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

Abstract

Objective: Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs.

Participants: Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public.

Evidence: A literature review was conducted by the committee. Recommendations of the committee were graded using the system of the American Heart Association. Expert opinion was used when published data were unavailable or scarce.

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 the management of metabolic complications of lipodystrophy. Metreleptin therapy is effective for metabolic complications in hypoleptinemic patients with generalized lipodystrophy and selected patients with partial lipodystrophy. Other treatments not specific for lipodystrophy may be helpful as well (eg, metformin for diabetes, and statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated.

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.589–2A>G; p.(Val197Glufs*32) mutation in the AGPAT2 gene. The patient had generalized loss of subcutaneous (sc) fat with acanthosis nigricans in the axillae and neck. She has umbilical prominence and acromegaloid features (enlarged mandible, hands, and feet). B, Lateral view of a 26-year-old female with familial partial lipodystrophy of the Dunnigan variety due to heterozygous c.575A>T; p.(Asp192Val) mutation in the LMNA gene. She had marked loss of sc fat from the upper and lower extremities and accumulation of sc fat in the face and chin. C, Anterior view of an 8-year-old German boy with acquired generalized lipodystrophy. He had severe generalized loss of sc fat with marked acanthosis nigricans in the neck, axillae, and groin. D, Anterior view of a 45-year-old Caucasian female with acquired partial lipodystrophy (Barraquer-Simons syndrome). She had marked loss of sc fat from the face, neck, upper extremities, and chest but had lipodystrophy on localized regions on the anterior thighs. She had increased sc fat deposition in the lower extremities.

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 sc fat loss and presence of prominent muscles, phlebomegaly, acanthosis nigricans, hepatomegaly, xanthomas, and acromegaloid or progeroid appearance. All patients should undergo a metabolic workup for insulin resistance, diabetes, dyslipidemia, and fatty liver disease. Conventional anthropometry including skinfold thickness measurements, ± dual energy x-ray absorptiometry, and whole-body magnetic resonance imaging (if available) should be performed to confirm the pattern of fat loss. Common genetic lipodystrophies include CGL, FPLD, and progeroid lipodystrophies. They require genotyping to confirm the diagnosis, followed by genetic counseling and screening of family members. Patients with progeroid lipodystrophies have progeroid features like bird-like facies, high-pitched voice, skin atrophy and pigmentation, alopecia, and nail dysplasia. Patients with FPLD have fat loss of the extremities typically occurring around puberty and can have a positive family history. Patients with CGL have near-complete lack of fat starting at birth or infancy. Acquired lipodystrophies have fat loss typically in late childhood. Patients with AGL have generalized loss of sc fat and often have associated autoimmune diseases. Patients with APL have cranio-caudal fat loss affecting the face, neck, shoulders, arms, and upper trunk, and most patients have low serum C3 levels.