c.ymcdn.com web viewword count: 3594. tables: 4. figures: 2. references: 120. ... thyrotoxicosis,...

Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016

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

Endorsing Societies (tentative):

1. Pediatric Endocrine Society

2. American Diabetes Association

3. American Association of Clinical Endocrinologists

4. Endocrine Society

5. Japanese Society for Pediatric Endocrinology

6. Australasian Paediatric Endocrine Group

7. European Society for Paediatric Endocrinology

8. Asia Pacific Paediatric Endocrine Society

9. African Society for Paediatric and Adolescent Endocrinology

Author names and institutions:

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

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

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

Yorifuji18

1 Committee Chair; all other authors appear in alphabetical order

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

Bethesda, MD, USA

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

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

1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24


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

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

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

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

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

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

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

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

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

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

Dallas, Texas, USA

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

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

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

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

Harvard Medical School, Boston, MA, USA

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

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

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

16 Institute of Cardiometabolism and Nutrition, Paris, France

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

Cambridge, United Kingdom

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

Hospital, Japan

2

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49


Abbreviated title: Diagnosis and Management of Lipodystrophy

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

Word count: 3594

Tables: 4

Figures: 2

References: 120

Supplemental Tables: 3

Corresponding Author and Reprint Requests:

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

Phone: 301-594-0609

Fax: 301-480-3675

Email: [email protected]

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

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

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

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

3

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

mailto:[email protected]


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

Foundation.

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

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

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

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

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

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

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

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

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

4

74

75

76

77

78

79

80

81

82

83

84

85


Abstract

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

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

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

guideline summarizes diagnosis and management of lipodystrophy syndromes.

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

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

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

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

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

data were not available or scarce.

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

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

and provided approval.

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

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

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

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

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

5

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109


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

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

6

110

111

112


INTRODUCTION

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 (Figure 1).

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

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

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

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

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

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

Lipodystrophy syndromes are frequently associated with hormonal and metabolic derangements resulting

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

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

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

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

(NAFLD) (1).

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

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

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

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

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

7

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136


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

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

Overview of lipodystrophy syndromes:

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

subtypes is in Table 3.

Congenital Generalized Lipodystrophy (CGL, Berardinelli-Seip Syndrome)

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

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

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

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

Cardiomyopathy or rhythm disturbances may occur.

Familial Partial Lipodystrophy (FPLD)

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

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

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

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

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

Acquired Generalized Lipodystrophy (AGL, Lawrence syndrome):

AGL is more common in females (F:M; 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 (4).

8

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160


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 (4,16).

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

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

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

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

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

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

are uncommon (17).

DIAGNOSIS OF LIPODYSTROPHY

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

metabolic status. (Class I, Level B)

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

lipodystrophy. (Class IIa, Level C)

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

A)

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

Serum complement levels and autoantibodies may support diagnosis of acquired

lipodystrophy syndromes. (Class IIa, Level B)

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

diagnostic approach.

9

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185


Establishing the presence of lipodystrophy

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

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

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

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

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

4.

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

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

help with choice of therapies.

Differential Diagnosis:

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

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

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

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

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

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

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

multiple symmetric lipomatosis.

10

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210


Establishing the subtype of lipodystrophy

Pattern of fat loss:

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

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

family.

Distinguishing genetic from acquired lipodystrophy:

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

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

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

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

especially those with de novo mutation.

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

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

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

Genetic testing:

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

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

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

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

Genetic counseling and screening of family members:

11

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

http://www.genetests.org/


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

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

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

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

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

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

specific LMNA mutations associated with cardiomyopathy and arrhythmia.

SCREENING FOR COMORBIDITIES

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

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

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

subtypes is not extensively discussed here.

Diabetes mellitus

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

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

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

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

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

Dyslipidemia

12

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259


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

or xanthomata. (Class I, Level C)

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

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

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

Liver disease

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

measured annually. (Class IIa, Level C)

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

Level C)

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

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

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

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

(19).

Reproductive dysfunction

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

clinically indicated. (Class IIa, Level C)

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

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

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

Cardiac disease

13

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284


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

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

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

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

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

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

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

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

Kidney disease

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

to creatinine ratio. (Class IIa, Level C)

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

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

(especially in APL) (17).

Malignancy

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

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

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

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

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

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

malignancy risk (Table 3).

14

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309


TREATMENT OF LIPODYSTROPHY SYNDROMES

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

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

Diet

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

C)

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

(Class I, Level C)

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

Level C)

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

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

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

in infants. (Class IIa, Level C)

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

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

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

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

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

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

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

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

15

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333


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

lipodystrophy should not be labeled as having malnutrition.

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

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

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

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

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

(<20 grams) diet should be used.

Exercise

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

contraindications. (Class IIa, Level C)

Patients with subtypes of lipodystrophy predisposed to cardiomyopathy should undergo

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

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

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

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

hepatosplenomegaly and CGL patients with lytic lesions in long bones.

Metreleptin

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 young children. (Class IIb, Level C)

16

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357


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

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

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

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

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

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

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

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

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

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

performed every 3-6 months.

Metreleptin in Generalized Lipodystrophy

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

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

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

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

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

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

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

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

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

17

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382


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

reduced metreleptin (47).

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

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

transplantation (52).

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

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

disease (34).

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

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

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

testosterone (45).

Metreleptin in Partial Lipodystrophy

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) (46). In a second study, metreleptin improved triglycerides

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

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

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

trials, compassionate use programs, and in Japan.

18

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407


Side effects of metreleptin

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

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

(erythema, urticaria).

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

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

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

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

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

Additional treatments for specific comorbidities

Diabetes

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

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

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

Thiazolidinediones may improve metabolic complications in patients with partial

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

Level B)

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

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

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

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

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

19

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432


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

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

lipodystrophy, but their efficacy has not been studied.

Dyslipidemia

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

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

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

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

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

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

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

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

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

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

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

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

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

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

myositis or muscular dystrophy (68).

Hypertension

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

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

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

20

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457


Liver disease

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

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

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

pioglitazone (in adults) (72,74) 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.

Cosmetic treatment

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)

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

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

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

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

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

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

elsewhere (81).

Contraception and hormone replacement therapy

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

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

considered. (Class IIa, Level C)

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

21

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482


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

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

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

Pregnancy

Pregnant patients should receive prenatal care from an obstetrician experienced in

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

C)

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

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

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

(Class IIc, level C)

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

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

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

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

Conclusions

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

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

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

multiple organs, and quality of life.

Acknowledgments

22

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506


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

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

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

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

23

507

508

509

510


Table 1: Subtypes and inheritance of lipodystrophy

Subtype of lipodystrophyPathogenesis: gene involved, altered

protein and functionInheritance

Refer-

ence

Generalized lipodystrophies

CGL1AGPAT2 : AGPAT2, synthesis of

triglycerides and glycerophospholipidsAR (84)

CGL2 BSCL2 : seipin, formation of lipid droplets AR (85)

CGL3CAV1:caveolin-1, formation of membrane

caveolae, lipid traffic

AR (single

case) (86)

CGL4PTRF : cavin-1, formation of membrane

caveolae, lipid trafficAR (11)

PPARG associatedPPARG: PPAR, transcription factor,

adipocyte differentiation

AR (single

case)(87)

AGL (Lawrence syndrome)Frequently associated with autoimmune

diseases and/or complement abnormalities- (4) (16)

Partial lipodystrophies

FPLD1 genetic cause unknown Usually AD (88)

FPLD2LMNA : lamin A/C, structure and functions

of nuclear laminaAD

(89)

(90)

FPLD3PPARG: PPAR, transcription factor,

adipocyte differentiationAD (91)

FPLD4PLIN1: perilipin-1, structure and function of

adipocyte lipid dropletAD (92)

FPLD5 CIDEC : CIDEC, structure and function of AR (single (93)

24

511


adipocyte lipid droplet case)

FPLD6LIPE : hormone sensitive lipase, regulation

of lipolysisAR

(94)

(95)

Akt2-linked lipodystrophy AKT2: Akt2, insulin signalingAD (single

family)(96)

APL (Barraquer-Simons

syndrome)

Frequently associated with autoimmune

diseases, complement 3 nephritic factor

and/or complement 3 abnormalities

- (17)

Progeroid and/or multisystem lipodystrophy syndromes

Hutchinson-Gilford

progeria syndrome (HGPS)

LMNA : lamin A/C, structure and functions

of nuclear laminade novo

(97)

(98)

Progeroid laminopathiesLMNA : lamin A/C, structure and functions

of nuclear laminaAD, de novo (99)

Mandibulo-acral dysplasia

type A (with partial

lipodystrophy)

LMNA : lamin A/C, structure and functions

of nuclear laminaAR (100)

Mandibulo-acral dysplasia

type B (with generalized

lipodystrophy)

ZMPSTE24: Zinc metalloproteinase,

prelamin A processingAR (101)

MDP syndromePOLD1: subunit of DNA polymerase ,

DNA polymerization and repairde novo (102)

Werner syndrome WRN: WRN DNA helicase, DNA repair AR (103)

Nestor-Guillermo progeria

Syndrome

BANF1: Barrier to autointegration factor

(BAF), required for the assembly of emerin

and A-type lamins at the reforming nuclear

AR (104)

25


envelope

Neonatal Marfan progeroid

syndromeFBN1: fibrillin 1, connective tissue de novo (105)

Keppen-Lubinsky

Syndrome

KCNJ6 (GIRK2): inwardly rectifying

potassium channelde novo (106)

Ruijs-Aalfs syndrome SPRTN: SprT-like N-terminal domain

protein, DNA repair AR(107)

Neonatal progeroid

syndrome

CAV1: Caveolin-1, formation of membrane

caveolae, lipid traffic de novo (108)

Auto-inflammatory syndromes with lipodystrophy

Auto-inflammatory

lipodystrophy (JMP,

CANDLE)

PSMB8: Proteasome (prosome, macropain)

subunit, beta type, 8; (PSMB8);

immunoproteasome subunit

AR (109)

Other syndromes with lipodystrophy

SHORTPIK3R1: regulatory subunits of the

phosphatidyl inositol-3 kinase of class IA

insulin signaling

AD, de

novo(110)

PCYT1A-linked

lipodystrophy

PCYT1A: phosphate cytidylyltransferase 1

alpha, synthesis of phosphatidylcholineAR (111)

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

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

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

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

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

26

512

513

514

515

516

517


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

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

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

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

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

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

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

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

syndrome RecQ like helicase; ZMPSTE24, Zinc metalloproteinase

27

518

519

520

521

522

523

524

525

526


Table 2: Major comorbidities and complications of lipodystrophy

Complication Affected subtypes Reference

Hyperphagia AGL, CGL,

±FPLD

(4,10,112)

Dyslipidemia (high triglycerides, low HDL-c,

acute pancreatitis, eruptive xanthomas)

AGL, CGL, FPLD (4,5,7,9,13,21,30)

Insulin resistance/diabetes, acanthosis nigricans

(and diabetes complications)

AGL, CGL, FPLD (4,5,7,9,13,17,20,21,67)

Reproductive dysfunction (PCOS,

oligomenorrhea, reduced fertility, hirsutism,

preeclampsia, miscarriage, macrosomia)

AGL, CGL, FPLD,

APL

(4,5,7,10,14,20,55,113)

Non-alcoholic fatty liver disease (ranging from

simple steatosis to cirrhosis)

AGL, CGL, FPLD,

±APL

(4,7,10,17,19,49,51,67,114)

Renal dysfunction (proteinuria, MPGN, FSGS,

diabetic nephropathy)

AGL, CGL, FPLD,

APL

(17,34,115)

Heart disease (hypertension, cardiomyopathy,

arrhythmias, conduction abnormalities, CAD)

AGL, CGL, FPLD (3-5,9,13,15,25)

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,

anxiety)

AGL, CGL, FPLD,

APL

(5)

Obstructive sleep apnea FPLD (118,119)

Early puberty CGL (10)

28

527


Accelerated linear growth & advanced bone age CGL (10,120)

AGL, acquired generalized lipodystrophy; APL, acquired partial lipodystrophy; CAD, coronary artery

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

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

ovary syndrome

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

29

528

529

530

531

532

533

534


Table 3: Phenotypes of Lipodystrophy Syndromes

Congenital Generalized Lipodystrophy

Subtype

(gene)

Gene-

tics

Onset ↓Fat ↑Fat Skin

Appendages

Muscle

Bone

Mineral

Cardio-

vascular

Meta-

bolic

Kidney Ner-

vous

GI

Liver

Spleen

GU

Endocrine

Other

CGL 1

(AGPAT2)AR

Birth

Child-

hood

Almost all

fat lost

Normal

mechanical

↓Marrow

None

AN

Hypertrichosis

Phlebomegaly

Eruptive

xanthomata

Acromegaloid

Muscle hypertrophy

Cystic bone lesions

Hyper-

trophic

cardio-

myopathy

(25%)

HTN

IR/DM

↑TG

↓Leptin

Proteinuria

MR

in-

freq-

uent

Hyperphagia

Acute

pancreatitis

NAFLD

Cirrhosis

Splenomegaly

Precocious

puberty (♀)

Accelerated

growth

↓Fertility (♀)

PCOS

African descent

(58%)

Umbilical

prominence/

hernia

CGL 2

(BSCL2)AR Birth

Almost all

fat lost

↓Mechanical

↓Marrow

None

AN

Hypertrichosis

Phlebomegaly

Eruptive

xanthomata

Acromegaloid

Muscle hypertrophy

Hyper-

trophic

cardio-

myopathy

(33%)

IR/DM

↑TG

↓Leptin

ProteinuriaMR

(75%)

Hyperphagia

Pancreatitis

NAFLD

Cirrhosis

Splenomegaly

Precocious

puberty (♀)

Accelerated

growth

↓Fertility (♀)

PCOS

Umbilical

prominence/

hernia

CGL 3

(CAV1)AR

Child-

hood

Almost all

fat lost

↓Mechanical

Normal

marrow

NoneAN

Hirsutism

Muscle hypertrophy

Hypocalcemia

Vitamin D resistance

Osteopenia

N

IR/DM

↑TG

↓Leptin

N N

Megaesophagus

NAFLD

Splenomegaly

Delayed growth

Short stature

Amenorrhea

Hyper-

androgenism

CGL 4 AR Child- Almost all None Hypertrichosis Percussion-induced Cardiac IR N N Hypertrophic Not reported Failure to thrive

30

535


(PTRF)

hood

fat lost

Normal

mechanical

Marrow fat

unknown

Acromegaloid

muscle mounding

Muscle weakness &

hypertrophy

Spinal rigidity

↑Lordosis

Osteoporosis

Atlanto-axial instability

Arthritis

Contractures

arrhyth-mia

Risk of

sudden

cardiac

death

Mild

↑glucose

↑TG

↓Leptin

pyloric stenosis

Esophageal

dysmotility

Hepato-

splenomegaly

↑ALT/AST

Umbilical

prominence

Transient immuno-

deficiency

Recurrent

infections

CGL

PPARG-

associated

ARChild-

hood

Almost all

fat lostNone

AN

Phlebomegaly

Eruptive

xanthomata

Muscle hypertrophy

IR/DM

↑TG

↓Leptin

N N

Acute

pancreatitis

Hepato-

splenomegaly

Irregular mensesHyper-

parathyroidism

Acquired Generalized Lipodystrophy

Subtype Gene-

tics


Appendages

Muscle

Bone

Mineral

Cardio-

vascular

Meta-

bolic

Kidney Nervous GI

Liver

Spleen

GU

Endocrine

Other

n/a n/a

After birth,

often before

adolescence

Almost all fat

lost

↓Mechanical

Normal marrow

None

AN

Hirsutism

Phlebo-

megaly

Muscular

appearance

Ischemic

cardio-

myopathy

± HTN

IR/ DM

↑ TG

↓ Leptin

N NHepato-

splenomegalyPCOS

3 variants: Panniculitis

Autoimmune (complement

abnormalities)

Idiopathic

31


Familial Partial Lipodystrophy

Subtype Gene-

tics


Appendages

Muscle

Bone

Mineral

Cardio-

vascular

Meta-

bolic

Kidney Nervous GI

Liver

Spleen

GU

Endocrine

Other

FPLD1 U

Child- or

Adult-

hood

Buttocks

Limbs

Face

Neck

Abd

(sc + visc.)

AN

Phlebomegaly

Eruptive

xanthomata

Hirsutism

Calf

hypertrophy

Coronary

artery

disease

HTN

IR/DM

↑TGN N Hepatomegaly N Only ♀

reported

FPLD2

(LMNA)AD Puberty

Buttocks

Limbs

Face

Neck

Abd

(visc.)

AN

Phlebomegaly

Eruptive

xanthomata

Hirsutism

Muscle

hypertrophy

Myalgia

Coronary

artery

disease

HTN

IR/DM

↑TG

Mild

↓Leptin

Proteinuria

in late

stages

Nerve

entrapment

syndromes

Pancreatitis

Hepatomegaly

Hepatic steatosis

PCOS

Labial pseudo-

hypertrophy

Breast

hypoplasia

Preeclampsia

Miscarriages

Lipomas

FPLD3

(PPAR)AD

Adult-

hood

Trunk

Buttocks

Limbs

±Abdomen

AN

Phlebomegaly

Hirsutism

Muscular

appearance HTN

IR/DM

↑TG

Mild

↓Leptin

N NHepatomegaly

Hepatic steatosisPCOS Preeclampsia

FPLD4

(PLIN1)AD

Child- or

adult-

hood

Buttocks

Limbs±Face AN

Muscle

hypertrophy HTN

IR/DM

↑TGN N

Hepatomegaly

Hepatic steatosisPCOS

Cushingoid

appearance

occasional

FPLD5 AR Child- Buttocks None AN Muscle IR/DM Proteinuria N Pancreatitis Irregular Diabetic

32


(CIDEC) hoodLower

limbshypertrophy HTN

↑TG

↓Leptin

Hepatomegaly

Hepatic steatosismenses ketoacidosis

FPLD6

(LIPE)AR

Adult-

hood

Lower

limbs

Neck

Axilla

±Back

Supra-clavicular

Below triceps

NMuscle

weaknessN

IR/DM

↑TGN N Hepatic steatosis N

Mild muscular

dystrophy

High CK

↑adiponectin

Akt2-

linked

lipodys-

trophy

ADAdult-

hood

Lower

limbs

Abd

(visc.)

IR/DM

↑TG

↓Leptin

N N Hepatic steatosis N

Acquired Partial Lipodystrophy

Subtyp

e

Gen

e-

tics


Appendages

Muscle

Bone

Mineral

Cardio-

vascular

Meta-

bolic

Kidney Nervous GI

Liver

Spleen

GU

Endocrine

Other

n/a n/a Child-

hood,

adolesce

nce,

adulthoo

d

Face, trunk,

upper

limbs,

Lower limbs - Muscular

appearance

- Infrequent

IR/ DM

↑ TG

-

Membrano

proliferativ

e

Glomerulon

ephritis

N Hepato-

splenomegaly

PCOS Association

with auto-

immune

diseases

Low C3

complement

levels, presence

of C3NeF (C3

nephritic

33


factor)

Progeroid and Autoinflammatory disorders

Subtype Gen

e-

tics

Onset ↓Fat ↑Fat Skin &

Appendages

Muscle

Bone

Mineral

Cardio-

vascular

Meta-

bolic

Kidney Nervous GI

Liver

Spleen

GU

Endocrine

Other

HGPS

(LMNA)

AD

de

novo

<1

year

Almost all

fat lost

(intra-

abdominal

fat spared)

None

Skin dimpling

& mottling

Sclerotic skin

changes

Prominent

cutaneous

vasculature

Alopecia

Dysplastic

nails

Ogival palate

Abnormal dentition

Stooped shoulders

Acroosteolysis

Coxa valga

Osteoporosis

Subluxed finger

joints

Joint stiffness

↓muscle mass

EKG & Echo

abnormalitie

s

Angina

HTN

Premature

athero-

sclerosis

Mild

IR

Mild

↑glucos

e

↑TG

NTIA

StrokeN

Pubertal delay

Mammary

aplasia

Dysmorphic facies

Aged appearance

Growth failure

Short stature

Nasal voice

Death in 2nd decade

Type A

MAD

(LMNA)

AR Child-

hood

Upper and

Lower

limbs

Face

Neck

Trunk

Pigmentary

skin changes

Alopecia

Soft tissue

calcinosis

Phlebo-

megaly

Mandibular

hypoplasia

Acroosteolysis

Dental crowding

Hypoplastic teeth

Wide cranial

sutures Wormian

Valvular

calcification

Premature

athero-

sclerosis

IR/DM

↑TG

N N N N Dysmorphic facies

Aged appearance

Growth failure

Short stature

34


bones

Joint stiffness

Bulbous fingertips

Type B

MAD

(ZMPSTE24)

AR<1

year

Almost all

fat lostNone

Mottled

pigmentation

Skin atrophy

Alopecia

Mandible &

clavicle hypoplasia

Acroosteolysis

Joint contractures

Delayed closure of

cranial sutures

SC calcifications

NIR/DM

↑TGN N N

Progressive

glomerulopathy

Dysmorphic facies

Néstor-

Guillermo

Progeria

Syndrome

(BANF1)

AR1-2

years

Almost all

fat lostNone

Skin atrophy

Pigmented

skin lesions

Alopecia

Phlebo-

megaly

Severe osteoporosis

Osteolysis

Micrognathia

Scoliosis

Dental crowding

Open cranial

sutures

Stiff joints

Sinus

tachycardia

Right bundle

branch block

Pulmonary

hypertension

N N N N N

Growth failure

Short stature

Atypical

Progeria

(LMNA)

AD

de

novo

Child-

hood

Pub-

erty

Partial or

generalized

fat loss

Normal

mechanical

None Alopecia

Mottled skin

pigment

Sclero-

dermatous

skin changes

Small mandible

Dental crowding

High arched palate

Mild clavicular

resorption

Acroosteolysis

Valvular

calcification

IR/DM

↑TG

N N Hepatom

egaly

Mammary

hypoplasia

Dysmorphic facies

Aged appearance

Short stature

35


fatMild flexion

contractures

Werner

syndrome

(RECQL2)

AR

2nd

decad

e

LimbsAbd-

omen

Sclero-

dermatous

skin changes

Tissue

calcification

and ulceration

Alopecia

Osteoporosis

Athero-

sclerosis

Myocardial

infarction

IR/DM

↑TGN N N

Dysmorphic facies

Growth failure

Short stature

Cataracts

↑Cancer

Bloom

Syndrome

(BLM)

ARChild-

hoodLimbs

Abd-

omen

Telangiec-

tasia

Altered skin

pigment

Photo-

sensitivity

Hyper-

trichosis

Polydactyly DMMild MR in some

patientsReduced fertility

Dysmorphic facies

Growth failure

↑Cancer

PCYT1A

Lipo-

dystrophy

ARChild-

hoodLimbs

Low

HDL-C

IR/DM

↑TG

Liver

steatosis

Growth failure

Short stature

MDPL

(POLD1)

AD

de

novo

Child-

hood

Almost all

fat lost

Visc. Telangiec-

tasia

Hypoplasia of

mandible &

N IR/DM

↑TG

N Sensori-neural

deafness

Hepato-

megaly

Hypogonadism

& cryptorchidism

Dysmorphic facies

Short stature

36


↓ in soles

of feet

Skin atrophy

Scleroderma

Normal hair

metatarsals

Joint contractures

Fused carpal bones

Dental crowding

Osteoporosis

↓muscle mass

(♂)

Hypoplastic

breasts(♀)

Cataracts

High-pitched voice

SHORT

(PIK3R1)AD

Child-

hood

Almost all

fat lost

(most

cases)

NoneThin, wrinkled

skin

Delayed dental

eruption

±Joint laxity

Micrognathia

Heart mal-

formations

IR/DM

Normal

TG

Nephro-

calcinosis

Sensori-neural

hearing loss

Speech delay

N Inguinal hernia

Dysmorphic facies

Aged appearance

IUGR

Short stature

Glaucoma

Rieger anomaly

Cataracts

Marfan

syndrome

with neonatal

progeroid

syndrome-

like lipo-

dystrophy

(FBN1)

AD

de

novo

BirthAlmost all

fat lostNone

Alopecia

Atrophic skin

Arthrogryposis

Arachno-dactyly

Hyperlaxity

Large fontanels

Aortic root

dilatationN N

Relative macro-

cephalyN N

Dysmorphic facies

Aged appearance

Myopia

Cockayne

syndrome

(ERCC6,

AR Birth

Child-

hood

Almost all

fat lost

None Dry skin

Photo-

sensitivity

Prognathism

Long limbs

Early athero-

sclerosis

HTN

N Renal

disease

Microcephaly

Severe MR

Sensorineural

N Irregular menses

Hypogonadism

Dysmorphic facies

FTT

Short stature

37


ERCC8)Skin atrophy

Alopecia

Large hands/feet

Joint contractures

Kyphosis

hearing loss

Seizures

Ataxia

Tremor

Weakness

Dementia

Congenital cataracts

Pigmentary retinopathy

Death before 15y

Neonatal

Progeroid

Syndrome

AR Birth

Face

Distal

extremities

±para-

vertebral

±gluteal

↓ in palms

Butt-

ocks

Ano-

geni-

tal

Alopecia

Thin wrinkled

skin

Hypoplastic

nails

Phlebomegaly

Large fontanels

Thin long bones

with enlarged

metaphyses

Loss of teeth

Joint contractures

↓muscle mass

Prominent

scalp veins ↑TG

Pelvi-

calyceal

ectasia

Macrocephaly

MR

Hypotonia

Truncal ataxia

N↑T4

Irregular menses

Dysmorphic facies

FTT

Short stature

Aged appearance

Ectropion

Death in childhood

Keppen-

Lubinsky

syndrome

(KCNJ6)

AD

de

novo

Child-

hood

Almost all

fat lostNone

Tightly

adherent facial

skin

Joint contractures

Scoliosis

MicrognathiaN N N

Microcephaly

MR

Hypertonia

Hyperreflexia

Spastic

tetraparesis

Seizures

N N

Dysmorphic facies

FTT

Short stature

Aged appearance

Ruijs-Aalfs

syndrome

(SPRTN)

AR Child-

hood

Almost all

fat lost

None Palmar

creases

Premature

graying of

scalp hair

Pectus excavatum

Sloping shoulders

Delayed bone age

Joint contractures

N N N N Hepato-

cellular

carcino

ma

N Dysmorphic facies

FTT

Short stature

Cataracts

38


Kyphoscoliosis

Clinodactyly

Pes planus

↓ muscle mass

Micrognathia

Sensitivity to

genotoxins

Nakajo-

Nishimura,

JMP,

CANDLE

syndromes

(PSMB8)

ARChild-

hood

Face

Hands

Feet

± Chest

None

Erythematous

nodular skin

lesions

Panniculitis

Dry, stiff skin

Joint contractures

Muscle weakness

↓ muscle mass

Hypertrophic

pulmonary osteo-

arthropathy

Long and thick

fingers

Cardiac

insufficiency

Arrhythmias

↑ TG N

MR

± Seizures

Basal ganglia

calcification

Hepato-

spleno-

megaly

Ab-

normal

liver

enzymes

N

Dysmorphic facies

FTT

Short stature

Recurrent fever

Microcytic anemia

↑ ESR

Hypergamma-

globulinemia

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

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

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

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

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

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

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

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

39

536

537

538

539

540

541

542

543

544


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

40

545


Autosomal dominant or recessive pattern of similar physical features or

metabolic complications

Significant hyperphagia (may manifest as irritability/aggression in

infants/children)

1Adapted from (18)

41

546


Figure Legends

Figure 1: 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.IVS4-2A>G mutation in

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

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

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

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

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

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

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

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

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

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

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

extremities.

Figure 2: Diagnostic approach to lipodystrophy 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 subcutaneous fat loss and presence of prominent muscles, phlebomegaly, acanthosis

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

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

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

42

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570


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

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

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

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

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

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

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

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

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

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

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

43

571

572

573

574

575

576

577

578

579

580

581

582


REFERENCES

1. Brown RJ, Gorden P. Leptin Therapy in Patients with Lipodystrophy and Syndromic Insulin Resistance. In: Dagogo-Jack S, ed. Leptin: Regulation and Clinical Applications. Switzerland: Springer International Publishing; 2015.

2. Bjornstad PG, Semb BK, Trygstad O, Seip M. Echocardiographic assessment of cardiac function and morphology in patients with generalised lipodystrophy. European journal of pediatrics 1985; 144:355-359

3. Lupsa BC, Sachdev V, Lungu AO, Rosing DR, Gorden P. Cardiomyopathy in congenital and acquired generalized lipodystrophy: a clinical assessment. Medicine (Baltimore) 2010; 89:245-250

4. Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore) 2003; 82:129-146

5. Jackson SN, Howlett TA, McNally PG, O'Rahilly S, Trembath RC. Dunnigan-Kobberling syndrome: an autosomal dominant form of partial lipodystrophy. QJM : monthly journal of the Association of Physicians 1997; 90:27-36

6. Seip M. Generalized lipodystrophy. In: Frick P vHG, Miller AF, Prader A, Schoen R, Wolf HP (eds), ed. Ergeb Inn Med Kinderheilkd: Springer Berlin; 1971:59-95.

7. Garg A. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab 2011; 96:3313-3325

8. Gibbons RJ, Smith S, Antman E, American College of C, American Heart A. American College of Cardiology/American Heart Association clinical practice guidelines: Part I: where do they come from? Circulation 2003; 107:2979-2986

9. Agarwal AK, Simha V, Oral EA, Moran SA, Gorden P, O'Rahilly S, Zaidi Z, Gurakan F, Arslanian SA, Klar A, Ricker A, White NH, Bindl L, Herbst K, Kennel K, Patel SB, Al-Gazali L, Garg A. Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab 2003; 88:4840-4847

10. Garg A. Acquired and inherited lipodystrophies. N Engl J Med 2004; 350:1220-123411. Hayashi YK, Matsuda C, Ogawa M, Goto K, Tominaga K, Mitsuhashi S, Park YE, Nonaka I, Hino-

Fukuyo N, Haginoya K, Sugano H, Nishino I. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest 2009; 119:2623-2633

12. Simha V, Garg A. Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or seipin genes. J Clin Endocrinol Metab 2003; 88:5433-5437

13. Van Maldergem L, Magre J, Khallouf TE, Gedde-Dahl T, Jr., Delepine M, Trygstad O, Seemanova E, Stephenson T, Albott CS, Bonnici F, Panz VR, Medina JL, Bogalho P, Huet F, Savasta S, Verloes A, Robert JJ, Loret H, De Kerdanet M, Tubiana-Rufi N, Megarbane A, Maassen J, Polak M, Lacombe D, Kahn CR, Silveira EL, D'Abronzo FH, Grigorescu F, Lathrop M, Capeau J, O'Rahilly S. Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. Journal of medical genetics 2002; 39:722-733

14. Vantyghem MC, Vincent-Desplanques D, Defrance-Faivre F, Capeau J, Fermon C, Valat AS, Lascols O, Hecart AC, Pigny P, Delemer B, Vigouroux C, Wemeau JL. Fertility and obstetrical complications in women with LMNA-related familial partial lipodystrophy. J Clin Endocrinol Metab 2008; 93:2223-2229

15. Hegele RA. Premature atherosclerosis associated with monogenic insulin resistance. Circulation 2001; 103:2225-2229

44

583

584585586587588589590591592593594595596597598599600601602603604605606607608609610611612613614615616617618619620621622623624625626627628


16. Savage DB, Semple RK, Clatworthy MR, Lyons PA, Morgan BP, Cochran EK, Gorden P, Raymond-Barker P, Murgatroyd PR, Adams C, Scobie I, Mufti GJ, Alexander GJ, Thiru S, Murano I, Cinti S, Chaudhry AN, Smith KG, O'Rahilly S. Complement abnormalities in acquired lipodystrophy revisited. J Clin Endocrinol Metab 2009; 94:10-16

17. Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore) 2004; 83:18-34

18. Handelsman Y, Oral EA, Bloomgarden ZT, Brown RJ, Chan JL, Einhorn D, Garber AJ, Garg A, Garvey WT, Grunberger G, Henry RR, Lavin N, Tapiador CD, Weyer C. The clinical approach to the detection of lipodystrophy - an aace consensus statement. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 2013; 19:107-116

19. Safar Zadeh E, Lungu AO, Cochran EK, Brown RJ, Ghany MG, Heller T, Kleiner DE, Gorden P. The liver diseases of lipodystrophy: the long-term effect of leptin treatment. J Hepatol 2013; 59:131-137

20. Pope E, Janson A, Khambalia A, Feldman B. Childhood acquired lipodystrophy: a retrospective study. J Am Acad Dermatol 2006; 55:947-950

21. Garg A. Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab 2000; 85:1776-1782

22. Savage DB, Soos MA, Powlson A, O'Rahilly S, McFarlane I, Halsall DJ, Barroso I, Thomas EL, Bell JD, Scobie I, Belchetz PE, Kelly WF, Schafer AJ. Familial partial lipodystrophy associated with compound heterozygosity for novel mutations in the LMNA gene. Diabetologia 2004; 47:753-756

23. Decaudain A, Vantyghem MC, Guerci B, Hecart AC, Auclair M, Reznik Y, Narbonne H, Ducluzeau PH, Donadille B, Lebbe C, Bereziat V, Capeau J, Lascols O, Vigouroux C. New metabolic phenotypes in laminopathies: LMNA mutations in patients with severe metabolic syndrome. J Clin Endocrinol Metab 2007; 92:4835-4844

24. Park JY, Chong AY, Cochran EK, Kleiner DE, Haller MJ, Schatz DA, Gorden P. Type 1 diabetes associated with acquired generalized lipodystrophy and insulin resistance: the effect of long-term leptin therapy. J Clin Endocrinol Metab 2008; 93:26-31

25. Brown RJ, Meehan CA, Gorden P. Leptin Does Not Mediate Hypertension Associated With Human Obesity. Cell 2015; 162:465-466

26. Ben Turkia H, Tebib N, Azzouz H, Abdelmoula MS, Ben Chehida A, Hubert P, Douira W, Ben Dridi MF. [Congenital generalized lipodystrophy: a case report with neurological involvement]. Archives de pediatrie : organe officiel de la Societe francaise de pediatrie 2009; 16:27-31

27. Debray FG, Baguette C, Colinet S, Van Maldergem L, Verellen-Dumouin C. Early infantile cardiomyopathy and liver disease: a multisystemic disorder caused by congenital lipodystrophy. Molecular genetics and metabolism 2013; 109:227-229

28. Araujo-Vilar D, Lado-Abeal J, Palos-Paz F, Lattanzi G, Bandin MA, Bellido D, Dominguez-Gerpe L, Calvo C, Perez O, Ramazanova A, Martinez-Sanchez N, Victoria B, Costa-Freitas AT. A novel phenotypic expression associated with a new mutation in LMNA gene, characterized by partial lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy. Clin Endocrinol (Oxf) 2008; 69:61-68

29. Bhayana S, Siu VM, Joubert GI, Clarson CL, Cao H, Hegele RA. Cardiomyopathy in congenital complete lipodystrophy. Clinical genetics 2002; 61:283-287

30. Caux F, Dubosclard E, Lascols O, Buendia B, Chazouilleres O, Cohen A, Courvalin JC, Laroche L, Capeau J, Vigouroux C, Christin-Maitre S. A new clinical condition linked to a novel mutation in

45

629630631632633634635636637638639640641642643644645646647648649650651652653654655656657658659660661662663664665666667668669670671672673674675


lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. J Clin Endocrinol Metab 2003; 88:1006-1013

31. Khalife WI, Mourtada MC, Khalil J. Dilated cardiomyopathy and myocardial infarction secondary to congenital generalized lipodystrophy. Texas Heart Institute journal / from the Texas Heart Institute of St Luke's Episcopal Hospital, Texas Children's Hospital 2008; 35:196-199

32. Rheuban KS, Blizzard RM, Parker MA, Carter T, Wilson T, Gutgesell HP. Hypertrophic cardiomyopathy in total lipodystrophy. The Journal of pediatrics 1986; 109:301-302

33. Andre P, Schneebeli S, Vigouroux C, Lascols O, Schaaf M, Chevalier P. Metabolic and cardiac phenotype characterization in 37 atypical Dunnigan patients with nonfarnesylated mutated prelamin A. American heart journal 2015; 169:587-593

34. Javor ED, Moran SA, Young JR, Cochran EK, DePaoli AM, Oral EA, Turman MA, Blackett PR, Savage DB, O'Rahilly S, Balow JE, Gorden P. Proteinuric nephropathy in acquired and congenital generalized lipodystrophy: baseline characteristics and course during recombinant leptin therapy. J Clin Endocrinol Metab 2004; 89:3199-3207

35. Brown RJ, Chan JL, Jaffe ES, Cochran E, DePaoli AM, Gautier JF, Goujard C, Vigouroux C, Gorden P. Lymphoma in acquired generalized lipodystrophy. Leuk Lymphoma 2015:1-6

36. Patni N, Alves C, von Schnurbein J, Wabitsch M, Tannin G, Rakheja D, Garg A. A novel syndrome of generalized lipodystrophy associated with pilocytic astrocytoma. J Clin Endocrinol Metab 2015:jc20152476

37. Robbins DC, Danforth E, Jr., Horton ES, Burse RL, Goldman RF, Sims EA. The effect of diet on thermogenesis in acquired lipodystrophy. Metabolism 1979; 28:908-916

38. Glueck CJ, Mellies MJ, Tsang RC, Kashyap ML, Steiner PM. Familial hypertriglyceridemia in children: dietary management. Pediatric research 1977; 11:953-957

39. Wilson DE, Chan IF, Stevenson KB, Horton SC, Schipke C. Eucaloric substitution of medium chain triglycerides for dietary long chain fatty acids in acquired total lipodystrophy: effects on hyperlipoproteinemia and endogenous insulin resistance. J Clin Endocrinol Metab 1983; 57:517-523

40. Meehan CA, Cochran E, Kassai A, Brown RJ, Gorden P. Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. Expert review of clinical pharmacology 2016; 9:59-68

41. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002; 346:570-578

42. Ebihara K, Kusakabe T, Hirata M, Masuzaki H, Miyanaga F, Kobayashi N, Tanaka T, Chusho H, Miyazawa T, Hayashi T, Hosoda K, Ogawa Y, DePaoli AM, Fukushima M, Nakao K. Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab 2007; 92:532-541

43. Moran SA, Patten N, Young JR, Cochran E, Sebring N, Reynolds J, Premkumar A, Depaoli AM, Skarulis MC, Oral EA, Gorden P. Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy. Metabolism 2004; 53:513-519

44. McDuffie JR, Riggs PA, Calis KA, Freedman RJ, Oral EA, DePaoli AM, Yanovski JA. Effects of exogenous leptin on satiety and satiation in patients with lipodystrophy and leptin insufficiency. J Clin Endocrinol Metab 2004; 89:4258-4263

45. Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P. The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in

46

676677678679680681682683684685686687688689690691692693694695696697698699700701702703704705706707708709710711712713714715716717718719720721


female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 2005; 54:255-263

46. Diker-Cohen T, Cochran E, Gorden P, Brown RJ. Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol Metab 2015; 100:1802-1810

47. Chan JL, Lutz K, Cochran E, Huang W, Peters Y, Weyer C, Gorden P. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr Pract 2011; 17:922-932

48. Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia 2010; 53:27-35

49. Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM, Premkumar A, Kleiner DE, Gorden P. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 2005; 41:753-760

50. Simha V, Szczepaniak LS, Wagner AJ, DePaoli AM, Garg A. Effect of leptin replacement on intrahepatic and intramyocellular lipid content in patients with generalized lipodystrophy. Diabetes Care 2003; 26:30-35

51. Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002; 109:1345-1350

52. Casey SP, Lokan J, Testro A, Farquharson S, Connelly A, Proietto J, Angus PW. Post-liver transplant leptin results in resolution of severe recurrence of lipodystrophy-associated nonalcoholic steatohepatitis. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2013; 13:3031-3034

53. Oral EA, Ruiz E, Andewelt A, Sebring N, Wagner AJ, Depaoli AM, Gorden P. Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 2002; 87:3110-3117

54. Abel BS, Muniyappa R, Stratton P, Skarulis MC, Gorden P, Brown RJ. Effects of Recombinant Human Leptin (Metreleptin) on Nocturnal LH Secretion in Lipodystrophy Patients. Neuroendocrinology 2015;

55. Lungu AO, Zadeh ES, Goodling A, Cochran E, Gorden P. Insulin resistance is a sufficient basis for hyperandrogenism in lipodystrophic women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2012; 97:563-567

56. Vatier C, Fetita S, Boudou P, Tchankou C, Deville L, Riveline J, Young J, Mathivon L, Travert F, Morin D, Cahen J, Lascols O, Andreelli F, Reznik Y, Mongeois E, Madelaine I, Vantyghem M, Gautier J, Vigouroux C. One-year metreleptin treatment improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes. Diabetes, obesity & metabolism 2015;

57. Simha V, Subramanyam L, Szczepaniak L, Quittner C, Adams-Huet B, Snell P, Garg A. Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety. J Clin Endocrinol Metab 2012; 97:785-792

58. Beltrand J, Lahlou N, Le Charpentier T, Sebag G, Leka S, Polak M, Tubiana-Rufi N, Lacombe D, de Kerdanet M, Huet F, Robert JJ, Chevenne D, Gressens P, Levy-Marchal C. Resistance to leptin-replacement therapy in Berardinelli-Seip congenital lipodystrophy: an immunological origin. Eur J Endocrinol 2010; 162:1083-1091

59. Chan JL, Koda J, Heilig JS, Cochran EK, Gorden P, Oral EA, Brown RJ. Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy. Clin Endocrinol (Oxf) 2015;

47

722723724725726727728729730731732733734735736737738739740741742743744745746747748749750751752753754755756757758759760761762763764765766767


60. Arioglu E, Duncan-Morin J, Sebring N, Rother KI, Gottlieb N, Lieberman J, Herion D, Kleiner DE, Reynolds J, Premkumar A, Sumner AE, Hoofnagle J, Reitman ML, Taylor SI. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med 2000; 133:263-274

61. Luedtke A, Boschmann M, Colpe C, Engeli S, Adams F, Birkenfeld AL, Haufe S, Rahn G, Luft FC, Schmidt HH, Jordan J. Thiazolidinedione response in familial lipodystrophy patients with LMNA mutations: a case series. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 2012; 44:306-311

62. Lane WS, Cochran EK, Jackson JA, Scism-Bacon JL, Corey IB, Hirsch IB, Skyler JS. High-dose insulin therapy: is it time for U-500 insulin? Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 2009; 15:71-79

63. Karges B, Boehm BO, Karges W. Early hypoglycaemia after accidental intramuscular injection of insulin glargine. Diabet Med 2005; 22:1444-1445

64. Bolli GB, Owens DR. Insulin glargine. Lancet 2000; 356:443-44565. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC,

Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC, Jr., Watson K, Wilson PW, American College of Cardiology/American Heart Association Task Force on Practice G. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology 2014; 63:2889-2934

66. Catapano AL, Chapman J, Wiklund O, Taskinen MR. The new joint EAS/ESC guidelines for the management of dyslipidaemias. Atherosclerosis 2011; 217:1

67. Bolan C, Oral EA, Gorden P, Taylor S, Leitman SF. Intensive, long-term plasma exchange therapy for severe hypertriglyceridemia in acquired generalized lipoatrophy. J Clin Endocrinol Metab 2002; 87:380-384

68. Settergren J, Eiermann B, Mannheimer B. Adherence to drug label recommendations for avoiding drug interactions causing statin-induced myopathy--a nationwide register study. PloS one 2013; 8:e69545

69. King P, Peacock I, Donnelly R. The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes. British journal of clinical pharmacology 1999; 48:643-648

70. Ahmad Z, Subramanyam L, Szczepaniak L, Simha V, Adams-Huet B, Garg A. Cholic acid for hepatic steatosis in patients with lipodystrophy: a randomized, controlled trial. Eur J Endocrinol 2013; 168:771-778

71. Mitchel EB, Lavine JE. Review article: the management of paediatric nonalcoholic fatty liver disease. Alimentary pharmacology & therapeutics 2014; 40:1155-1170

72. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR, Nash CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362:1675-1685

73. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Unalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR, Nonalcoholic Steatohepatitis Clinical Research N. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. Jama 2011; 305:1659-1668

48

768769770771772773774775776777778779780781782783784785786787788789790791792793794795796797798799800801802803804805806807808809810811812


74. Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Alimentary pharmacology & therapeutics 2012; 35:66-75

75. Graivier MH, Bass LS, Busso M, Jasin ME, Narins RS, Tzikas TL. Calcium hydroxylapatite (Radiesse) for correction of the mid- and lower face: consensus recommendations. Plastic and reconstructive surgery 2007; 120:55S-66S

76. Hurwitz PJ, Sarel R. Facial reconstruction in partial lipodystrophy. Ann Plast Surg 1982; 8:253-257

77. Calderoni DR, Ramos TM, de Castro JR, Kharmandayan P. Surgical management of phenotypic alterations related to the Dunnigan variety of familial partial lipodystrophy. Journal of plastic, reconstructive & aesthetic surgery : JPRAS 2011; 64:1248-1250

78. Hughes JM, Stephen C, Johnson AB, Wilson S. Breast augmentation in Familial Partial Lipodystrophy: a case report. Journal of plastic, reconstructive & aesthetic surgery : JPRAS 2011; 64:e121-124

79. Araujo-Vilar D, Sanchez-Iglesias S, Guillin-Amarelle C, Castro A, Lage M, Pazos M, Rial JM, Blasco J, Guillen-Navarro E, Domingo-Jimenez R, del Campo MR, Gonzalez-Mendez B, Casanueva FF. Recombinant human leptin treatment in genetic lipodystrophic syndromes: the long-term Spanish experience. Endocrine 2015; 49:139-147

80. Eberting CL, Javor E, Gorden P, Turner ML, Cowen EW. Insulin resistance, acanthosis nigricans, and hypertriglyceridemia. J Am Acad Dermatol 2005; 52:341-344

81. Loriaux DL. An approach to the patient with hirsutism. J Clin Endocrinol Metab 2012; 97:2957-2968

82. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991; 325:1196-1204

83. Adami S, Rossini M, Zamberlan N, Bertoldo F, Dorizzi R, Lo Cascio V. Long-term effects of transdermal and oral estrogens on serum lipids and lipoproteins in postmenopausal women. Maturitas 1993; 17:191-196

84. Agarwal AK, Arioglu E, De Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI, Garg A. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 2002; 31:21-23

85. Magre J, Delepine M, Khallouf E, Gedde-Dahl T, Jr., Van Maldergem L, Sobel E, Papp J, Meier M, Megarbane A, Bachy A, Verloes A, d'Abronzo FH, Seemanova E, Assan R, Baudic N, Bourut C, Czernichow P, Huet F, Grigorescu F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret H, Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M, Robert JJ, Tric P, Tubiana-Rufi N, Vigouroux C, Weissenbach J, Savasta S, Maassen JA, Trygstad O, Bogalho P, Freitas P, Medina JL, Bonnicci F, Joffe BI, Loyson G, Panz VR, Raal FJ, O'Rahilly S, Stephenson T, Kahn CR, Lathrop M, Capeau J, Group BW. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 2001; 28:365-370

86. Kim CA, Delepine M, Boutet E, El Mourabit H, Le Lay S, Meier M, Nemani M, Bridel E, Leite CC, Bertola DR, Semple RK, O'Rahilly S, Dugail I, Capeau J, Lathrop M, Magre J. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab 2008; 93:1129-1134

87. Dyment DA, Gibson WT, Huang L, Bassyouni H, Hegele RA, Innes AM. Biallelic mutations at PPARG cause a congenital, generalized lipodystrophy similar to the Berardinelli-Seip syndrome. European journal of medical genetics 2014; 57:524-526

49

813814815816817818819820821822823824825826827828829830831832833834835836837838839840841842843844845846847848849850851852853854855856857858


88. Herbst KL, Tannock LR, Deeb SS, Purnell JQ, Brunzell JD, Chait A. Kobberling type of familial partial lipodystrophy: an underrecognized syndrome. Diabetes Care 2003; 26:1819-1824

89. Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 2000; 9:109-112

90. Shackleton S, Lloyd DJ, Jackson SN, Evans R, Niermeijer MF, Singh BM, Schmidt H, Brabant G, Kumar S, Durrington PN, Gregory S, O'Rahilly S, Trembath RC. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 2000; 24:153-156

91. Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, O'Rahilly S. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999; 402:880-883

92. Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Charpentier G, Auclair M, Delepine M, Barroso I, Semple RK, Lathrop M, Lascols O, Capeau J, O'Rahilly S, Magre J, Savage DB, Vigouroux C. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med 2011; 364:740-748

93. Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, Hyden CS, Bottomley W, Vigouroux C, Magre J, Raymond-Barker P, Murgatroyd PR, Chawla A, Skepper JN, Chatterjee VK, Suliman S, Patch AM, Agarwal AK, Garg A, Barroso I, Cinti S, Czech MP, Argente J, O'Rahilly S, Savage DB, Consortium LDS. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol Med 2009; 1:280-287

94. Albert JS, Yerges-Armstrong LM, Horenstein RB, Pollin TI, Sreenivasan UT, Chai S, Blaner WS, Snitker S, O'Connell JR, Gong DW, Breyer RJ, 3rd, Ryan AS, McLenithan JC, Shuldiner AR, Sztalryd C, Damcott CM. Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes. N Engl J Med 2014; 370:2307-2315

95. Farhan SM, Robinson JF, McIntyre AD, Marrosu MG, Ticca AF, Loddo S, Carboni N, Brancati F, Hegele RA. A novel LIPE nonsense mutation found using exome sequencing in siblings with late-onset familial partial lipodystrophy. Can J Cardiol 2014; 30:1649-1654

96. George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, Williams RM, Acerini CL, Dunger DB, Barford D, Umpleby AM, Wareham NJ, Davies HA, Schafer AJ, Stoffel M, O'Rahilly S, Barroso I. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 2004; 304:1325-1328

97. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 2003; 423:293-298

98. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M, Levy N. Lamin a truncation in Hutchinson-Gilford progeria. Science 2003; 300:2055

99. Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, Botha EG, Garg A, Hanson NB, Martin GM, Mian IS, Kennedy BK, Oshima J. LMNA mutations in atypical Werner's syndrome. Lancet 2003; 362:440-445

100. Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D'Apice MR, Massart C, Capon F, Sbraccia P, Federici M, Lauro R, Tudisco C, Pallotta R, Scarano G, Dallapiccola B, Merlini L, Bonne G. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 2002; 71:426-431

101. Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet 2003; 12:1995-2001

50

859860861862863864865866867868869870871872873874875876877878879880881882883884885886887888889890891892893894895896897898899900901902903904905


102. Weedon MN, Ellard S, Prindle MJ, Caswell R, Lango Allen H, Oram R, Godbole K, Yajnik CS, Sbraccia P, Novelli G, Turnpenny P, McCann E, Goh KJ, Wang Y, Fulford J, McCulloch LJ, Savage DB, O'Rahilly S, Kos K, Loeb LA, Semple RK, Hattersley AT. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet 2013; 45:947-950

103. Donadille B, D'Anella P, Auclair M, Uhrhammer N, Sorel M, Grigorescu R, Ouzounian S, Cambonie G, Boulot P, Laforet P, Carbonne B, Christin-Maitre S, Bignon YJ, Vigouroux C. Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome. Orphanet journal of rare diseases 2013; 8:106

104. Cabanillas R, Cadinanos J, Villameytide JA, Perez M, Longo J, Richard JM, Alvarez R, Duran NS, Illan R, Gonzalez DJ, Lopez-Otin C. Nestor-Guillermo progeria syndrome: a novel premature aging condition with early onset and chronic development caused by BANF1 mutations. American journal of medical genetics Part A 2011; 155A:2617-2625

105. Graul-Neumann LM, Kienitz T, Robinson PN, Baasanjav S, Karow B, Gillessen-Kaesbach G, Fahsold R, Schmidt H, Hoffmann K, Passarge E. Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene. Am J Med Genet A 2010; 152A:2749-2755

106. Masotti A, Uva P, Davis-Keppen L, Basel-Vanagaite L, Cohen L, Pisaneschi E, Celluzzi A, Bencivenga P, Fang M, Tian M, Xu X, Cappa M, Dallapiccola B. Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6. American journal of human genetics 2015; 96:295-300

107. Lessel D, Vaz B, Halder S, Lockhart PJ, Marinovic-Terzic I, Lopez-Mosqueda J, Philipp M, Sim JC, Smith KR, Oehler J, Cabrera E, Freire R, Pope K, Nahid A, Norris F, Leventer RJ, Delatycki MB, Barbi G, von Ameln S, Hogel J, Degoricija M, Fertig R, Burkhalter MD, Hofmann K, Thiele H, Altmuller J, Nurnberg G, Nurnberg P, Bahlo M, Martin GM, Aalfs CM, Oshima J, Terzic J, Amor DJ, Dikic I, Ramadan K, Kubisch C. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet 2014; 46:1239-1244

108. Garg A, Kircher M, Del Campo M, Amato RS, Agarwal AK, University of Washington Center for Mendelian G. Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome. Am J Med Genet A 2015; 167:1796-1806

109. Agarwal AK, Xing C, DeMartino GN, Mizrachi D, Hernandez MD, Sousa AB, Martinez de Villarreal L, dos Santos HG, Garg A. PSMB8 encoding the beta5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet 2010; 87:866-872

110. Thauvin-Robinet C, Auclair M, Duplomb L, Caron-Debarle M, Avila M, St-Onge J, Le Merrer M, Le Luyer B, Heron D, Mathieu-Dramard M, Bitoun P, Petit JM, Odent S, Amiel J, Picot D, Carmignac V, Thevenon J, Callier P, Laville M, Reznik Y, Fagour C, Nunes ML, Capeau J, Lascols O, Huet F, Faivre L, Vigouroux C, Riviere JB. PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am J Hum Genet 2013; 93:141-149

111. Payne F, Lim K, Girousse A, Brown RJ, Kory N, Robbins A, Xue Y, Sleigh A, Cochran E, Adams C, Dev Borman A, Russel-Jones D, Gorden P, Semple RK, Saudek V, O'Rahilly S, Walther TC, Barroso I, Savage DB. Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease. Proc Natl Acad Sci U S A 2014; 111:8901-8906

112. Aotani D, Ebihara K, Sawamoto N, Kusakabe T, Aizawa-Abe M, Kataoka S, Sakai T, Iogawa H, Ebihara C, Fujikura J, Hosoda K, Fukuyama H, Nakao K. Functional magnetic resonance imaging

51

906907908909910911912913914915916917918919920921922923924925926927928929930931932933934935936937938939940941942943944945946947948949950951


analysis of food-related brain activity in patients with lipodystrophy undergoing leptin replacement therapy. J Clin Endocrinol Metab 2012; 97:3663-3671

113. Panchal R, Bosio P, Waugh J. Familial partial lipodystrophy complicated by pre-eclampsia. J Obstet Gynaecol 2005; 25:196-197

114. Ludtke A, Genschel J, Brabant G, Bauditz J, Taupitz M, Koch M, Wermke W, Worman HJ, Schmidt HH. Hepatic steatosis in Dunnigan-type familial partial lipodystrophy. Am J Gastroenterol 2005; 100:2218-2224

115. Peters DK, Charlesworth JA, Sissons JG, Williams DG, Boulton-Jones JM, Evans DJ, Kourilsky O, Morel-Maroger L. Mesangiocapillary nephritis, partial lipodystrophy, and hypocomplementaemia. Lancet 1973; 2:535-538

116. Aslam A, Savage DB, Coulson IH. Acquired generalized lipodystrophy associated with peripheral T cell lymphoma with cutaneous infiltration. Int J Dermatol 2013;

117. Yiannias JA, DiCaudo DJ, Maskin E. Peripheral T-cell lymphoma presenting as lipoatrophy and nodules. Int J Dermatol 2006; 45:1415-1419

118. Hegele RA, Al-Attar SA, Rutt BK. Obstructive sleep apnea in 2 women with familial partial lipodystrophy due to a heterozygous LMNA R482Q mutation. CMAJ 2007; 177:743-745

119. Patel K, Roseman D, Burbank H, Attarian H. Obstructive sleep apnea in familial partial lipodystrophy type 2 with atypical skin findings and vascular disease. Sleep Breath 2009; 13:425-427

120. Christensen JD, Lungu AO, Cochran E, Collins MT, Gafni RI, Rother KI, Gorden P, Brown RJ. Bone Mineral Content in Patients With Congenital Generalized Lipodystrophy Is Unaffected by Metreleptin Replacement Therapy. J Clin Endocrinol Metab 2014:jc20141353

Supplemental Tables

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 harmfulLevel of Evidence A: Sufficient evidence from multiple randomized trials B: Limited evidence from single, randomized trial or other nonrandomized studies C: Based on expert opinion, case studies, or standard of care

52

952953954955956957958959960961962963964965966967968969970971972973

974

975

976

977

Brown, Rebecca (NIH/NIDDK) [E], 03/16/16,

Need permission to adapt this table from: Gibbons, R.J., Smith, S., Antman, E., American College of, C., and American Heart, A. 2003. American College of Cardiology/American Heart Association clinical practice guidelines: Part I: where do they come from? Circulation 107:2979-2986.


53

978

c.ymcdn.com web viewword count: 3594. tables: 4. figures: 2. references: 120. ... thyrotoxicosis,...

Documents