodystrophy</title><p>Lipodystrophy 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, and whole-body magnetic resonance imaging (<ext-link ext-link-type="uri" xlink:href="http://press.endocrine.org/doi/suppl/10.1210/jc.2016-2466/suppl_file/jc-16-2466.pdf">Supplemental Table 3</ext-link>) (<xref rid="B18" ref-type="bibr">18</xref>). Recognizing the loss of sc 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, the loss of fat may be gradual, delaying diagnosis.</p><p>Physical, historical, and comorbid features that increase the suspicion of lipodystrophy (<xref rid="B18" ref-type="bibr">18</xref>) are shown in <xref ref-type="table" rid="T3">Table 3</xref>.</p><table-wrap id="T3" position="float"><label>Table 3.</label><caption><p>Clinical Features That Increase the Suspicion of Lipodystrophy</p></caption><table frame="hsides" rules="groups"><tbody valign="top"><tr><td align="left" rowspan="1" colspan="1">Essential feature</td></tr><tr><td align="left" rowspan="1" colspan="1"> Generalized or regional absence of body fat</td></tr><tr><td align="left" rowspan="1" colspan="1">Physical features</td></tr><tr><td align="left" rowspan="1" colspan="1"> Failure to thrive (infants and children)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Prominent muscles</td></tr><tr><td align="left" rowspan="1" colspan="1"> Prominent veins (phlebomegaly)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Severe acanthosis nigricans</td></tr><tr><td align="left" rowspan="1" colspan="1"> Eruptive xanthomata</td></tr><tr><td align="left" rowspan="1" colspan="1"> Cushingoid appearance</td></tr><tr><td align="left" rowspan="1" colspan="1"> Acromegaloid appearance</td></tr><tr><td align="left" rowspan="1" colspan="1"> Progeroid (premature aging) appearance</td></tr><tr><td align="left" rowspan="1" colspan="1">Comorbid conditions</td></tr><tr><td align="left" rowspan="1" colspan="1"> Diabetes mellitus with high insulin requirements</td></tr><tr><td align="left" rowspan="1" colspan="1"> ≥200 U/d</td></tr><tr><td align="left" rowspan="1" colspan="1"> ≥2 U/kg/d</td></tr><tr><td align="left" rowspan="1" colspan="1"> Requiring U-500 insulin</td></tr><tr><td align="left" rowspan="1" colspan="1"> Severe hypertriglyceridemia</td></tr><tr><td align="left" rowspan="1" colspan="1"> ≥500 mg/dL with or without therapy</td></tr><tr><td align="left" rowspan="1" colspan="1"> ≥250 mg/dL despite diet and medical therapy</td></tr><tr><td align="left" rowspan="1" colspan="1"> History of acute pancreatitis secondary to hypertriglyceridemia</td></tr><tr><td align="left" rowspan="1" colspan="1"> Non-alcoholic steatohepatitis in a non-obese individual</td></tr><tr><td align="left" rowspan="1" colspan="1"> Early-onset cardiomyopathy</td></tr><tr><td align="left" rowspan="1" colspan="1"> PCOS</td></tr><tr><td align="left" rowspan="1" colspan="1">Other historical clues</td></tr><tr><td align="left" rowspan="1" colspan="1"> Autosomal dominant or recessive pattern of similar physical features or metabolic complications</td></tr><tr><td align="left" rowspan="1" colspan="1"> Significant hyperphagia (may manifest as irritability/aggression in infants/children)</td></tr></tbody></table><table-wrap-foot><fn fn-type="other"><p>Adapted from Ref. <xref rid="B18" ref-type="bibr">18</xref>.</p></fn></table-wrap-foot></table-wrap><p>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 the choice of therapies.</p></sec><sec><title>Differential diagnosis</title><p>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 because both may have extreme hypertriglyceridemia. However, restoring glycemic control in patients with nonlipodystrophic diabetes leads to a regain of body fat. Generalized lipodystrophies can be confused with mutations of the insulin receptor or acromegaly/gigantism, and FPLD with Cushing's syndrome, truncal obesity, and multiple symmetric lipomatosis.</p></sec><sec><title>Establishing the subtype of lipodystrophy</title><sec><title>Pattern of fat loss</title><p>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 families.</p></sec><sec><title>Distinguishing genetic from acquired lipodystrophy</title><p>Pedigree analysis can suggest genetic vs acquired lipodystrophy. Review of photographs from infancy may distinguish CGL from AGL because 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 (<xref rid="B4" ref-type="bibr">4</xref>). Patients with AGL lack family history but can be confused with any type of genetic lipodystrophy, especially de novo mutations.</p><p>The presence of autoimmune diseases (myositis, type 1 diabetes, autoimmune hepatitis, and others) (<xref rid="B4" ref-type="bibr">4</xref>, <xref rid="B10" ref-type="bibr">10</xref>, <xref rid="B16" ref-type="bibr">16</xref>, <xref rid="B17" ref-type="bibr">17</xref>, <xref rid="B19" ref-type="bibr">19</xref>, <xref rid="B20" ref-type="bibr">20</xref>) increases the suspicion of acquired lipodystrophy. In APL, low serum C3, C3 nephritic factor, proteinuria, or biopsy-proven MPGN support the diagnosis.</p></sec><sec><title>Genetic testing</title><p>Genotyping may include limited candidate gene sequencing, a panel of candidate genes, or whole-exome/whole-genome sequencing. The website <ext-link ext-link-type="uri" xlink:href="http://www.genetests.org">www.genetests.org</ext-link> lists clinical and research laboratories conducting genetic testing for lipodystrophy syndromes. Because there is strong evidence for additional loci for genetic lipodystrophies, negative tests do not rule out a genetic condition.</p></sec><sec><title>Genetic counseling and screening of family members</title><p>Genetic counseling must take into consideration that the current understanding of the natural history of genetic lipodystrophies is incomplete. In affected pedigrees, premarital counseling with genetic testing to detect carrier status can be considered.</p><p>Clinical diagnosis of lipodystrophy may be difficult in men (<xref rid="B21" ref-type="bibr">21</xref>), and some genotypes are associated with mild lipodystrophy phenotypes (<xref rid="B22" ref-type="bibr">22</xref>, <xref rid="B23" ref-type="bibr">23</xref>). Genetic screening of family members may help identify individuals with subtle phenotypes. Genetic screening may be particularly important for families with specific <italic>LMNA</italic> mutations associated with cardiomyopathy and arrhythmia.</p></sec></sec></sec><sec><title>Screening for Comorbidities</title><p>All patients should be screened for diabetes, dyslipidemia, NAFLD, and 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.</p><sec><title>Diabetes mellitus</title><list list-type="bullet"><list-item><p>Diabetes screening should be performed annually. (Class IIa, Level C)</p></list-item></list><p>Diabetes screening should follow the guidelines of the American Diabetes Association (fasting plasma glucose, oral glucose tolerance test, or glycosylated hemoglobin [HbA1c]). Patients with AGL may develop type 1 diabetes in addition to insulin resistance (<xref rid="B24" ref-type="bibr">24</xref>); measurement of autoantibodies may clarify the diagnosis.</p></sec><sec><title>Dyslipidemia</title><list list-type="bullet"><list-item><p>Triglycerides should be measured at least annually and with occurrence of abdominal pain or xanthomata. (Class I, Level C)</p></list-item><list-item><p>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)</p></list-item></list></sec><sec><title>Liver disease</title><list list-type="bullet"><list-item><p>Alanine aminotransferase and aspartate aminotransferase should be measured annually. (Class IIa, Level C)</p></list-item><list-item><p>Liver ultrasound should be performed at diagnosis, then as clinically indicated. (Class IIa, Level C)</p></list-item><list-item><p>Liver biopsy should be performed as clinically indicated. (Class IIa, Level C)</p></list-item></list><p>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 (<xref rid="B19" ref-type="bibr">19</xref>).</p></sec><sec><title>Reproductive dysfunction</title><list list-type="bullet"><list-item><p>Gonadal steroids, gonadotropins, and pelvic ultrasonography should be performed as clinically indicated. (Class IIa, Level C)</p></list-item><list-item><p>Pubertal staging should be performed annually in children. (Class IIa, Level C)</p></list-item></list><p>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.</p></sec><sec><title>Cardiac disease</title><list list-type="bullet"><list-item><p>Blood pressure should be measured at least annually. (Class I, Level C)</p></list-item><list-item><p>Electrocardiogram and echocardiogram should be performed annually in CGL and progeroid disorders, at diagnosis, and as clinically indicated in FPLD and AGL. (Class IIa, Level C)</p></list-item><list-item><p>Evaluation for ischemia and rhythm monitoring should be considered in patients with progeroid disorders and FPLD2 with cardiomyopathy. (Class IIa, Level C)</p></list-item></list><p>Hypertension is common (<xref rid="B25" ref-type="bibr">25</xref>), even in children. In patients with CGL4, atypical progeroid syndromes, and FPLD2 due to <italic>LMNA</italic> mutations, cardiac abnormalities including ischemic heart disease, cardiomyopathy, arrhythmias, and sudden death are reported (<xref rid="B3" ref-type="bibr">3</xref>, <xref rid="B23" ref-type="bibr">23</xref>, <xref rid="B26" ref-type="bibr">26</xref><xref ref-type="bibr" rid="B27">–</xref><xref rid="B33" ref-type="bibr">33</xref>).</p></sec><sec><title>Kidney disease</title><list list-type="bullet"><list-item><p>Urine protein should be measured annually using 24-hour urine collection or spot urine protein-to-creatinine ratio. (Class IIa, Level C)</p></list-item></list><p>Proteinuria is common (<xref rid="B34" ref-type="bibr">34</xref>). Kidney biopsy should be performed as clinically indicated, and pathology may include diabetic nephropathy, focal segmental glomerulosclerosis (especially in CGL) (<xref rid="B34" ref-type="bibr">34</xref>) or MPGN (especially in APL) (<xref rid="B17" ref-type="bibr">17</xref>).</p></sec><sec><title>Malignancy</title><p>Lymphomas, particularly peripheral T-cell lymphoma, occur in AGL, with a prevalence of approximately 7% (<xref rid="B4" ref-type="bibr">4</xref>, <xref rid="B35" ref-type="bibr">35</xref>). 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 after cancer therapy (<xref rid="B36" ref-type="bibr">36</xref>). Clinicians should consider screening for brain tumors in children who present with idiopathic AGL or atypical CGL. Specific progeroid syndromes (eg, Bloom and Werner syndromes) are associated with increased malignancy risk (<ext-link ext-link-type="uri" xlink:href="http://press.endocrine.org/doi/suppl/10.1210/jc.2016-2466/suppl_file/jc-16-2466.pdf">Supplemental Table 2</ext-link>).</p></sec></sec><sec><title>Treatment of Lipodystrophy Syndromes</title><p>Current therapies prevent or ameliorate the comorbidities of lipodystrophy syndromes. There is no cure for lipodystrophy and no treatment that can regrow adipose tissue.</p><sec><title>Diet</title><list list-type="bullet"><list-item><p>Most patients should follow diets with balanced macronutrient composition. (Class IIa, Level C)</p></list-item><list-item><p>Energy-restricted diets improve metabolic abnormalities and may be appropriate in adults. (Class I, Level C)</p></list-item><list-item><p>Very-low-fat diets should be used in chylomicronemia-induced acute pancreatitis. (Class I, Level C)</p></list-item><list-item><p>A dietician should be consulted for specialized dietary needs, especially in infants and young children.Overfeeding should be avoided. (Class IIa, Level C)</p></list-item><list-item><p>Medium-chain triglyceride oil formulas can provide energy and reduce triglycerides in infants. (Class IIa, Level C)</p></list-item></list><p>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.</p><p>Patients with lipodystrophy, especially generalized forms, are typically hyperphagic due to leptin deficiency. Energy-restricted diets in adolescents and adults lower triglycerides and glucose (<xref rid="B37" ref-type="bibr">37</xref>), but dietary restriction is challenging to achieve. Food restriction to control metabolic complications must be balanced by requirements for growth in children. Overfeeding to achieve normal weight may worsen metabolic complications and hepatic steatosis. Assessment of weight-for-length and body mass index by comparison to reference growth data is not appropriate because body composition is atypical. Low weight-for-length or body mass index is acceptable provided linear growth is maintained.</p><p>Patients should follow a 50–60% carbohydrate, 20–30% fat, and approximately 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, medium-chain triglyceride-based formula may help (<xref rid="B38" ref-type="bibr">38</xref>, <xref rid="B39" ref-type="bibr">39</xref>). During acute pancreatitis, bowel rest followed by a very-low-fat (<20 g) diet should be used.</p></sec><sec><title>Exercise</title><list list-type="bullet"><list-item><p>Patients with lipodystrophy should be encouraged to exercise in the absence of specific contraindications. (Class IIa, Level C)</p></list-item><list-item><p>Patients with subtypes of lipodystrophy predisposed to cardiomyopathy should undergo cardiac evaluation before initiating an exercise regimen. (Class III, Level C)</p></list-item></list><p>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 bone lesions.</p></sec><sec><title>Metreleptin</title><list list-type="bullet"><list-item><p>In 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 children. (Class IIb, Level C)</p></list-item><list-item><p>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)</p></list-item></list><p>Currently, metreleptin (recombinant human methionyl leptin) is the only drug approved specifically for lipodystrophy. It is approved in the United States as an adjunct to diet for treatment of metabolic complications in patients with generalized lipodystrophy (<ext-link ext-link-type="uri" xlink:href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm387060.htm">http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm387060.htm</ext-link>). In Japan, it is approved for both generalized and partial lipodystrophy (<ext-link ext-link-type="uri" xlink:href="http://www.shionogi.co.jp/en/company/news/2013/pmrltj0000000ufd-att/e_130325.pdf">http://www.shionogi.co.jp/en/company/news/2013/pmrltj0000000ufd-att/e_130325.pdf</ext-link>). It is available in other parts of the world (eg, Europe) through compassionate use programs. There is no age limit for initiation of metreleptin; children as young as 6 months have been treated. A dosing algorithm is provided in <ext-link ext-link-type="uri" xlink:href="http://press.endocrine.org/doi/suppl/10.1210/jc.2016-2466/suppl_file/jc-16-2466.pdf">Supplemental Table 4</ext-link> (<xref rid="B40" ref-type="bibr">40</xref>). Dose adjustments should be made in response to metabolic parameters and weight change, with clinical and laboratory assessment performed every 3–6 months.</p></sec><sec><title>Metreleptin in generalized lipodystrophy</title><p>Metreleptin decreases hyperphagia (<xref rid="B41" ref-type="bibr">41</xref><xref ref-type="bibr" rid="B42">–</xref><xref rid="B45" ref-type="bibr">45</xref>), 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 (<ext-link ext-link-type="uri" xlink:href="http://press.endocrine.org/doi/suppl/10.1210/jc.2016-2466/suppl_file/jc-16-2466.pdf">Supplemental Table 4</ext-link>) (<xref rid="B40" ref-type="bibr">40</xref>).</p><p>Metreleptin markedly improved fasting glucose as early as the first week (<xref rid="B42" ref-type="bibr">42</xref>) and lowered HbA1c by 2% after 1 year (<xref rid="B46" ref-type="bibr">46</xref>). To reduce the risk of hypoglycemia, frequent glucose monitoring is recommended. Providers should consider reducing insulin doses by approximately 50% on initiation of metreleptin in patients with well-controlled diabetes. Many young patients with CGL are able to discontinue insulin (<xref rid="B46" ref-type="bibr">46</xref>).</p><p>Metreleptin lowered triglycerides within 1 week (<xref rid="B42" ref-type="bibr">42</xref>), reaching 60% reduction at 1 year (<xref rid="B46" ref-type="bibr">46</xref>). Metreleptin also decreased LDL- and total cholesterol but did not change HDL-cholesterol (<xref rid="B47" ref-type="bibr">47</xref>, <xref rid="B48" ref-type="bibr">48</xref>). Acute pancreatitis due to hypertriglyceridemia has occurred in patients who acutely discontinued or reduced metreleptin (<xref rid="B47" ref-type="bibr">47</xref>).</p><p>Metreleptin reduced hepatic steatosis, serum transaminases, and NASH scores within 6 to 12 months (<xref rid="B42" ref-type="bibr">42</xref>, <xref rid="B49" ref-type="bibr">49</xref><xref ref-type="bibr" rid="B50">–</xref><xref rid="B51" ref-type="bibr">51</xref>). In one case, metreleptin ameliorated recurrence of severe hepatic steatosis after liver transplantation (<xref rid="B52" ref-type="bibr">52</xref>).</p><p>Metreleptin decreased proteinuria in most patients (<xref rid="B34" ref-type="bibr">34</xref>, <xref rid="B42" ref-type="bibr">42</xref>). However, four patients had worsened renal disease during metreleptin treatment, so renal function should be monitored closely with preexisting renal disease (<xref rid="B34" ref-type="bibr">34</xref>).</p><p>In females, metreleptin normalized gonadotropin secretion, leading to normal progression of puberty, normalization of menstrual periods (<xref rid="B42" ref-type="bibr">42</xref>, <xref rid="B45" ref-type="bibr">45</xref>, <xref rid="B53" ref-type="bibr">53</xref>, <xref rid="B54" ref-type="bibr">54</xref>), and improved fertility (<xref rid="B1" ref-type="bibr">1</xref>). Metreleptin decreased T in women but did not alter ovarian morphology (<xref rid="B45" ref-type="bibr">45</xref>, <xref rid="B53" ref-type="bibr">53</xref>, <xref rid="B55" ref-type="bibr">55</xref>). In males, metreleptin increased T (<xref rid="B45" ref-type="bibr">45</xref>).</p></sec><sec><title>Metreleptin in partial lipodystrophy</title><p>The 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) (<xref rid="B46" ref-type="bibr">46</xref>). In a second study, metreleptin improved triglycerides and indices of insulin sensitivity and secretion in FPLD2 patients with moderate to severe hypoleptinemia (<xref rid="B56" ref-type="bibr">56</xref>). However, in a third study, no glycemic improvement was observed in FPLD2 patients with serum leptin <7 ng/mL (<xref rid="B57" ref-type="bibr">57</xref>). Metreleptin is only available to patients with partial lipodystrophy through clinical trials, compassionate use programs, and in Japan.</p></sec><sec><title>Side effects of metreleptin</title><p>Approximately 30% of patients experience side effects (<xref rid="B47" ref-type="bibr">47</xref>). The most clinically important are hypoglycemia (in patients receiving concomitant insulin) and infrequent injection-site reactions (erythema, urticaria).</p><p>In vivo neutralizing antibody activity to leptin has been reported (<xref rid="B58" ref-type="bibr">58</xref>, <xref rid="B59" ref-type="bibr">59</xref>). The clinical implications remain unclear, but may include treatment failure and sepsis (<xref rid="B59" ref-type="bibr">59</xref>). 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 (<xref rid="B35" ref-type="bibr">35</xref>), pancreatitis (<xref rid="B47" ref-type="bibr">47</xref>), and worsening of liver (<xref rid="B47" ref-type="bibr">47</xref>) and kidney (<xref rid="B34" ref-type="bibr">34</xref>) disease.</p></sec><sec><title>Additional treatments for specific comorbidities</title><sec><title>Diabetes</title><list list-type="bullet"><list-item><p>Metformin is a first-line agent for diabetes and insulin resistance. (Class IIa, Level C)</p></list-item><list-item><p>Insulin is effective for hyperglycemia. In some patients, concentrated preparations and high-doses may be required. (Class IIa, Level C)</p></list-item><list-item><p>Thiazolidinediones may improve metabolic complications in partial lipodystrophy but should only be used with caution in generalized lipodystrophy. (Class IIb, Level B)</p></list-item></list><p>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 (<ext-link ext-link-type="uri" xlink:href="http://press.endocrine.org/doi/suppl/10.1210/jc.2016-2466/suppl_file/jc-16-2466.pdf">Supplemental Table 5</ext-link>) (<xref rid="B60" ref-type="bibr">60</xref>, <xref rid="B61" ref-type="bibr">61</xref>). In patients with high insulin requirements, concentrated insulins should be considered (<xref rid="B62" ref-type="bibr">62</xref>). Insulin glargine and degludec kinetics may be altered when injected in lipodystrophic areas because their long duration of action requires sc fat (<xref rid="B63" ref-type="bibr">63</xref>, <xref rid="B64" ref-type="bibr">64</xref>). Patients with generalized lipodystrophy may have to take insulin by im routes for the lack of sc fat. Many other hypoglycemic agents have been used in lipodystrophy, but their efficacy has not been studied.</p></sec><sec><title>Dyslipidemia</title><list list-type="bullet"><list-item><p>Statins should be used concomitantly with lifestyle modification (after consideration of age, reproductive status, and tolerance). (Class 1, Level C)</p></list-item><list-item><p>Fibrates and/or long-chain omega-3 fatty acids should be used for triglycerides >500 mg/dL and may be considered for triglycerides >200 mg/dL. (Class IIb, Level C)</p></list-item></list><p>Lipids should be managed in accordance with U.S. and European guidelines for the general population, with statins as first-line therapy (<xref rid="B65" ref-type="bibr">65</xref><xref ref-type="bibr" rid="B66">–</xref><xref rid="B67" ref-type="bibr">67</xref>). Statins and fibrates should be used with caution due to increased risk of myopathy, especially in the presence of known myositis or muscular dystrophy (<xref rid="B68" ref-type="bibr">68</xref>). Because cardiovascular risk may be enhanced in lipodystrophic syndromes independent of other risk factors, clinicians may consider applying stricter lipid targets (eg, LDL-cholesterol <100 mg/dL, non-HDL-cholesterol <130 mg/dL, triglycerides <200 mg/dL), even in patients without diabetes. In addition to diet, fibrates and long-chain omega-3-fatty acids from fish oils have wide clinical use to avoid acute complications of severe hypertriglyceridemia (<xref rid="B46" ref-type="bibr">46</xref>) but have not been formally studied. Plasmapheresis has been used in extreme hypertriglyceridemia, but must be repeated frequently (<xref rid="B69" ref-type="bibr">69</xref>). Additional lipid-lowering drugs have not been studied in patients with lipodystrophy.</p></sec><sec><title>Hypertension</title><list list-type="bullet"><list-item><p>Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are first-line treatments for hypertension in patients with diabetes. (Class IIa, Level C)</p></list-item></list><p>As in other patients with diabetes, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should be used for hypertension (<xref rid="B70" ref-type="bibr">70</xref>).</p></sec><sec><title>Liver disease</title><p>Cholic acid did not reduce hepatic steatosis in patients with FPLD in a double-blind, placebo-controlled crossover study (<xref rid="B71" ref-type="bibr">71</xref>). In NAFLD not associated with lipodystrophy, diet and exercise are first-line treatments (<xref rid="B72" ref-type="bibr">72</xref>), and among pharmacological treatments, vitamin E (in children and adults) (<xref rid="B73" ref-type="bibr">73</xref>, <xref rid="B74" ref-type="bibr">74</xref>) and pioglitazone (in adults) (<xref rid="B73" ref-type="bibr">73</xref>, <xref rid="B75" ref-type="bibr">75</xref>) have shown the most consistent benefit for liver histopathology. However, these treatments have not been studied in patients with lipodystrophy and are not approved for NAFLD.</p></sec><sec><title>Cosmetic treatment</title><list list-type="bullet"><list-item><p>Patients should be assessed for distress related to lipodystrophy and referred as necessary to mental health professionals and/or plastic surgeons. (Class IIa, Level C)</p></list-item></list><p>Changes in physical appearance from lipodystrophy can cause psychological distress and physical discomfort (eg, from absent fat pads in feet or buttocks). Data regarding cosmetic surgery are limited. For facial lipoatrophy, autologous fat transfer (in APL), dermal fillers (<xref rid="B7" ref-type="bibr">7</xref>, <xref rid="B76" ref-type="bibr">76</xref>), or muscle grafts (<xref rid="B77" ref-type="bibr">77</xref>) may be used. Excess fat from the head, neck, or vulva may be surgically reduced or ameliorated by liposuction (<xref rid="B7" ref-type="bibr">7</xref>). Breast implants are helpful in some women (<xref rid="B78" ref-type="bibr">78</xref>, <xref rid="B79" ref-type="bibr">79</xref>). Acanthosis nigricans is improved through successful treatment of insulin resistance (<xref rid="B80" ref-type="bibr">80</xref>, <xref rid="B81" ref-type="bibr">81</xref>). Management of hirsutism is reviewed elsewhere (<xref rid="B82" ref-type="bibr">82</xref>).</p></sec><sec><title>Contraception and hormone replacement therapy</title><list list-type="bullet"><list-item><p>Oral estrogens are contraindicated. (Class IIa, Level C)</p></list-item><list-item><p>If contraception is needed, progestin-only or nonhormonal contraceptives should be considered. (Class IIa, Level C)</p></list-item><list-item><p>If estrogen replacement is needed, transdermal estrogen should be used. (Class IIa, Level C)</p></list-item></list><p>Oral estrogens are contraindicated in lipodystrophy syndromes due to the risk of severe hypertriglyceridemia and acute pancreatitis. Transdermal estrogens may be safer due to lesser hepatic exposure (<xref rid="B83" ref-type="bibr">83</xref>). There is clinical experience in the safe use of oral progestins and progestin-containing intrauterine devices.</p></sec><sec><title>Pregnancy</title><list list-type="bullet"><list-item><p>Pregnant patients should receive prenatal care from an obstetrician experienced in managing diabetes and a physician experienced in managing lipodystrophy. (Class IIa, level C)</p></list-item><list-item><p>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 the effects of metreleptin in pregnancy are unknown (FDA category C), and wishes to continue. (Class IIc, level C)</p></list-item></list><p>In patients with lipodystrophy with extreme insulin resistance, worsening insulin resistance during pregnancy may make diabetes management difficult, with attendant fetal risks. Furthermore, metreleptin withdrawal has been associated with rebound hypertriglyceridemia (<xref rid="B41" ref-type="bibr">41</xref>), placing patients at risk for pancreatitis, endangering both mother and fetus.</p></sec></sec></sec><sec sec-type="conclusions"><title>Conclusions</title><p>Lipodystrophy syndromes are heterogeneous 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.</p></sec></body><back><fn-group content-type="abbreviations"><fn fn-type="abbr"><p>Abbreviations:
<def-list><def-item><term id="G1">AGL</term><def><p>acquired generalized lipodystrophy</p></def></def-item><def-item><term id="G2">APL</term><def><p>acquired partial lipodystrophy</p></def></def-item><def-item><term id="G3">C3</term><def><p>complement 3</p></def></def-item><def-item><term id="G4">CGL</term><def><p>congenital generalized lipodystrophy</p></def></def-item><def-item><term id="G5">FPLD</term><def><p>familial partial lipodystrophy</p></def></def-item><def-item><term id="G6">HbA1c</term><def><p>glycosylated hemoglobin</p></def></def-item><def-item><term id="G7">HDL</term><def><p>high-density lipoprotein</p></def></def-item><def-item><term id="G8">LDL</term><def><p>low-density lipoprotein</p></def></def-item><def-item><term id="G9">MPGN</term><def><p>membranoproliferative glomerulonephritis</p></def></def-item><def-item><term id="G10">NAFLD</term><def><p>nonalcoholic fatty liver disease</p></def></def-item><def-item><term id="G11">PCOS</term><def><p>polycystic ovary syndrome.</p></def></def-item></def-list></p></fn></fn-group><ack><title>Acknowledgments</title><p>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.</p><p content-type="financial-disclosure">This practice guideline was sponsored and organized by the <funding-source id="GS1">Pediatric Endocrine Society</funding-source> via an unrestricted education grant from <funding-source id="GS2">AstraZeneca</funding-source>. Individual authors were supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Grants RO1-DK088114, RO1-DK105448, and RO1-DK101941; the Sopha Fund for Lipodystrophy Research at the University of Michigan, and Grant 14-35-00026 of the Russian Science Foundation.</p><p>Endorsing Societies include: Pediatric Endocrine Society, American Diabetes Association, American Association of Clinical Endocrinologists, Endocrine Society, Japanese Society for Pediatric Endocrinology, Australasian Pediatric Endocrine Group, European Society for Pediatric Endocrinology, Asia Pacific Pediatric Endocrine Society, African Society for Pediatric and Adolescent Endocrinology, and International Society for Pediatric and Adolescent Diabetes.</p><p>Disclosure Summary: R.J.B., P.T.C., D.D., M.J., L.M., N.P., K.R., J.v.S., E.S., T.S., M.W., R.W., and T.Y. have nothing to declare. A.G. 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). D.A.-V. has consulted for Bristol-Myers Squibb and AstraZeneca. E.A.O. 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. 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