Lipodystrophy Diagnosis and Treatment Consensus Statement

Lipodystrophy Diagnosis and Treatment Consensus Statement Final Draft March 22, 2016

1 The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline

3 Endorsing Societies (tentative):

4 1. Pediatric Endocrine Society

5 2. American Diabetes Association

6 3. American Association of Clinical Endocrinologists

7 4. Endocrine Society

8 5. Japanese Society for Pediatric Endocrinology

9 6. Australasian Paediatric Endocrine Group

10 7. European Society for Paediatric Endocrinology

11 8. Asia Pacific Paediatric Endocrine Society

12 9. African Society for Paediatric and Adolescent Endocrinology

14 Author names and institutions:

15 Rebecca J. Brown1,2, David Araujo-Vilar3, Pik To Cheung4, David Dunger5, Abhimanyu Garg6, Michelle

16 Jack7, Lucy Mungai8, Elif A. Oral9, Nivedita Patni10, Kristina Rother2, Julia von Schnurbein11, Ekaterina

17 Sorkina12, Takara Stanley13, Corinne Vigouroux14,15,16, Martin Wabitsch11, Rachel Williams17, Tohru

18 Yorifuji18

20 1 Committee Chair; all other authors appear in alphabetical order

1 Lipodystrophy Diagnosis and Treatment Consensus Statement Final Draft March 22, 2016

21 2 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,

22 Bethesda, MD, USA

23 3 Department of Medicine, University of Santiago de Compostela, Spain

24 4 Department of Paediatrics and Adolescent Medicine, The University of Hong Kong

25 5 Department of Paediatrics, University of Cambridge Box 116 Level 8, Cambridge Biomedical Campus,

26 Cambridge CB2 0QQ), MRL Wellcome Trust MRC Institute of Metabolic Science, NIHR Cambridge

27 Comprehensive Biomedical Research Centre, UK, MRC Epidemiology Unit, University of Cambridge

28 6 Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for

29 Human Nutrition, UT Southwestern Medical Center, Dallas, Texas, USA

30 7 Royal North Shore Hospital, Northern Clinical School, University of Sydney St Leonards NSW 2126

31 8 Department of Paediatrics and Child Health, University of Nairobi, Kenya

32 9 Brehm Center for Diabetes and Division of Metabolism, Endocrinology, and Diabetes; Department of

33 Internal Medicine; University of Michigan Medical School and Health Systems, Ann Arbor, USA

34 10 Division of Pediatric Endocrinology, Department of Pediatrics, UT Southwestern Medical Center,

35 Dallas, Texas, USA

36 11 Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine,

37 University of Ulm, Eythstr. 24 / 89075 Ulm, Germany

38 12 Clamp technologies laboratory, Endocrinology Research Center, Moscow, Russia

39 13 Pediatric Endocrine Unit and Program in Nutritional Metabolism, Massachusetts General Hospital and

40 Harvard Medical School, Boston, MA, USA

41 14 Sorbonne Universities, UPMC Univ Paris 6, Inserm UMRS 938, Saint-Antoine Research Center,

42 and Institute of Cardiometabolism and Nutrition (ICAN), Paris, France

43 15 AP-HP, Saint-Antoine Hospital, Molecular Biology and Genetics Department, Paris, France

44 16 Institute of Cardiometabolism and Nutrition, Paris, France

45 17Department of Paediatric Endocrinology, Cambridge University Hospitals NHS Trust, Hills Road,

46 Cambridge, United Kingdom

47 18Division of Pediatric Endocrinology and Metabolism, Children’s Medical Center, Osaka City General

48 Hospital, Japan

50 Abbreviated title: Diagnosis and Management of Lipodystrophy

51 Keywords: Lipodystrophy, lipoatrophy, lipoatrophic diabetes, metabolic syndrome, insulin resistance

53 Word count: 3594

54 Tables: 4

55 Figures: 2

56 References: 120

57 Supplemental Tables: 3

59 Corresponding Author and Reprint Requests:

60 Rebecca J. Brown, MD, MHSc

61 National Institute of Diabetes and Digestive and Kidney Diseases

62 National Institutes of Health

63 Building 10-CRC, Room 6-5942

64 10 Center Drive

65 Bethesda, MD, 20892

66 Phone: 301-594-0609

67 Fax: 301-480-3675

68 Email: [email protected]

70 Grant and Fellowship Support: This practice guideline was sponsored and organized by the Pediatric

71 Endocrine Society via an unrestricted education grant from AstraZeneca. Individual authors were

72 supported by the intramural research program of the National Institute of Diabetes and Digestive and

73 Kidney Diseases, NIH grants RO1-DK088114, RO1-DK105448, RO1-DK101941, the Sopha Fund for

74 Lipodystrophy Research at the University of Michigan, and grant 14-35-0026 of the Russian Science

75 Foundation.

76 Disclosures: RJB, PTC, MJ, LM, NP, KR, JvS, ES, TS, MW, and TY have nothing to declare. AG

77 consults for Aegerion Pharmaceuticals, Ionis, and Amgen, previously consulted for Biomedical Insights,

78 Clearview Healthcare, Gerson Lehrman, and Smithsolve, and received grant support from Aegerion

79 Pharmaceuticals, Pfizer (2013-2016), and Ionis Pharmaceuticals (2015-2017). DA-V has consulted for

80 Bristol-Myers Squibb and AstraZeneca. EAO received past grant/drug support from Bristol-Myers

81 Squibb, AstraZeneca, and Amylin Pharmaceuticals, current research/drug support from Aegerion

82 Pharmaceuticals, and Ionis Pharmaceuticals, previously consulted for all of the previously listed

83 companies, and is a current consultant to AstraZeneca, Aegerion and Ionis Pharmaceuticals. CV is a

84 member of the Aegerion “Metreleptin Expanded Access Review Board.”

86 Abstract

88 Objective: Lipodystrophy syndromes are extremely rare disorders of deficient body fat complicated by

89 potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis.

90 Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice

91 guideline summarizes diagnosis and management of lipodystrophy syndromes.

93 Participants: Seventeen participants were nominated by worldwide endocrine societies or selected by the

94 committee as content experts. Funding was via unrestricted educational grant (Astra Zeneca) to the

95 Pediatric Endocrine Society. Meetings were not open to the general public.

97 Evidence: Literature review was conducted by the committee. Recommendations of the committee were

98 graded using the system of the American Heart Association. Expert opinion was used when published

99 data were not available or scarce.

101 Consensus Process: The guideline was drafted by committee members, and reviewed, revised, and

102 approved by the entire committee during group meetings. Contributing societies reviewed the document

103 and provided approval.

105 Conclusions: Lipodystrophy syndromes are heterogeneous, and are diagnosed by clinical phenotype,

106 supplemented by genetic testing in certain forms. Patients with most lipodystrophy syndromes should be

107 screened for diabetes, dyslipidemia, and liver, kidney, and heart disease annually. Diet is essential for

108 management of metabolic complications of lipodystrophy. Metreleptin therapy is effective for metabolic

109 complications in hypoleptinemic patients with generalized lipodystrophy, and selected patients with

110 partial lipodystrophy. Other treatments not specific for lipodystrophy may be helpful as well (e.g.

111 metformin for diabetes, statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated.

113 INTRODUCTION

115 The lipodystrophy syndromes are a heterogeneous group of rare disorders that have in common selective

116 deficiency of adipose tissue in the absence of nutritional deprivation or catabolic state (Figure 1).

117 Lipodystrophies are categorized based on etiology (genetic or acquired) and distribution of lost adipose

118 tissue, affecting the entire body (generalized) or only regions (partial). This yields four major categories:

119 congenital generalized lipodystrophy (CGL), familial partial lipodystrophy (FPLD), acquired generalized

120 lipodystrophy (AGL), and acquired partial lipodystrophy (APL) (Figure 1). Additional subtypes include

121 progeroid disorders, autoinflammatory disorders, and others (Table 1). This practice guideline will not

122 discuss lipodystrophy in HIV infected patients or localized lipodystrophy (e.g. from injectable drugs).

124 Lipodystrophy syndromes are frequently associated with hormonal and metabolic derangements resulting

125 in severe comorbidities (Table 2) that depend on the subtype, extent of fat loss, age, and gender. Many

126 complications of lipodystrophy are secondary to deficient adipose mass, resulting in ectopic lipid storage

127 in the liver, muscle, and other organs, causing insulin resistance. Insulin resistance leads to diabetes,

128 hypertriglyceridemia, polycystic ovarian syndrome (PCOS), and non-alcoholic fatty liver disease

129 (NAFLD) (1).

131 Major causes of mortality in patients with lipodystrophy include heart disease (cardiomyopathy, heart

132 failure, myocardial infarction, arrhythmia) (2-5), liver disease (liver failure, gastrointestinal hemorrhage,

133 hepatocellular carcinoma) (6,7), kidney failure (6), acute pancreatitis (7), and sepsis.

135 Due to the rarity of lipodystrophy syndromes, most clinicians are unfamiliar with their diagnosis and

136 management. In December 2015, an expert panel including representatives from endocrine societies

137 around the world convened to generate this practice guideline. The panel used the evidence rating system

138 of the American Heart Association (Supplemental Table 1) (8).

140 Overview of lipodystrophy syndromes:

141 This section reviews major categories of lipodystrophy. Detailed phenotypic information on individual

142 subtypes is in Table 3.

144 Congenital Generalized Lipodystrophy (CGL, Berardinelli-Seip Syndrome)

145 CGL is an autosomal recessive disorder characterized by near-complete lack of fat starting at birth or

146 infancy, prominent muscles, phlebomegaly, acanthosis nigricans, hepatomegaly, umbilical prominence,

147 and voracious appetite in childhood (9,10). Multiple genetic causes have been identified, each with

148 unique clinical features (11-13). Metabolic complications are frequent and may be severe.

149 Cardiomyopathy or rhythm disturbances may occur.

151 Familial Partial Lipodystrophy (FPLD)

152 FPLD is a group of usually autosomal dominant disorders characterized by loss of fat affecting the limbs,

153 buttocks, and hips (10). Regional excess fat accumulation is frequent, varies by subtype, and may result in

154 a Cushingoid appearance. Fat distribution is typically normal in early childhood, with loss of fat occurring

155 around puberty. Muscular hypertrophy is common. Metabolic complications are common in adulthood

156 (14), with increased risk of coronary heart disease (15) and occasionally early cardiomyopathy.

158 Acquired Generalized Lipodystrophy (AGL, Lawrence syndrome):

159 AGL is more common in females (F:M; 3:1), and appears usually before adolescence (but may develop at

160 any time in life) with progressive loss of fat affecting the whole body including palms and soles (4).

161 Some fat accumulation can appear in the face, neck or axillae. Metabolic complications are frequent and

162 may be severe. AGL is often associated with autoimmune diseases (4,16).

164 Acquired Partial Lipodystrophy (APL, Barraquer-Simons syndrome):

165 APL is more frequent in females (F:M; 4:1) and usually begins in childhood or adolescence. Loss of fat

166 follows a cranio-caudal trend, progressively affecting the face, neck, shoulders, arms, and trunk. Fat

167 accumulation can appear in the hips, buttocks and legs (17). APL is associated with autoimmune

168 diseases, especially membranoproliferative glomerulonephritis (MPGN) in ~20% (17). Most patients have

169 low serum complement 3 levels, and some have presence of C3 nephritic factor. Metabolic complications

170 are uncommon (17).

173 DIAGNOSIS OF LIPODYSTROPHY

174  Diagnosis of lipodystrophy is based on history, physical examination, body composition, and

175 metabolic status. (Class I, Level B)

176  There are no defined serum leptin levels that establish or rule out the diagnosis of

177 lipodystrophy. (Class IIa, Level C)

178  Confirmatory genetic testing is helpful in suspected familial lipodystrophies. (Class I, Level

179 A)

180  Genetic testing should be considered in at-risk family members. (Class IIa, Level C)

181  Serum complement levels and autoantibodies may support diagnosis of acquired

182 lipodystrophy syndromes. (Class IIa, Level B)

184 Firm diagnostic criteria for lipodystrophy have not been established. Figure 2 shows a suggested

185 diagnostic approach.

187 Establishing the presence of lipodystrophy

188 Lipodystrophy should be suspected in patients with regional or generalized lack of adipose tissue outside

189 of the normal range by physical examination, which can be supported by anthropometry, dual energy X-

190 ray absorptiometry (DXA), and whole-body magnetic resonance imaging (MRI) (18). Recognizing loss of

191 subcutaneous fat is particularly challenging in partial lipodystrophy and especially in men, in whom low

192 body fat overlaps with normal variation, and metabolic manifestations of lipodystrophy are less severe. In

193 both genetic and acquired lipodystrophies, loss of fat may be gradual, delaying diagnosis.

195 Physical, historical, and comorbid features that increase the suspicion of lipodystrophy (18) are in Table

196 4.

198 Because serum leptin assays are not standardized and leptin concentrations in patients with lipodystrophy

199 (especially partial forms) overlap the general population, leptin levels do not help in diagnosis, but may

200 help with choice of therapies.

202 Differential Diagnosis:

203 Differential diagnosis should include conditions presenting with severe weight loss (malnutrition,

204 anorexia nervosa, uncontrolled diabetes mellitus, thyrotoxicosis, adrenocortical insufficiency, cancer

205 cachexia, HIV-associated wasting, chronic infections). Especially difficult is differentiating lipodystrophy

206 from uncontrolled diabetes, as both may present with extreme hypertriglyceridemia. However, restoring

207 glycemic control in patients with non-lipodystrophic diabetes leads to regain of body fat. Generalized

208 lipodystrophies can be confused with Donohue or Rabson Mendenhall syndromes (mutations of the

209 insulin receptor) or acromegaly/gigantism, and FPLD with Cushing’s syndrome, truncal obesity, and

210 multiple symmetric lipomatosis.

212 Establishing the subtype of lipodystrophy

213 Pattern of fat loss:

214 Although the pattern of body fat loss in patients with a particular subtype of genetic lipodystrophy is quite

215 characteristic, heterogeneity occurs in the onset, severity, and pattern of fat loss, even within a single

216 family.

218 Distinguishing genetic from acquired lipodystrophy:

219 Pedigree analysis can suggest genetic versus acquired lipodystrophy. Review of photographs from

220 infancy may distinguish CGL from AGL, as infants typically show absent fat in CGL, and normal fat in

221 AGL. However, there have been cases of AGL with loss of fat during the first few months of life (4).

222 Patients with AGL lack family history, but can be confused with any type of genetic lipodystrophy,

223 especially those with de novo mutation.

225 The presence of autoimmune diseases (myositis, type 1 diabetes, autoimmune hepatitis, and others)

226 (4,10,16,17,19,20) increases the suspicion of acquired lipodystrophy. In APL, low serum C3, presence of

227 C3NeF, proteinuria or biopsy-proven MPGN support the diagnosis.

229 Genetic testing:

230 Genotyping may include limited candidate gene sequencing, a panel of candidate genes, or whole

231 exome/whole genome sequencing. The website, www.genetests.org, lists clinical and research

232 laboratories conducting genetic testing for lipodystrophy syndromes. Since there is strong evidence for

233 additional loci for genetic lipodystrophies, negative tests do not rule out a genetic condition.

235 Genetic counseling and screening of family members:

236 Genetic counseling must take into consideration that current understanding of the natural history of

237 genetic lipodystrophies and their complications is incomplete. In affected pedigrees, premarital

238 counseling with genetic testing to detect carrier status can be considered.

240 Clinical diagnosis of lipodystrophy may be difficult in men (21), and some genotypes are associated with

241 mild lipodystrophy phenotypes (22,23). Genetic screening of family members may help identify

242 individuals with subtle phenotypes. Genetic screening may be particularly important for families with

243 specific LMNA mutations associated with cardiomyopathy and arrhythmia.

246 SCREENING FOR COMORBIDITIES

247 All patients should be screened for diabetes, dyslipidemia, NAFLD, cardiovascular, and reproductive

248 dysfunction. Because patients with APL are at low risk for metabolic complications, clinical judgment

249 should guide follow-up screening. Screening for comorbidities specific to individual lipodystrophy

250 subtypes is not extensively discussed here.

252 Diabetes mellitus

253  Diabetes screening should be performed annually. (Class IIa, Level C)

254 Diabetes screening should follow the guidelines of the American Diabetes Association (fasting plasma

255 glucose, oral glucose tolerance test, or hemoglobin A1c). Children with CGL may manifest diabetes in

256 the first years of life (9). Patients with AGL may develop Type 1 diabetes in addition to insulin resistance

257 (24); measurement of auto-antibodies may clarify the diagnosis.

259 Dyslipidemia

260  Triglycerides should be measured at least annually, and with occurrence of abdominal pain

261 or xanthomata. (Class I, Level C)

262  Fasting lipid panel (total cholesterol, low density lipoprotein [LDL]-cholesterol, high density

263 lipoprotein [HDL]-cholesterol, triglycerides) should be measured at diagnosis and annually

264 after age 10 years. (Class IIa, Level C)

266 Liver disease

267  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be

268 measured annually. (Class IIa, Level C)

269  Liver ultrasound should be performed at diagnosis, then as clinically indicated. (Class IIa,

270 Level C)

271  Liver biopsy should be performed as clinically indicated. (Class IIa, Level C)

272 In addition to physical examination, ultrasound and elastography are useful to estimate liver and spleen

273 size, severity of steatosis and fibrosis, and existence of portal hypertension. Patients with CGL2 are at

274 high risk for early cirrhosis, and those with AGL may have autoimmune hepatitis in addition to NAFLD

275 (19).

277 Reproductive dysfunction

278  Gonadal steroids, gonadotropins, and pelvic ultrasonography should be performed as

279 clinically indicated. (Class IIa, Level C)

280  Pubertal staging should be performed annually in children. (Class IIa, Level C)

281 Early adrenarche, true precocious puberty, or central hypogonadism may occur in children with

282 generalized lipodystrophy. Oligo/amenorrhea, decreased fertility, and PCOS are common in women.

284 Cardiac disease

285  Blood pressure should be measured at least annually. (Class I, Level C)

286  ECG and echocardiogram should be performed annually in CGL and progeroid disorders,

287 and at diagnosis and as clinically indicated in FPLD and AGL. (Class IIa, Level C)

288  Evaluation for ischemia and rhythm monitoring should be considered in patients with

289 progeroid disorders and FPLD2 with cardiomyopathy. (Class IIa, Level C)

290 Hypertension is common (25), even in children. In patients with CGL4, atypical progeroid syndromes,

291 and FPLD2 due to LMNA mutations, cardiac abnormalities including ischemic heart disease,

292 cardiomyopathy, arrhythmias, and sudden death are reported (3,23,26-33).

294 Kidney disease

295  Urine protein should be measured annually using 24 hour urine collection or urine protein

296 to creatinine ratio. (Class IIa, Level C)

297 Proteinuria is common (34). Kidney biopsy should be performed as clinically indicated, and pathology

298 may include diabetic nephropathy, focal segmental glomerulosclerosis (especially in CGL) (34) or MPGN

299 (especially in APL) (17).

301 Malignancy

302 Lymphomas, particularly peripheral T-cell lymphoma, occur in AGL, with prevalence of ~7% (4,35).

303 Appropriate screening has not been established, but would reasonably include annual skin and lymph

304 node examination. Generalized lipodystrophy has been reported as a paraneoplastic manifestation of

305 pilocytic astrocytoma in three children who regained body fat following cancer therapy (36). Clinicians

306 should consider screening for brain tumors in children who present with idiopathic AGL or atypical CGL.

307 Specific progeroid syndromes (e.g. Bloom and Werner syndrome) are associated with increased

308 malignancy risk (Table 3).

310 TREATMENT OF LIPODYSTROPHY SYNDROMES

311 Current therapies prevent or ameliorate the comorbidities of lipodystrophy syndromes. There is no cure

312 for lipodystrophy, and no treatment that can regrow adipose tissue.

314 Diet

315  Most patients should follow diets with balanced macronutrient composition. (Class IIa, Level

316 C)

317  Energy restricted diets improve metabolic abnormalities, and may be appropriate in adults.

318 (Class I, Level C)

319  Very low fat diets should be used in chylomicronemia-induced acute pancreatitis. (Class I,

320 Level C)

321  A dietician should be consulted for specialized dietary needs, especially in infants and young

322 children. Overfeeding should be avoided. (Class IIa, Level C)

323  Medium chain triglyceride (MCT) oil formulas can provide energy and reduce triglycerides

324 in infants. (Class IIa, Level C)

325 The cornerstone of therapy for metabolic complications of lipodystrophy is diet. Studies of specific diets

326 in lipodystrophy are lacking, and recommendations rely on sparse literature and clinical experience.

328 Patients with lipodystrophy, especially generalized forms, are typically hyperphagic due to leptin

329 deficiency. Energy-restricted diets in adolescents and adults lower triglycerides and glucose (37), but

330 dietary restriction is challenging to achieve. Food restriction to control metabolic complications must be

331 balanced by requirements for growth and development in children. Overfeeding to achieve normal weight

332 may worsen metabolic complications and hepatic steatosis. Assessment of weight-for-length and body

333 mass index (BMI) by comparison to reference growth data is not appropriate because body composition is

334 atypical. Low weight-for-length or BMI is acceptable provided linear growth is maintained. Patients with

335 lipodystrophy should not be labeled as having malnutrition.

337 Patients should follow a 50-60% carbohydrate, 20-30% fat, and ~20% protein diet. Simple sugars should

338 be restricted in preference for high-fiber complex carbohydrates, distributed evenly among meals and

339 snacks and consumed in combination with protein or fat. Dietary fat should be primarily cis-mono-

340 unsaturated fats and long chain omega-3 fatty acids. In extremely hypertriglyceridemic infants, MCT-

341 based formula may help (38,39). During acute pancreatitis, parenteral nutrition followed by very low fat

342 (<20 grams) diet should be used.

344 Exercise

345  Patients with lipodystrophy should be encouraged to exercise in the absence of specific

346 contraindications. (Class IIa, Level C)

347  Patients with subtypes of lipodystrophy predisposed to cardiomyopathy should undergo

348 cardiac evaluation prior to initiating an exercise regimen. (Class III, Level C)

349 Individuals with lipodystrophy engaged in intense exercise have amelioration of metabolic complications.

350 Most patients should be encouraged to be physically active. However, strenuous exercise should be

351 avoided in patients with cardiomyopathy. Contact sports should be avoided in patients with severe

352 hepatosplenomegaly and CGL patients with lytic lesions in long bones.

354 Metreleptin

355  In generalized lipodystrophy, metreleptin (with diet) is a first-line treatment for metabolic

356 and endocrine abnormalities (Class I, Level B), and may be considered for prevention of

357 these comorbidities in young children. (Class IIb, Level C)

358  Metreleptin may be considered for hypoleptinemic (leptin < 4 ng/mL) patients with partial

359 lipodystrophy and severe metabolic derangements (HbA1C > 8% and/or triglycerides > 500

360 mg/dL). (Class IIb, Level B)

362 Currently, metreleptin (recombinant human methionyl leptin) is the only drug approved specifically for

363 lipodystrophy. It is approved in the US as an adjunct to diet for treatment of metabolic complications in

364 patients with generalized lipodystrophy. In Japan, it is approved for both generalized and partial

365 lipodystrophy. It is available in other parts of the world (e.g. Europe) through compassionate use

366 programs. There is no age limit for initiation of metreleptin; children as young as 15 months have been

367 treated. A dosing algorithm is provided in Supplemental Table 2 (40). Dose adjustments should be made

368 in response to metabolic parameters and weight change, with clinical and laboratory assessment

369 performed every 3-6 months.

371 Metreleptin in Generalized Lipodystrophy

372 Metreleptin decreases hyperphagia (41-45), frequently leading to weight loss. Reduced food intake is at

373 least partially responsible for many of the metabolic improvements. If excessive weight loss occurs, the

374 dose of metreleptin should be reduced (Supplemental Table 2) (40).

376 Metreleptin markedly improved fasting glucose as early as the first week (42), and lowered HbA1c by 2%

377 after one year (46). To reduce the risk of hypoglycemia, frequent glucose monitoring is recommended.

378 Providers should consider reducing insulin doses by ~50% on initiation of metreleptin in patients with

379 well-controlled diabetes. Many young patients with CGL are able to discontinue insulin (46).

381 Metreleptin lowered triglycerides within one week (42), reaching 60% reduction at one year (46).

382 Metreleptin also decreased LDL- and total cholesterol, but did not change HDL-cholesterol (47,48).

383 Acute pancreatitis due to hypertriglyceridemia has occurred in patients who acutely discontinued or

384 reduced metreleptin (47).

386 Metreleptin reduced hepatic steatosis, serum transaminases, and NASH scores within 6 to 12 months

387 (42,49-51). In one case, metreleptin ameliorated recurrence of severe hepatic steatosis after liver

388 transplantation (52).

390 Metreleptin decreased proteinuria in most patients (34,42). However, 4 patients had worsened renal

391 disease during metreleptin treatment, so renal function should be monitored closely with preexisting renal

392 disease (34).

394 In females, metreleptin normalized gonadotropin secretion, leading to normal progression of puberty,

395 normalization of menstrual periods (42,45,53,54), and improved fertility (1). Metreleptin decreased

396 testosterone in women, but did not alter ovarian morphology (45,53,55). In males, metreleptin increased

397 testosterone (45).

399 Metreleptin in Partial Lipodystrophy

400 The response to metreleptin in partial lipodystrophy is less robust than in generalized lipodystrophy. In

401 one study, metreleptin reduced hypertriglyceridemia and improved glycemia in severely hypoleptinemic

402 patients with partial lipodystrophy and severe metabolic derangements (baseline HbA1C > 8%,

403 triglycerides > 500 mg/dL, leptin < 4 ng/mL) (46). In a second study, metreleptin improved triglycerides

404 and indices of insulin sensitivity and secretion in FPLD2 patients with moderate to severe hypoleptinemia

405 (56). However, in a third study, no glycemic improvement was observed in FPLD2 patients with serum

406 leptin <7 ng/mL (57). Metreleptin is only available to patients with partial lipodystrophy through clinical

407 trials, compassionate use programs, and in Japan.

409 Side effects of metreleptin

410 Approximately 30% of patients experience side effects (47). The most clinically important are

411 hypoglycemia (in patients receiving concomitant insulin) and infrequent injection-site reactions

412 (erythema, urticaria).

414 In vivo neutralizing antibody activity to leptin has been reported (58,59). The clinical implications

415 remain unclear, but may include treatment failure and sepsis (59). Additional serious adverse events

416 occurring during metreleptin treatment are likely related to the underlying lipodystrophy syndrome, rather

417 than metreleptin. These include T-cell lymphoma in patients with AGL (35), pancreatitis (47), and

418 worsening of liver (47) and kidney (34) disease.

420 Additional treatments for specific comorbidities

421 Diabetes

422  Metformin is a first-line agent for diabetes and insulin resistance (Class IIa, Level C)

423  Insulin is effective for hyperglycemia. In some patients, concentrated preparations and

424 high-doses may be required. (Class IIa, Level C)

425  Thiazolidinediones may improve metabolic complications in patients with partial

426 lipodystrophy, but should be used only with caution in generalized lipodystrophy. (Class IIb,

427 Level B)

428 Among the oral hypoglycemic agents, metformin is used most frequently. In patients with partial

429 lipodystrophy, thiazolidinediones improved HbA1c, triglycerides, hepatic volume and steatosis, but may

430 increase regional fat excess (Supplemental Table 3) (60,61). In patients with high insulin requirements,

431 concentrated insulins should be considered where available (62). Insulin glargine and degludec kinetics

432 may be altered when injected in lipodystrophic areas, as their long duration of action requires

433 subcutaneous fat (63,64). Patients with generalized lipodystrophy may have to take insulin by

434 intramuscular routes for lack of subcutaneous fat. Many other hypoglycemic agents have been used in

435 lipodystrophy, but their efficacy has not been studied.

437 Dyslipidemia

438  In adults with diabetes, target LDL-cholesterol is <100 mg/dL, and non-HDL-cholesterol

439 <130 mg/dL (Class IIb, Level C)

440  Lipid-lowering medications should be used when lifestyle modification fails to reach

441 objectives in 3 months. (Class I, Level C)

442  Fibrates should be used for triglycerides > 500 mg/dl, and may be considered for

443 triglycerides >200 mg/dL (Class IIb, Level C)

444 Lipids should be managed in accordance with US and European guidelines for the general population,

445 with statins as first-line therapy (65,66). Because cardiovascular risk may be enhanced in lipodystrophic

446 syndromes independent of other risk factors, clinicians may consider applying stricter lipid targets (e.g.

447 LDL-cholesterol < 100 mg/dl, triglycerides < 200 mg/dL) even in patients without diabetes. In addition

448 to diet, fibrates and long-chain omega-3-fatty acids (eicosapentaenoic and docosahexaenoic acid from fish

449 oils) have wide clinical use to avoid acute complications of severe hypertriglyceridemia (46), but have not

450 been formally studied. Plasmapheresis has been used in extreme hypertriglyceridemia, but must be

451 repeated frequently (67). Statins and fibrates should be used only with caution in the presence of known

452 myositis or muscular dystrophy (68).

454 Hypertension

455  Angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARB)

456 are first-line treatments for hypertension in patients with diabetes. (Class IIa, Level C)

457 As in other patients with diabetes, ACE-inhibitors or ARBs should be used for hypertension (69).

459 Liver disease

460 Cholic acid did not reduce hepatic steatosis in patients with FPLD in a double-blind, placebo-controlled

461 cross-over study (70). In NAFLD not associated with lipodystrophy, diet and exercise are first-line

462 treatments (71), and among pharmacologic treatments, Vitamin E (in children and adults) (72,73) and

463 pioglitazone (in adults) (72,74) have shown the most consistent benefit for liver histopathology.

464 However, these treatments have not been studied in patients with lipodystrophy and are not approved for

465 NAFLD.

467 Cosmetic treatment

468  Patients should be assessed for distress related to lipodystrophy, and referred as necessary

469 to mental health professionals and/or plastic surgeons. (Class IIa, Level C)

470 Changes in physical appearance from lipodystrophy can cause psychological distress and physical

471 discomfort (e.g. from absent fat pads in feet or buttocks). Data regarding cosmetic surgery are limited.

472 For facial lipoatrophy, autologous fat transfer (in APL), dermal fillers (7,75), or muscle grafts (76) may

473 be used. Excess fat from the head, neck, or vulva may be surgically reduced or ameliorated by

474 liposuction (7). Breast implants are helpful in some women (77,78). Acanthosis nigricans is improved

475 through successful treatment of insulin resistance (79,80). Management of hirsutism is reviewed

476 elsewhere (81).

478 Contraception and hormone replacement therapy

479  Oral estrogens are contraindicated. (Class IIa, Level C)

480  If contraception is needed, progestin-only or non-hormonal contraceptives should be

481 considered. (Class IIa, Level C)

482  If estrogen replacement is needed, transdermal estrogen should be used. (Class IIa, Level C)

483 Oral estrogens are contraindicated in lipodystrophy syndromes due to risk of severe hypertriglyceridemia

484 and acute pancreatitis. Transdermal estrogens may be safer due to lesser hepatic exposure (82,83). There

485 is clinical experience in the safe use of oral progestins and progestin containing intrauterine devices.

487 Pregnancy

488  Pregnant patients should receive prenatal care from an obstetrician experienced in

489 managing diabetes, and a physician experienced in managing lipodystrophy. (Class IIa, level

490 C)

491  Should a patient become pregnant while taking metreleptin, clinicians may consider

492 continuing metreleptin if withdrawal would harm the mother and fetus, and the patient

493 understands that effects of metreleptin in pregnancy are unknown, and wishes to continue.

494 (Class IIc, level C)

495 In patients with lipodystrophy who have extreme insulin resistance at baseline, worsening insulin

496 resistance during pregnancy may make diabetes management difficult, with attendant fetal risks.

497 Furthermore, metreleptin withdrawal has been associated with rebound hypertriglyceridemia (41), placing

498 patients at risk for pancreatitis, endangering both mother and fetus.

500 Conclusions

501 Lipodystrophy syndromes are a group of heterogeneous syndromes with diverse pathophysiology. For

502 diagnosis, clinical recognition and physical examination are critical. In management efforts, attention

503 should be paid to metabolic derangements, and to many other facets of these syndromes affecting

504 multiple organs, and quality of life.

506 Acknowledgments

507 This work was generously supported by an educational grant from AstraZeneca. We thank the staff of the

508 Pediatric Endocrine Society for their help in sponsoring and organizing this practice guideline, the

509 patients from around the world whose contributions to research allowed the development of these

510 guidelines, and Elaine Cochran for providing the guideline for metreleptin dosing.

511 Table 1: Subtypes and inheritance of lipodystrophy

Pathogenesis: gene involved, altered Refer- Subtype of lipodystrophy Inheritance protein and function ence Generalized lipodystrophies AGPAT2 : AGPAT2, synthesis of CGL1 AR (84) triglycerides and glycerophospholipids CGL2 BSCL2 : seipin, formation of lipid droplets AR (85) CAV1:caveolin-1, formation of membrane AR (single CGL3 (86) caveolae, lipid traffic case) PTRF : cavin-1, formation of membrane CGL4 AR (11) caveolae, lipid traffic PPARG: PPAR, transcription factor, AR (single PPARG associated (87) adipocyte differentiation case) Frequently associated with autoimmune AGL (Lawrence syndrome) - (4) (16) diseases and/or complement abnormalities Partial lipodystrophies FPLD1 genetic cause unknown Usually AD (88) LMNA : lamin A/C, structure and functions (89) FPLD2 AD of nuclear lamina (90) PPARG: PPAR, transcription factor, FPLD3 AD (91) adipocyte differentiation PLIN1: perilipin-1, structure and function of FPLD4 AD (92) adipocyte lipid droplet CIDEC : CIDEC, structure and function of AR (single FPLD5 (93) adipocyte lipid droplet case) LIPE : hormone sensitive lipase, regulation (94) FPLD6 AR of lipolysis (95) AD (single Akt2-linked lipodystrophy AKT2: Akt2, insulin signaling (96) family) Frequently associated with autoimmune APL (Barraquer-Simons diseases, complement 3 nephritic factor - (17) syndrome) and/or complement 3 abnormalities Progeroid and/or multisystem lipodystrophy syndromes Hutchinson-Gilford LMNA : lamin A/C, structure and functions (97) de novo progeria syndrome (HGPS) of nuclear lamina (98) LMNA : lamin A/C, structure and functions Progeroid laminopathies AD, de novo (99) of nuclear lamina Mandibulo-acral dysplasia LMNA : lamin A/C, structure and functions type A (with partial AR (100) of nuclear lamina lipodystrophy) Mandibulo-acral dysplasia ZMPSTE24: Zinc metalloproteinase, AR (101) type B (with generalized prelamin A processing

lipodystrophy)

POLD1: subunit of DNA polymerase , MDP syndrome de novo (102) DNA polymerization and repair Werner syndrome WRN: WRN DNA helicase, DNA repair AR (103) BANF1: Barrier to autointegration factor Nestor-Guillermo progeria (BAF), required for the assembly of emerin AR (104) Syndrome and A-type lamins at the reforming nuclear envelope Neonatal Marfan progeroid FBN1: fibrillin 1, connective tissue de novo (105) syndrome Keppen-Lubinsky KCNJ6 (GIRK2): inwardly rectifying de novo (106) Syndrome potassium channel Ruijs-Aalfs syndrome SPRTN: SprT-like N-terminal domain (107) protein, DNA repair AR Neonatal progeroid CAV1: Caveolin-1, formation of membrane de novo (108) syndrome caveolae, lipid traffic Auto-inflammatory syndromes with lipodystrophy Auto-inflammatory PSMB8: Proteasome (prosome, macropain) lipodystrophy (JMP, subunit, beta type, 8; (PSMB8); AR (109) CANDLE) immunoproteasome subunit Other syndromes with lipodystrophy SHORT PIK3R1: regulatory subunits of the phosphatidyl inositol-3 kinase of class IA AD, de novo (110) insulin signaling PCYT1A-linked PCYT1A: phosphate cytidylyltransferase 1 AR (111) lipodystrophy alpha, synthesis of phosphatidylcholine 512

513 AD, autosomal dominant; AGL, acquired generalized lipodystrophy; AGPAT2, acylglycerol-3-

514 phosphate-O-acyltransferase 2; AKT2, v-akt murine thymoma viral oncogene homolog 2 ; APL, acquired

515 partial lipodystrophy; AR, autosomal recessive; BANF1, barrier to autointegration factor 1; BSCL2,

516 Berardinelli-Seip congenital lipodystrophy 2; CANDLE, Chronic Atypical Neutrophilic Dermatosis with

517 Lipodystrophy and Elevated Temperature syndrome; CAV1, caveolin 1; CGL, congenital generalized

518 lipodystrophy; CIDEC, cell death inducing DFFA like effector c; FPLD, familial partial lipodystrophy;

519 FBN1, fibrillin 1; ; JMP, joint contractures, muscle atrophy; KCNJ6, potassium voltage-gated channel

520 subfamily J member 6; LIPE, lipase E, hormone sensitive type ; LMNA, lamin A/C; Microcytic anemia

521 and Panniculitis induced lipodystrophy syndrome; MDP, mandibular hypoplasia, deafness and progeroid

522 features; PCYT1A, phosphate cytidylyltransferase 1, choline, alpha ; PIK3R1, phosphoinositide-3-kinase

523 regulatory subunit 1; PLIN1, perilipin 1; POLD1, polymerase, delta 1, catalytic subunit; PPARG,

524 peroxisome proliferator activated receptor gamma; PSMB8, proteasome subunit beta 8; PTRF ,

525 polymerase I and transcript release factor; SPRTN, SprT-like N-terminal domain; WRN, Werner

526 syndrome RecQ like helicase; ZMPSTE24, Zinc metalloproteinase Table 2: Major comorbidities and

527 complications of lipodystrophy

Complication Affected subtypes Reference Hyperphagia AGL, CGL, (4,10,112) ±FPLD Dyslipidemia (high triglycerides, low HDL-c, AGL, CGL, FPLD (4,5,7,9,13,21,30) acute pancreatitis, eruptive xanthomas) Insulin resistance/diabetes, acanthosis nigricans AGL, CGL, FPLD (4,5,7,9,13,17,20,21,67) (and diabetes complications) Reproductive dysfunction (PCOS, AGL, CGL, FPLD, (4,5,7,10,14,20,55,113) oligomenorrhea, reduced fertility, hirsutism, APL preeclampsia, miscarriage, macrosomia) Non-alcoholic fatty liver disease (ranging from AGL, CGL, FPLD, (4,7,10,17,19,49,51,67,114) simple steatosis to cirrhosis) ±APL Renal dysfunction (proteinuria, MPGN, FSGS, AGL, CGL, FPLD, (17,34,115) diabetic nephropathy) APL Heart disease (hypertension, cardiomyopathy, AGL, CGL, FPLD (3-5,9,13,15,25) arrhythmias, conduction abnormalities, CAD) Autoimmune disease AGL, APL (4,10,17,19,20) T-cell lymphoma AGL (35,116,117) Mild mental retardation CGL2 (9,13) Focal osteolytic lesions in long bones CGL (9,13)

Psychological distress (fatigue, pain, depression, AGL, CGL, FPLD, (5) anxiety) APL Obstructive sleep apnea FPLD (118,119) Early puberty CGL (10) Accelerated linear growth & advanced bone age CGL (10,120) 528 AGL, acquired generalized lipodystrophy; APL, acquired partial lipodystrophy; CAD, coronary artery

529 disease; CGL, congenital generalized lipodystrophy; FPLD, familial partial lipodystrophy; MPGN,

530 membranoproliferative glomerulonephritis; FSGS, focal segmental glomerulosclerosis; PCOS, polycystic

531 ovary syndrome

533 Many of these features are also found in other forms of lipodystrophy, including progeroid disorders.

535 Table 3: Phenotypes of Lipodystrophy Syndromes

Congenital Generalized Lipodystrophy Subtype Gene- Onset ↓Fat ↑Fat Muscle Cardio-vascular Meta-bolic Ki Ner-vous G GU Other (gene) tics Bone dn I Endocrine Mineral ey L i v e r S p l e e n CGL 1 AR Birth Almost all None Hyper-trophic IR/DM Pr MR in-freq-uent H Precocious African descent (AGPAT2) Child- fat lost Muscle hypertrophy cardio-myopathy ↑TG ote y puberty (♀) (58%) hood Normal Cystic bone lesions (25%) ↓Leptin inu p Accelerated Umbilical mechanical HTN ria e growth prominence/ ↓Marrow r ↓Fertility (♀) hernia p PCOS h a g i a A c u t e p a n c r e a ti ti s N A F L D C ir

r h o s i s S p l e n o m e g a l y CGL 2 AR Birth Almost all None Muscle hypertrophy Hyper-trophic IR/DM Pr MR H Precocious Umbilical (BSCL2) fat lost cardio-myopathy ↑TG ote (75%) y puberty (♀) prominence/ ↓Mechanica (33%) ↓Leptin inu p Accelerated hernia l ria e growth ↓Marrow r ↓Fertility (♀) p PCOS h a g i a P a n c r e a ti ti s N A F L D C ir r h o s

i s S p l e n o m e g a l y M e g a e s o p h a g Almost all u s fat lost Delayed growth Muscle hypertrophy N ↓ IR/DM Short stature CGL 3 Child- Mechanica Hypocalcemia A AR None N ↑TG N N Amenorrhea (CAV1) hood l Vitamin D resistance F Hyper- Normal Osteopenia ↓Leptin L androgenism marrow D S p l e n o m e g a l y CGL 4 AR Child- Almost all None Percussion-induced Cardiac arrhyth- IR N N H Not reported Failure to thrive (PTRF) hood fat lost muscle mounding mia Mild y Umbilical Normal Muscle weakness & Risk of sudden ↑glucose p prominence mechanical hypertrophy cardiac death ↑TG e Transient immuno- Marrow fat Spinal rigidity ↓Leptin rt deficiency unknown ↑Lordosis r Recurrent

Osteoporosis o infections Atlanto-axial p instability h Arthritis i Contractures c p y l o ri c s t e n o s i s E s o p h a g e a l d y s m o ti li t y H e p a t o - s p l e n

o m e g a l y ↑ A L T / A S T A c u t e p a n c r e a ti ti s H CGL IR/DM Child- Almost all e Hyper- PPARG- AR None Muscle hypertrophy ↑TG N N Irregular menses hood fat lost p parathyroidism associated ↓Leptin a t o - s p l e n o m e g a l y

Acquired Generalized Lipodystrophy Subtype Gene- Onset ↓Fat ↑Fat Skin Muscle Cardio-vascular Meta-bolic Nervous GU Other tics App Bone Endoc enda Mineral rine ges AN Hirs utis Almost all fat 3 variants: Panniculitis After birth, m Ischemic cardio- IR/ DM lost Muscular Autoimmune (complement n/a n/a often before None Phle myopathy ↑ TG N PCOS ↓ appearance abnormalities) adolescence Mechanical bo- ± HTN ↓ Leptin Idiopathic Normal marrow meg aly

Familial Partial Lipodystrophy Subtype Gene- Onset ↓Fat ↑Fat Skin Muscle Cardio- Meta-bolic Ki Nervous GI GU Other tics Append Bone vascular dn Liver Endocrine ages Mineral ey Splee n AN Phlebo Face megaly IR/DM Child- or Coronary artery Hepat Buttocks Neck Eruptive Calf ↑ FPLD1 U Adult- disease TG N N omeg N Only ♀ Limbs Abd xantho hypertrophy hood HTN aly reported (sc + visc.) mata Hirsutis m Pr Pancr AN ote eatitis PCOS Phlebo inu Hepat Labial pseudo- Face megaly IR/DM ria Muscle Coronary artery omeg hypertrophy FPLD2 Buttocks Neck Eruptive ↑ in Nerve entrapment AD Puberty hypertrophy disease TG aly Breast Lipomas (LMNA) Limbs Abd xantho lat syndromes Myalgia HTN Mild Hepat hypoplasia (visc.) mata e ↓Leptin ic Preeclampsia Hirsutis sta steato Miscarriages m ge sis s Hepat AN IR/DM omeg Trunk Phlebo aly FPLD3 Adult- Muscular ↑TG AD Buttocks ±Abdomen megaly HTN N N Hepat PCOS Preeclampsia (PPAR) hood appearance Mild Limbs Hirsutis ic m ↓Leptin steato sis FPLD4 AD Child- or Buttocks ±Face AN Muscle IR/DM N N Hepat PCOS Cushingoid (PLIN1) adult- Limbs hypertrophy HTN ↑TG omeg appearance hood aly occasional Hepat ic

steato sis Pancr eatitis Hepat Pr Buttocks IR/DM omeg FPLD5 Child- Muscle ote Irregular Diabetic AR Lower None AN ↑TG N aly (CIDEC) hood hypertrophy HTN inu menses ketoacidosis limbs Hepat ↓Leptin ria ic steato sis Neck Hepat Mild muscular Axilla FPLD6 Adult- Lower Muscle IR/DM ic dystrophy AR ±Back N N N N N (LIPE) hood limbs weakness ↑ steato High CK Supra-clavicular Below TG sis ↑ triceps adiponectin Akt2- IR/DM Hepat linked Adult- Lower Abd ic AD ↑TG N N N lipodys- hood limbs (visc.) steato trophy ↓Leptin sis Acquired Partial Lipodystrophy Subtype Gene- Onset ↓Fat ↑Fat Skin Muscle Cardio-vascular Meta-bolic Ki Nervous GI GU Other tics Append Bone dn Liver Endocrine ages Mineral ey Splee n M em bra no Association pr with auto- Child- oli Hepat immune hood, Infrequent fer Face, trunk, o- diseases adolesce - Muscular IR/ DM ati n/a n/a upper Lower limbs - N spleno PCOS Low C3 nce, appearance ↑ ve limbs, TG megal complement adulthoo Gl - y levels, presence d om of C3NeF (C3 eru nephritic factor) lon ep hri tis

Progeroid and Autoinflammatory disorders Subtype Gen Onset ↓Fat ↑Fat Muscle Cardio-vascular Meta-bolic Nervous GU Other e- Bone Endocrine tics Mineral

HGPS AD <1 Almost all None Ogival palate EKG & Echo Mild IR TIA Pubertal delay Dysmorphic facies (LMNA) de year fat lost Abnormal abnormalities Mild Stroke Mammary Aged appearance

dentition Stooped shoulders Acroosteolysis Angina Growth failure (intra- ↑glucose Coxa valga HTN Short stature novo abdominal ↑ aplasia Osteoporosis Premature athero- TG Nasal voice fat spared) Subluxed finger sclerosis Death in 2nd decade joints Joint stiffness ↓muscle mass Mandibular hypoplasia Acroosteolysis Dental crowding Hypoplastic Dysmorphic facies Type A Child- Upper and Face Valvular calcification IR/DM teeth Aged appearance MAD AR hood Lower Neck Premature athero- ↑ N N TG Growth failure (LMNA) limbs Trunk Wide cranial sclerosis sutures Wormian Short stature bones Joint stiffness Bulbous fingertips Mandible & clavicle hypoplasia Type B <1 Almost all Acroosteolysis IR/DM Progressive Dysmorphic facies MAD AR None N N year fat lost Joint contractures ↑ glomerulopathy (ZMPSTE24) TG Delayed closure of cranial sutures SC calcifications Severe osteoporosis Sinus tachycardia Néstor- Osteolysis Right bundle branch Guillermo Micrognathia Growth failure 1-2 Almost all block Progeria AR None Scoliosis N N N Short stature years fat lost Pulmonary Syndrome Dental crowding hypertension (BANF1) Open cranial sutures Stiff joints Small mandible Dental crowding Partial or High arched Child- Dysmorphic facies Atypical AD generalized palate hood Valvular calcification IR/DM Mammary Aged appearance Progeria de fat loss None N Pub- Mild clavicular ↑ hypoplasia Short stature (LMNA) novo Normal TG erty resorption mechanical Acroosteolysis fat Mild flexion contractures Werner AR 2nd Limbs Abd-omen Osteoporosis Athero-sclerosis IR/DM N Dysmorphic facies

Growth failure syndrome decad Short stature Myocardial infarction ↑ (RECQL2) e TG Cataracts ↑Cancer

Bloom Dysmorphic facies Child- Syndrome AR Limbs Abd-omen Polydactyly DM Mild MR in some patients Reduced fertility Growth failure hood (BLM) ↑Cancer

PCYT1A Low HDL-C Child- Growth failure Lipo- AR Limbs IR/DM hood Short stature dystrophy ↑TG Hypoplasia of mandible & metatarsals Hypogonadism Almost all & Dysmorphic facies AD Joint contractures Child- fat lost IR/DM cryptorchidism Short stature MDPL de Visc. Fused carpal N Sensori-neural deafness hood ↓ ↑ (♂) Cataracts (POLD1) novo in soles bones TG of feet Dental crowding Hypoplastic High-pitched voice Osteoporosis breasts(♀) ↓muscle mass Dysmorphic facies Delayed dental Aged appearance Almost all eruption IUGR SHORT Child- fat lost IR/DM Sensori-neural hearing loss AD None ±Joint laxity Heart mal-formations Inguinal hernia Short stature (PIK3R1) hood (most Normal TG Speech delay Micrognathia Glaucoma cases) Rieger anomaly Cataracts Marfan syndrome with neonatal Arthrogryposis AD Dysmorphic facies progeroid Almost all Arachno-dactyly de Birth None Aortic root dilatation N Relative macro-cephaly N Aged appearance syndrome- fat lost Hyperlaxity novo Myopia like lipo- Large fontanels dystrophy (FBN1) Microcephaly Severe MR Dysmorphic facies Prognathism Cockayne Sensorineural hearing loss FTT Birth Long limbs syndrome Almost all Early athero-sclerosis Seizures Irregular menses Short stature AR Child- None Large hands/feet N (ERCC6, fat lost HTN Ataxia Hypogonadism Congenital cataracts hood Joint contractures ERCC8) Tremor Pigmentary retinopathy Kyphosis Weakness Death before 15y Dementia Neonatal AR Birth Face Butt-ocks Ano-geni-tal Large fontanels Prominent scalp veins ↑TG Macrocephaly ↑T4 Dysmorphic facies Progeroid Distal Thin long bones MR Irregular menses FTT Syndrome extremities with enlarged Hypotonia Short stature ±para- metaphyses Truncal ataxia Aged appearance vertebral Loss of teeth Ectropion

±gluteal Joint contractures Death in childhood ↓ in palms ↓muscle mass Microcephaly Keppen- Joint contractures MR Dysmorphic facies Lubinsky AD Child- Almost all Scoliosis Hypertonia FTT syndrome de None N N N hood fat lost Micrognathia Hyperreflexia Short stature (KCNJ6) novo Spastic tetraparesis Aged appearance Seizures Pectus excavatum Sloping shoulders Dysmorphic facies FTT Ruijs-Aalfs Delayed bone age Child- Almost all Short stature syndrome AR None Joint contractures N N N N hood fat lost Cataracts (SPRTN) Kyphoscoliosis Clinodactyly Sensitivity to Pes planus genotoxins ↓ muscle mass Micrognathia Joint contractures Dysmorphic facies Nakajo- Muscle weakness FTT Nishimura, Face ↓ Short stature muscle mass MR JMP, Child- Hands Cardiac insufficiency Recurrent fever AR None Hypertrophic ↑ ± Seizures N CANDLE hood Feet Arrhythmias TG Microcytic anemia pulmonary osteo- Basal ganglia calcification syndromes ± Chest arthropathy ↑ ESR (PSMB8) Long and thick Hypergamma- fingers globulinemia 536

537 1 Palms, soles, orbits, scalp, and periarticular regions

538 AD, autosomal dominant; AN, acanthosis nigricans; AR, autosomal recessive; BM, bone marrow fat; CANDLE, chronic neutrophilic dermatosis

539 with lipodystrophy and elevated temperature; DM, diabetes mellitus; ESR, erythrocyte sedimentation rate ; FTT, failure to thrive; HTN,

540 hypertension; IR, insulin resistance; IUGR, intrauterine growth restriction; JMP, joint contractures, muscle atrophy, microcytic anemia, and

541 panniculitis-induced lipodystrophy; MAD, Mandibuloacral dysplasia; MDPL, mandibular hypoplasia, deafness, progeroid features, and

542 lipodystrophy; MR, mental retardation ; N, No alterations reported; NAFLD, non-alcoholic fatty liver disease; PCOS, polycystic ovarian

543 syndrome; SC, subcutaneous; SHORT, short stature, hyperestensibility, hernia, ocular depression, Rieger anomaly, and teething delay; TG,

544 triglyceride; TIA, transient ischemic attack; U, unknown; Visc, visceral

545 Table 4: Clinical Features that Increase the Suspicion of Lipodystrophy1

Essential feature Generalized or regional absence of body fat Physical Features Failure to thrive (infants and children) Prominent muscles Prominent veins (phlebomegaly) Severe acanthosis nigricans Eruptive xanthomata Cushingoid appearance Acromegaloid appearance Progeroid (premature aging) appearance Comorbid Conditions Diabetes mellitus with high insulin requirements ≥200 units/day ≥2 units/kg/day Requiring U-500 insulin Severe hypertriglyceridemia ≥500 mg/dL with or without therapy ≥250 mg/dL despite diet and medical therapy History of acute pancreatitis secondary to hypertriglyceridemia Non-alcoholic steatohepatitis in a non-obese individual Early-onset cardiomyopathy Polycystic Ovarian Syndrome Other Historical Clues Autosomal dominant or recessive pattern of similar physical features or metabolic complications Significant hyperphagia (may manifest as irritability/aggression in infants/children) 546 1Adapted from (18)

547 Figure Legends

548 Figure 1: Physical appearance of patients with the four main subtypes of lipodystrophy syndromes

549 A. Lateral view of a 33-year-old Hispanic female with congenital generalized lipodystrophy (also known

550 as Berardinelli-Seip congenital lipodystrophy), type 1 due to homozygous c.IVS4-2A>G mutation in

551 AGPAT2 gene. The patient had generalized loss of subcutaneous fat with acanthosis nigricans in the

552 axillae and neck. She has umbilical prominence and acromegaloid features (enlarged mandible, hands and

553 feet). B. Anterior view of a 40-year-old Caucasian female with familial partial lipodystrophy of the

554 Dunnigan variety due to heterozygous p.Arg482Gln mutation in LMNA gene. She had marked loss of

555 subcutaneous fat from the limbs and anterior truncal region. The breasts were atrophic. She had increased

556 subcutaneous fat deposits in the face, anterior neck and vulvar regions. C. Anterior view of an 8-year-old

557 German boy with acquired generalized lipodystrophy. He had severe generalized loss of subcutaneous fat

558 with marked acanthosis nigricans in the neck, axillae and groin. D. Anterior view of a 45-year-old

559 Caucasian female with acquired partial lipodystrophy (Barraquer-Simons syndrome). She had marked

560 loss of subcutaneous fat from the face, neck, upper extremities, and chest and but had lipodystrophy on

561 localized regions on anterior thighs. She had increased subcutaneous fat deposition in the lower

562 extremities.

564 Figure 2: Diagnostic approach to lipodystrophy syndromes

565 Lipodystrophy should be suspected in patients with regional or generalized lack of adipose tissue. History

566 should assess age of onset of fat loss and comorbidities. Physical examination should determine

567 distribution of subcutaneous fat loss and presence of prominent muscles, phlebomegaly, acanthosis

568 nigricans, hepatomegaly, xanthomas, and acromegaloid or progeroid appearance. All patients should

569 undergo metabolic work up for insulin resistance, diabetes, dyslipidemia and fatty liver disease.

570 Conventional anthropometry including skinfold thickness measurements, ± DXA and whole body MRI (if

571 available) should be performed to confirm the pattern of fat loss. Common genetic lipodystrophies

572 include congenital generalized lipodystrophy (CGL), familial partial lipodystrophy (FPLD) and progeroid

573 lipodystrophies. They require genotyping to confirm the diagnosis followed by genetic counseling and

574 screening of family members. Patients with progeroid lipodystrophies have progeroid features like bird

575 like facies, high-pitched voice, skin atrophy and pigmentation, alopecia and nail dysplasia. Patients with

576 FPLD have fat loss of the extremities typically occurring around puberty and can have positive family

577 history. Patients with CGL have near-complete lack of fat starting at birth or infancy. Acquired

578 lipodystrophies have fat loss typically in late childhood. Patients with acquired generalized lipodystrophy

579 (AGL) have generalized loss of subcutaneous fat and often have associated autoimmune diseases. Patients

580 with acquired partial lipodystrophy (APL) have cranio-caudal fat loss affecting the face, neck, shoulders,

581 arms, and upper trunk and most patients have low serum complement 3 levels.

583 REFERENCES

584 1. Brown RJ, Gorden P. Leptin Therapy in Patients with Lipodystrophy and Syndromic Insulin 585 Resistance. In: Dagogo-Jack S, ed. Leptin: Regulation and Clinical Applications. Switzerland: 586 Springer International Publishing; 2015. 587 2. Bjornstad PG, Semb BK, Trygstad O, Seip M. Echocardiographic assessment of cardiac function 588 and morphology in patients with generalised lipodystrophy. European journal of pediatrics 1985; 589 144:355-359 590 3. Lupsa BC, Sachdev V, Lungu AO, Rosing DR, Gorden P. Cardiomyopathy in congenital and 591 acquired generalized lipodystrophy: a clinical assessment. Medicine (Baltimore) 2010; 89:245- 592 250 593 4. Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized 594 lipodystrophy: case reports and review of the literature. Medicine (Baltimore) 2003; 82:129-146 595 5. Jackson SN, Howlett TA, McNally PG, O'Rahilly S, Trembath RC. Dunnigan-Kobberling syndrome: 596 an autosomal dominant form of partial lipodystrophy. QJM : monthly journal of the Association 597 of Physicians 1997; 90:27-36 598 6. Seip M. Generalized lipodystrophy. In: Frick P vHG, Miller AF, Prader A, Schoen R, Wolf HP (eds), 599 ed. Ergeb Inn Med Kinderheilkd: Springer Berlin; 1971:59-95. 600 7. Garg A. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J Clin 601 Endocrinol Metab 2011; 96:3313-3325 602 8. Gibbons RJ, Smith S, Antman E, American College of C, American Heart A. American College of 603 Cardiology/American Heart Association clinical practice guidelines: Part I: where do they come 604 from? Circulation 2003; 107:2979-2986 605 9. Agarwal AK, Simha V, Oral EA, Moran SA, Gorden P, O'Rahilly S, Zaidi Z, Gurakan F, Arslanian SA, 606 Klar A, Ricker A, White NH, Bindl L, Herbst K, Kennel K, Patel SB, Al-Gazali L, Garg A. Phenotypic 607 and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab 608 2003; 88:4840-4847 609 10. Garg A. Acquired and inherited lipodystrophies. N Engl J Med 2004; 350:1220-1234 610 11. Hayashi YK, Matsuda C, Ogawa M, Goto K, Tominaga K, Mitsuhashi S, Park YE, Nonaka I, Hino- 611 Fukuyo N, Haginoya K, Sugano H, Nishino I. Human PTRF mutations cause secondary deficiency 612 of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest 2009; 613 119:2623-2633 614 12. Simha V, Garg A. Phenotypic heterogeneity in body fat distribution in patients with congenital 615 generalized lipodystrophy caused by mutations in the AGPAT2 or seipin genes. J Clin Endocrinol 616 Metab 2003; 88:5433-5437 617 13. Van Maldergem L, Magre J, Khallouf TE, Gedde-Dahl T, Jr., Delepine M, Trygstad O, Seemanova 618 E, Stephenson T, Albott CS, Bonnici F, Panz VR, Medina JL, Bogalho P, Huet F, Savasta S, Verloes 619 A, Robert JJ, Loret H, De Kerdanet M, Tubiana-Rufi N, Megarbane A, Maassen J, Polak M, 620 Lacombe D, Kahn CR, Silveira EL, D'Abronzo FH, Grigorescu F, Lathrop M, Capeau J, O'Rahilly S. 621 Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. Journal of 622 medical genetics 2002; 39:722-733 623 14. Vantyghem MC, Vincent-Desplanques D, Defrance-Faivre F, Capeau J, Fermon C, Valat AS, 624 Lascols O, Hecart AC, Pigny P, Delemer B, Vigouroux C, Wemeau JL. Fertility and obstetrical 625 complications in women with LMNA-related familial partial lipodystrophy. J Clin Endocrinol 626 Metab 2008; 93:2223-2229 627 15. Hegele RA. Premature atherosclerosis associated with monogenic insulin resistance. Circulation 628 2001; 103:2225-2229

629 16. Savage DB, Semple RK, Clatworthy MR, Lyons PA, Morgan BP, Cochran EK, Gorden P, Raymond- 630 Barker P, Murgatroyd PR, Adams C, Scobie I, Mufti GJ, Alexander GJ, Thiru S, Murano I, Cinti S, 631 Chaudhry AN, Smith KG, O'Rahilly S. Complement abnormalities in acquired lipodystrophy 632 revisited. J Clin Endocrinol Metab 2009; 94:10-16 633 17. Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune 634 derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. 635 Medicine (Baltimore) 2004; 83:18-34 636 18. Handelsman Y, Oral EA, Bloomgarden ZT, Brown RJ, Chan JL, Einhorn D, Garber AJ, Garg A, 637 Garvey WT, Grunberger G, Henry RR, Lavin N, Tapiador CD, Weyer C. The clinical approach to 638 the detection of lipodystrophy - an aace consensus statement. Endocrine practice : official 639 journal of the American College of Endocrinology and the American Association of Clinical 640 Endocrinologists 2013; 19:107-116 641 19. Safar Zadeh E, Lungu AO, Cochran EK, Brown RJ, Ghany MG, Heller T, Kleiner DE, Gorden P. The 642 liver diseases of lipodystrophy: the long-term effect of leptin treatment. J Hepatol 2013; 59:131- 643 137 644 20. Pope E, Janson A, Khambalia A, Feldman B. Childhood acquired lipodystrophy: a retrospective 645 study. J Am Acad Dermatol 2006; 55:947-950 646 21. Garg A. Gender differences in the prevalence of metabolic complications in familial partial 647 lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab 2000; 85:1776-1782 648 22. Savage DB, Soos MA, Powlson A, O'Rahilly S, McFarlane I, Halsall DJ, Barroso I, Thomas EL, Bell 649 JD, Scobie I, Belchetz PE, Kelly WF, Schafer AJ. Familial partial lipodystrophy associated with 650 compound heterozygosity for novel mutations in the LMNA gene. Diabetologia 2004; 47:753- 651 756 652 23. Decaudain A, Vantyghem MC, Guerci B, Hecart AC, Auclair M, Reznik Y, Narbonne H, Ducluzeau 653 PH, Donadille B, Lebbe C, Bereziat V, Capeau J, Lascols O, Vigouroux C. New metabolic 654 phenotypes in laminopathies: LMNA mutations in patients with severe metabolic syndrome. J 655 Clin Endocrinol Metab 2007; 92:4835-4844 656 24. Park JY, Chong AY, Cochran EK, Kleiner DE, Haller MJ, Schatz DA, Gorden P. Type 1 diabetes 657 associated with acquired generalized lipodystrophy and insulin resistance: the effect of long- 658 term leptin therapy. J Clin Endocrinol Metab 2008; 93:26-31 659 25. Brown RJ, Meehan CA, Gorden P. Leptin Does Not Mediate Hypertension Associated With 660 Human Obesity. Cell 2015; 162:465-466 661 26. Ben Turkia H, Tebib N, Azzouz H, Abdelmoula MS, Ben Chehida A, Hubert P, Douira W, Ben Dridi 662 MF. [Congenital generalized lipodystrophy: a case report with neurological involvement]. 663 Archives de pediatrie : organe officiel de la Societe francaise de pediatrie 2009; 16:27-31 664 27. Debray FG, Baguette C, Colinet S, Van Maldergem L, Verellen-Dumouin C. Early infantile 665 cardiomyopathy and liver disease: a multisystemic disorder caused by congenital lipodystrophy. 666 Molecular genetics and metabolism 2013; 109:227-229 667 28. Araujo-Vilar D, Lado-Abeal J, Palos-Paz F, Lattanzi G, Bandin MA, Bellido D, Dominguez-Gerpe L, 668 Calvo C, Perez O, Ramazanova A, Martinez-Sanchez N, Victoria B, Costa-Freitas AT. A novel 669 phenotypic expression associated with a new mutation in LMNA gene, characterized by partial 670 lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy. Clin 671 Endocrinol (Oxf) 2008; 69:61-68 672 29. Bhayana S, Siu VM, Joubert GI, Clarson CL, Cao H, Hegele RA. Cardiomyopathy in congenital 673 complete lipodystrophy. Clinical genetics 2002; 61:283-287 674 30. Caux F, Dubosclard E, Lascols O, Buendia B, Chazouilleres O, Cohen A, Courvalin JC, Laroche L, 675 Capeau J, Vigouroux C, Christin-Maitre S. A new clinical condition linked to a novel mutation in 676 lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated

677 leukomelanodermic papules, liver steatosis, and cardiomyopathy. J Clin Endocrinol Metab 2003; 678 88:1006-1013 679 31. Khalife WI, Mourtada MC, Khalil J. Dilated cardiomyopathy and myocardial infarction secondary 680 to congenital generalized lipodystrophy. Texas Heart Institute journal / from the Texas Heart 681 Institute of St Luke's Episcopal Hospital, Texas Children's Hospital 2008; 35:196-199 682 32. Rheuban KS, Blizzard RM, Parker MA, Carter T, Wilson T, Gutgesell HP. Hypertrophic 683 cardiomyopathy in total lipodystrophy. The Journal of pediatrics 1986; 109:301-302 684 33. Andre P, Schneebeli S, Vigouroux C, Lascols O, Schaaf M, Chevalier P. Metabolic and cardiac 685 phenotype characterization in 37 atypical Dunnigan patients with nonfarnesylated mutated 686 prelamin A. American heart journal 2015; 169:587-593 687 34. Javor ED, Moran SA, Young JR, Cochran EK, DePaoli AM, Oral EA, Turman MA, Blackett PR, 688 Savage DB, O'Rahilly S, Balow JE, Gorden P. Proteinuric nephropathy in acquired and congenital 689 generalized lipodystrophy: baseline characteristics and course during recombinant leptin 690 therapy. J Clin Endocrinol Metab 2004; 89:3199-3207 691 35. Brown RJ, Chan JL, Jaffe ES, Cochran E, DePaoli AM, Gautier JF, Goujard C, Vigouroux C, Gorden 692 P. Lymphoma in acquired generalized lipodystrophy. Leuk Lymphoma 2015:1-6 693 36. Patni N, Alves C, von Schnurbein J, Wabitsch M, Tannin G, Rakheja D, Garg A. A novel syndrome 694 of generalized lipodystrophy associated with pilocytic astrocytoma. J Clin Endocrinol Metab 695 2015:jc20152476 696 37. Robbins DC, Danforth E, Jr., Horton ES, Burse RL, Goldman RF, Sims EA. The effect of diet on 697 thermogenesis in acquired lipodystrophy. Metabolism 1979; 28:908-916 698 38. Glueck CJ, Mellies MJ, Tsang RC, Kashyap ML, Steiner PM. Familial hypertriglyceridemia in 699 children: dietary management. Pediatric research 1977; 11:953-957 700 39. Wilson DE, Chan IF, Stevenson KB, Horton SC, Schipke C. Eucaloric substitution of medium chain 701 triglycerides for dietary long chain fatty acids in acquired total lipodystrophy: effects on 702 hyperlipoproteinemia and endogenous insulin resistance. J Clin Endocrinol Metab 1983; 57:517- 703 523 704 40. Meehan CA, Cochran E, Kassai A, Brown RJ, Gorden P. Metreleptin for injection to treat the 705 complications of leptin deficiency in patients with congenital or acquired generalized 706 lipodystrophy. Expert review of clinical pharmacology 2016; 9:59-68 707 41. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman 708 ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med 709 2002; 346:570-578 710 42. Ebihara K, Kusakabe T, Hirata M, Masuzaki H, Miyanaga F, Kobayashi N, Tanaka T, Chusho H, 711 Miyazawa T, Hayashi T, Hosoda K, Ogawa Y, DePaoli AM, Fukushima M, Nakao K. Efficacy and 712 safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with 713 generalized lipodystrophy. J Clin Endocrinol Metab 2007; 92:532-541 714 43. Moran SA, Patten N, Young JR, Cochran E, Sebring N, Reynolds J, Premkumar A, Depaoli AM, 715 Skarulis MC, Oral EA, Gorden P. Changes in body composition in patients with severe 716 lipodystrophy after leptin replacement therapy. Metabolism 2004; 53:513-519 717 44. McDuffie JR, Riggs PA, Calis KA, Freedman RJ, Oral EA, DePaoli AM, Yanovski JA. Effects of 718 exogenous leptin on satiety and satiation in patients with lipodystrophy and leptin insufficiency. 719 J Clin Endocrinol Metab 2004; 89:4258-4263 720 45. Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P. The long-term effect of 721 recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in 722 female and pituitary function in male and female hypoleptinemic lipodystrophic patients. 723 Metabolism 2005; 54:255-263

724 46. Diker-Cohen T, Cochran E, Gorden P, Brown RJ. Partial and generalized lipodystrophy: 725 comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol Metab 726 2015; 100:1802-1810 727 47. Chan JL, Lutz K, Cochran E, Huang W, Peters Y, Weyer C, Gorden P. Clinical effects of long-term 728 metreleptin treatment in patients with lipodystrophy. Endocr Pract 2011; 17:922-932 729 48. Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of 730 human lipodystrophy. Diabetologia 2010; 53:27-35 731 49. Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM, Premkumar A, Kleiner DE, Gorden P. 732 Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 733 2005; 41:753-760 734 50. Simha V, Szczepaniak LS, Wagner AJ, DePaoli AM, Garg A. Effect of leptin replacement on 735 intrahepatic and intramyocellular lipid content in patients with generalized lipodystrophy. 736 Diabetes Care 2003; 26:30-35 737 51. Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, 738 Gorden P, Shulman GI. Leptin reverses insulin resistance and hepatic steatosis in patients with 739 severe lipodystrophy. J Clin Invest 2002; 109:1345-1350 740 52. Casey SP, Lokan J, Testro A, Farquharson S, Connelly A, Proietto J, Angus PW. Post-liver 741 transplant leptin results in resolution of severe recurrence of lipodystrophy-associated 742 nonalcoholic steatohepatitis. American journal of transplantation : official journal of the 743 American Society of Transplantation and the American Society of Transplant Surgeons 2013; 744 13:3031-3034 745 53. Oral EA, Ruiz E, Andewelt A, Sebring N, Wagner AJ, Depaoli AM, Gorden P. Effect of leptin 746 replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin 747 Endocrinol Metab 2002; 87:3110-3117 748 54. Abel BS, Muniyappa R, Stratton P, Skarulis MC, Gorden P, Brown RJ. Effects of Recombinant 749 Human Leptin (Metreleptin) on Nocturnal LH Secretion in Lipodystrophy Patients. 750 Neuroendocrinology 2015; 751 55. Lungu AO, Zadeh ES, Goodling A, Cochran E, Gorden P. Insulin resistance is a sufficient basis for 752 hyperandrogenism in lipodystrophic women with polycystic ovarian syndrome. J Clin Endocrinol 753 Metab 2012; 97:563-567 754 56. Vatier C, Fetita S, Boudou P, Tchankou C, Deville L, Riveline J, Young J, Mathivon L, Travert F, 755 Morin D, Cahen J, Lascols O, Andreelli F, Reznik Y, Mongeois E, Madelaine I, Vantyghem M, 756 Gautier J, Vigouroux C. One-year metreleptin treatment improves insulin secretion in patients 757 with diabetes linked to genetic lipodystrophic syndromes. Diabetes, obesity & metabolism 2015; 758 57. Simha V, Subramanyam L, Szczepaniak L, Quittner C, Adams-Huet B, Snell P, Garg A. Comparison 759 of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic 760 patients with familial partial lipodystrophy of the Dunnigan variety. J Clin Endocrinol Metab 761 2012; 97:785-792 762 58. Beltrand J, Lahlou N, Le Charpentier T, Sebag G, Leka S, Polak M, Tubiana-Rufi N, Lacombe D, de 763 Kerdanet M, Huet F, Robert JJ, Chevenne D, Gressens P, Levy-Marchal C. Resistance to leptin- 764 replacement therapy in Berardinelli-Seip congenital lipodystrophy: an immunological origin. Eur 765 J Endocrinol 2010; 162:1083-1091 766 59. Chan JL, Koda J, Heilig JS, Cochran EK, Gorden P, Oral EA, Brown RJ. Immunogenicity associated 767 with metreleptin treatment in patients with obesity or lipodystrophy. Clin Endocrinol (Oxf) 2015; 768 60. Arioglu E, Duncan-Morin J, Sebring N, Rother KI, Gottlieb N, Lieberman J, Herion D, Kleiner DE, 769 Reynolds J, Premkumar A, Sumner AE, Hoofnagle J, Reitman ML, Taylor SI. Efficacy and safety of 770 troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med 2000; 133:263-274

771 61. Luedtke A, Boschmann M, Colpe C, Engeli S, Adams F, Birkenfeld AL, Haufe S, Rahn G, Luft FC, 772 Schmidt HH, Jordan J. Thiazolidinedione response in familial lipodystrophy patients with LMNA 773 mutations: a case series. Hormone and metabolic research = Hormon- und 774 Stoffwechselforschung = Hormones et metabolisme 2012; 44:306-311 775 62. Lane WS, Cochran EK, Jackson JA, Scism-Bacon JL, Corey IB, Hirsch IB, Skyler JS. High-dose insulin 776 therapy: is it time for U-500 insulin? Endocrine practice : official journal of the American College 777 of Endocrinology and the American Association of Clinical Endocrinologists 2009; 15:71-79 778 63. Karges B, Boehm BO, Karges W. Early hypoglycaemia after accidental intramuscular injection of 779 insulin glargine. Diabet Med 2005; 22:1444-1445 780 64. Bolli GB, Owens DR. Insulin glargine. Lancet 2000; 356:443-445 781 65. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, 782 Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC, Jr., Watson K, 783 Wilson PW, American College of Cardiology/American Heart Association Task Force on Practice 784 G. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic 785 cardiovascular risk in adults: a report of the American College of Cardiology/American Heart 786 Association Task Force on Practice Guidelines. Journal of the American College of Cardiology 787 2014; 63:2889-2934 788 66. Catapano AL, Chapman J, Wiklund O, Taskinen MR. The new joint EAS/ESC guidelines for the 789 management of dyslipidaemias. Atherosclerosis 2011; 217:1 790 67. Bolan C, Oral EA, Gorden P, Taylor S, Leitman SF. Intensive, long-term plasma exchange therapy 791 for severe hypertriglyceridemia in acquired generalized lipoatrophy. J Clin Endocrinol Metab 792 2002; 87:380-384 793 68. Settergren J, Eiermann B, Mannheimer B. Adherence to drug label recommendations for 794 avoiding drug interactions causing statin-induced myopathy--a nationwide register study. PloS 795 one 2013; 8:e69545 796 69. King P, Peacock I, Donnelly R. The UK prospective diabetes study (UKPDS): clinical and 797 therapeutic implications for type 2 diabetes. British journal of clinical pharmacology 1999; 798 48:643-648 799 70. Ahmad Z, Subramanyam L, Szczepaniak L, Simha V, Adams-Huet B, Garg A. Cholic acid for 800 hepatic steatosis in patients with lipodystrophy: a randomized, controlled trial. Eur J Endocrinol 801 2013; 168:771-778 802 71. Mitchel EB, Lavine JE. Review article: the management of paediatric nonalcoholic fatty liver 803 disease. Alimentary pharmacology & therapeutics 2014; 40:1155-1170 804 72. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, 805 Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck 806 PR, Nash CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 807 2010; 362:1675-1685 808 73. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, 809 Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Unalp A, Clark JM, Brunt EM, Kleiner DE, 810 Hoofnagle JH, Robuck PR, Nonalcoholic Steatohepatitis Clinical Research N. Effect of vitamin E or 811 metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the 812 TONIC randomized controlled trial. Jama 2011; 305:1659-1668 813 74. Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver 814 histology and fibrosis in patients with non-alcoholic steatohepatitis. Alimentary pharmacology & 815 therapeutics 2012; 35:66-75 816 75. Graivier MH, Bass LS, Busso M, Jasin ME, Narins RS, Tzikas TL. Calcium hydroxylapatite 817 (Radiesse) for correction of the mid- and lower face: consensus recommendations. Plastic and 818 reconstructive surgery 2007; 120:55S-66S

819 76. Hurwitz PJ, Sarel R. Facial reconstruction in partial lipodystrophy. Ann Plast Surg 1982; 8:253- 820 257 821 77. Calderoni DR, Ramos TM, de Castro JR, Kharmandayan P. Surgical management of phenotypic 822 alterations related to the Dunnigan variety of familial partial lipodystrophy. Journal of plastic, 823 reconstructive & aesthetic surgery : JPRAS 2011; 64:1248-1250 824 78. Hughes JM, Stephen C, Johnson AB, Wilson S. Breast augmentation in Familial Partial 825 Lipodystrophy: a case report. Journal of plastic, reconstructive & aesthetic surgery : JPRAS 2011; 826 64:e121-124 827 79. Araujo-Vilar D, Sanchez-Iglesias S, Guillin-Amarelle C, Castro A, Lage M, Pazos M, Rial JM, Blasco 828 J, Guillen-Navarro E, Domingo-Jimenez R, del Campo MR, Gonzalez-Mendez B, Casanueva FF. 829 Recombinant human leptin treatment in genetic lipodystrophic syndromes: the long-term 830 Spanish experience. Endocrine 2015; 49:139-147 831 80. Eberting CL, Javor E, Gorden P, Turner ML, Cowen EW. Insulin resistance, acanthosis nigricans, 832 and hypertriglyceridemia. J Am Acad Dermatol 2005; 52:341-344 833 81. Loriaux DL. An approach to the patient with hirsutism. J Clin Endocrinol Metab 2012; 97:2957- 834 2968 835 82. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal 836 estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J 837 Med 1991; 325:1196-1204 838 83. Adami S, Rossini M, Zamberlan N, Bertoldo F, Dorizzi R, Lo Cascio V. Long-term effects of 839 transdermal and oral estrogens on serum lipids and lipoproteins in postmenopausal women. 840 Maturitas 1993; 17:191-196 841 84. Agarwal AK, Arioglu E, De Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI, Garg A. 842 AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat 843 Genet 2002; 31:21-23 844 85. Magre J, Delepine M, Khallouf E, Gedde-Dahl T, Jr., Van Maldergem L, Sobel E, Papp J, Meier M, 845 Megarbane A, Bachy A, Verloes A, d'Abronzo FH, Seemanova E, Assan R, Baudic N, Bourut C, 846 Czernichow P, Huet F, Grigorescu F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret H, 847 Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M, Robert JJ, Tric P, Tubiana-Rufi N, Vigouroux 848 C, Weissenbach J, Savasta S, Maassen JA, Trygstad O, Bogalho P, Freitas P, Medina JL, Bonnicci F, 849 Joffe BI, Loyson G, Panz VR, Raal FJ, O'Rahilly S, Stephenson T, Kahn CR, Lathrop M, Capeau J, 850 Group BW. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on 851 chromosome 11q13. Nat Genet 2001; 28:365-370 852 86. Kim CA, Delepine M, Boutet E, El Mourabit H, Le Lay S, Meier M, Nemani M, Bridel E, Leite CC, 853 Bertola DR, Semple RK, O'Rahilly S, Dugail I, Capeau J, Lathrop M, Magre J. Association of a 854 homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J 855 Clin Endocrinol Metab 2008; 93:1129-1134 856 87. Dyment DA, Gibson WT, Huang L, Bassyouni H, Hegele RA, Innes AM. Biallelic mutations at 857 PPARG cause a congenital, generalized lipodystrophy similar to the Berardinelli-Seip syndrome. 858 European journal of medical genetics 2014; 57:524-526 859 88. Herbst KL, Tannock LR, Deeb SS, Purnell JQ, Brunzell JD, Chait A. Kobberling type of familial 860 partial lipodystrophy: an underrecognized syndrome. Diabetes Care 2003; 26:1819-1824 861 89. Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type 862 familial partial lipodystrophy. Hum Mol Genet 2000; 9:109-112 863 90. Shackleton S, Lloyd DJ, Jackson SN, Evans R, Niermeijer MF, Singh BM, Schmidt H, Brabant G, 864 Kumar S, Durrington PN, Gregory S, O'Rahilly S, Trembath RC. LMNA, encoding lamin A/C, is 865 mutated in partial lipodystrophy. Nat Genet 2000; 24:153-156

866 91. Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, 867 Lewis H, Schafer AJ, Chatterjee VK, O'Rahilly S. Dominant negative mutations in human 868 PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. 869 Nature 1999; 402:880-883 870 92. Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Charpentier G, Auclair M, 871 Delepine M, Barroso I, Semple RK, Lathrop M, Lascols O, Capeau J, O'Rahilly S, Magre J, Savage 872 DB, Vigouroux C. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J 873 Med 2011; 364:740-748 874 93. Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, Hyden CS, Bottomley W, 875 Vigouroux C, Magre J, Raymond-Barker P, Murgatroyd PR, Chawla A, Skepper JN, Chatterjee VK, 876 Suliman S, Patch AM, Agarwal AK, Garg A, Barroso I, Cinti S, Czech MP, Argente J, O'Rahilly S, 877 Savage DB, Consortium LDS. Partial lipodystrophy and insulin resistant diabetes in a patient with 878 a homozygous nonsense mutation in CIDEC. EMBO Mol Med 2009; 1:280-287 879 94. Albert JS, Yerges-Armstrong LM, Horenstein RB, Pollin TI, Sreenivasan UT, Chai S, Blaner WS, 880 Snitker S, O'Connell JR, Gong DW, Breyer RJ, 3rd, Ryan AS, McLenithan JC, Shuldiner AR, Sztalryd 881 C, Damcott CM. Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes. N 882 Engl J Med 2014; 370:2307-2315 883 95. Farhan SM, Robinson JF, McIntyre AD, Marrosu MG, Ticca AF, Loddo S, Carboni N, Brancati F, 884 Hegele RA. A novel LIPE nonsense mutation found using exome sequencing in siblings with late- 885 onset familial partial lipodystrophy. Can J Cardiol 2014; 30:1649-1654 886 96. George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, 887 Williams RM, Acerini CL, Dunger DB, Barford D, Umpleby AM, Wareham NJ, Davies HA, Schafer 888 AJ, Stoffel M, O'Rahilly S, Barroso I. A family with severe insulin resistance and diabetes due to a 889 mutation in AKT2. Science 2004; 304:1325-1328 890 97. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses 891 TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Recurrent 892 de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 2003; 893 423:293-298 894 98. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, 895 Munnich A, Le Merrer M, Levy N. Lamin a truncation in Hutchinson-Gilford progeria. Science 896 2003; 300:2055 897 99. Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, Botha EG, Garg A, Hanson 898 NB, Martin GM, Mian IS, Kennedy BK, Oshima J. LMNA mutations in atypical Werner's syndrome. 899 Lancet 2003; 362:440-445 900 100. Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D'Apice MR, Massart C, Capon F, Sbraccia P, 901 Federici M, Lauro R, Tudisco C, Pallotta R, Scarano G, Dallapiccola B, Merlini L, Bonne G. 902 Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum 903 Genet 2002; 71:426-431 904 101. Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase, ZMPSTE24, is mutated in 905 mandibuloacral dysplasia. Hum Mol Genet 2003; 12:1995-2001 906 102. Weedon MN, Ellard S, Prindle MJ, Caswell R, Lango Allen H, Oram R, Godbole K, Yajnik CS, 907 Sbraccia P, Novelli G, Turnpenny P, McCann E, Goh KJ, Wang Y, Fulford J, McCulloch LJ, Savage 908 DB, O'Rahilly S, Kos K, Loeb LA, Semple RK, Hattersley AT. An in-frame deletion at the 909 polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet 910 2013; 45:947-950 911 103. Donadille B, D'Anella P, Auclair M, Uhrhammer N, Sorel M, Grigorescu R, Ouzounian S, 912 Cambonie G, Boulot P, Laforet P, Carbonne B, Christin-Maitre S, Bignon YJ, Vigouroux C. Partial

913 lipodystrophy with severe insulin resistance and adult progeria Werner syndrome. Orphanet 914 journal of rare diseases 2013; 8:106 915 104. Cabanillas R, Cadinanos J, Villameytide JA, Perez M, Longo J, Richard JM, Alvarez R, Duran NS, 916 Illan R, Gonzalez DJ, Lopez-Otin C. Nestor-Guillermo progeria syndrome: a novel premature 917 aging condition with early onset and chronic development caused by BANF1 mutations. 918 American journal of medical genetics Part A 2011; 155A:2617-2625 919 105. Graul-Neumann LM, Kienitz T, Robinson PN, Baasanjav S, Karow B, Gillessen-Kaesbach G, 920 Fahsold R, Schmidt H, Hoffmann K, Passarge E. Marfan syndrome with neonatal progeroid 921 syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of 922 the FBN1-gene. Am J Med Genet A 2010; 152A:2749-2755 923 106. Masotti A, Uva P, Davis-Keppen L, Basel-Vanagaite L, Cohen L, Pisaneschi E, Celluzzi A, 924 Bencivenga P, Fang M, Tian M, Xu X, Cappa M, Dallapiccola B. Keppen-Lubinsky syndrome is 925 caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6. American journal 926 of human genetics 2015; 96:295-300 927 107. Lessel D, Vaz B, Halder S, Lockhart PJ, Marinovic-Terzic I, Lopez-Mosqueda J, Philipp M, Sim JC, 928 Smith KR, Oehler J, Cabrera E, Freire R, Pope K, Nahid A, Norris F, Leventer RJ, Delatycki MB, 929 Barbi G, von Ameln S, Hogel J, Degoricija M, Fertig R, Burkhalter MD, Hofmann K, Thiele H, 930 Altmuller J, Nurnberg G, Nurnberg P, Bahlo M, Martin GM, Aalfs CM, Oshima J, Terzic J, Amor DJ, 931 Dikic I, Ramadan K, Kubisch C. Mutations in SPRTN cause early onset hepatocellular carcinoma, 932 genomic instability and progeroid features. Nat Genet 2014; 46:1239-1244 933 108. Garg A, Kircher M, Del Campo M, Amato RS, Agarwal AK, University of Washington Center for 934 Mendelian G. Whole exome sequencing identifies de novo heterozygous CAV1 mutations 935 associated with a novel neonatal onset lipodystrophy syndrome. Am J Med Genet A 2015; 936 167:1796-1806 937 109. Agarwal AK, Xing C, DeMartino GN, Mizrachi D, Hernandez MD, Sousa AB, Martinez de Villarreal 938 L, dos Santos HG, Garg A. PSMB8 encoding the beta5i proteasome subunit is mutated in joint 939 contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy 940 syndrome. Am J Hum Genet 2010; 87:866-872 941 110. Thauvin-Robinet C, Auclair M, Duplomb L, Caron-Debarle M, Avila M, St-Onge J, Le Merrer M, Le 942 Luyer B, Heron D, Mathieu-Dramard M, Bitoun P, Petit JM, Odent S, Amiel J, Picot D, Carmignac 943 V, Thevenon J, Callier P, Laville M, Reznik Y, Fagour C, Nunes ML, Capeau J, Lascols O, Huet F, 944 Faivre L, Vigouroux C, Riviere JB. PIK3R1 mutations cause syndromic insulin resistance with 945 lipoatrophy. Am J Hum Genet 2013; 93:141-149 946 111. Payne F, Lim K, Girousse A, Brown RJ, Kory N, Robbins A, Xue Y, Sleigh A, Cochran E, Adams C, 947 Dev Borman A, Russel-Jones D, Gorden P, Semple RK, Saudek V, O'Rahilly S, Walther TC, Barroso 948 I, Savage DB. Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with 949 congenital lipodystrophy and fatty liver disease. Proc Natl Acad Sci U S A 2014; 111:8901-8906 950 112. Aotani D, Ebihara K, Sawamoto N, Kusakabe T, Aizawa-Abe M, Kataoka S, Sakai T, Iogawa H, 951 Ebihara C, Fujikura J, Hosoda K, Fukuyama H, Nakao K. Functional magnetic resonance imaging 952 analysis of food-related brain activity in patients with lipodystrophy undergoing leptin 953 replacement therapy. J Clin Endocrinol Metab 2012; 97:3663-3671 954 113. Panchal R, Bosio P, Waugh J. Familial partial lipodystrophy complicated by pre-eclampsia. J 955 Obstet Gynaecol 2005; 25:196-197 956 114. Ludtke A, Genschel J, Brabant G, Bauditz J, Taupitz M, Koch M, Wermke W, Worman HJ, Schmidt 957 HH. Hepatic steatosis in Dunnigan-type familial partial lipodystrophy. Am J Gastroenterol 2005; 958 100:2218-2224

959 115. Peters DK, Charlesworth JA, Sissons JG, Williams DG, Boulton-Jones JM, Evans DJ, Kourilsky O, 960 Morel-Maroger L. Mesangiocapillary nephritis, partial lipodystrophy, and 961 hypocomplementaemia. Lancet 1973; 2:535-538 962 116. Aslam A, Savage DB, Coulson IH. Acquired generalized lipodystrophy associated with peripheral 963 T cell lymphoma with cutaneous infiltration. Int J Dermatol 2013; 964 117. Yiannias JA, DiCaudo DJ, Maskin E. Peripheral T-cell lymphoma presenting as lipoatrophy and 965 nodules. Int J Dermatol 2006; 45:1415-1419 966 118. Hegele RA, Al-Attar SA, Rutt BK. Obstructive sleep apnea in 2 women with familial partial 967 lipodystrophy due to a heterozygous LMNA R482Q mutation. CMAJ 2007; 177:743-745 968 119. Patel K, Roseman D, Burbank H, Attarian H. Obstructive sleep apnea in familial partial 969 lipodystrophy type 2 with atypical skin findings and vascular disease. Sleep Breath 2009; 13:425- 970 427 971 120. Christensen JD, Lungu AO, Cochran E, Collins MT, Gafni RI, Rother KI, Gorden P, Brown RJ. Bone 972 Mineral Content in Patients With Congenital Generalized Lipodystrophy Is Unaffected by 973 Metreleptin Replacement Therapy. J Clin Endocrinol Metab 2014:jc20141353

975 Supplemental Tables

976 Supplemental Table 1: Evidence rating system

Classification 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 harmful Level 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 977