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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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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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.”
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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
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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.
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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
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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).
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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.
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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.
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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:
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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
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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
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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).
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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
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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)
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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).
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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.
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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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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).
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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)
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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.
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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)
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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514
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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)
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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532
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
(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
Onset ↓Fat ↑Fat Skin
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
Familial Partial Lipodystrophy
Subtype Gene-
tics
Onset ↓Fat ↑Fat Skin
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
(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
Onset ↓Fat ↑Fat Skin
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
↓ 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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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)
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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.
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Lipodystrophy Diagnosis and Treatment Consensus StatementFinal Draft March 22, 2016
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analysis of food-related brain activity in patients with lipodystrophy undergoing leptin replacement therapy. J Clin Endocrinol Metab 2012; 97:3663-3671
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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
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974
975
976
977
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978