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Familial partial lipodystrophy, Dunnigan type
Familial Partial lipodystrophy, Dunnigan type (FPLD2) is a rare form of genetic lipodystrophy (see this term) characterized by a loss of subcutaneous adipose tissue from the trunk, buttocks and limbs; fat accumulation in the neck, face, axillary and pelvic regions; muscular hypertrophy; and usually associated with metabolic complications such as insulin resistance, diabetes mellitus, dyslipidemia and liver steatosis.
ORPHA:2348Classification level: Disorder
The prevalence is unknown but FPLD2 is the most frequent form of familial partial lipodystrophy (FPLD; see this term).
Onset of lipodystrophy usually occurs at or around puberty, with regional loss of subcutaneous adipose tissue from the limbs, buttocks and trunk, followed by a progressive fat accumulation on the face, neck and axillary regions giving patients a cushingoid appearance. Females often have a more severe phenotype than males. An increased skeletal muscle volume and mass is also noted. Prominent veins (due to lipoatrophy) are noted in the limbs. Metabolic complications appear progressively in adolescence or in adulthood and include insulin resistance, diabetes, hepatic steatosis, acanthosis nigricans, high blood pressure, and premature atherosclerosis with an increased risk of coronary heart disease. Some patients may display the features of polycystic ovary syndrome such as hirsutism, oligomenorrhea, polycystic ovaries and infertility. All patients are typically predisposed to early cardiovascular diseases. Other manifestations may include complications of diabetes, recurrent acute pancreatitis and liver steatohepatitis or cirrhosis.
FPLD2 is caused by mutations in the LMNA gene (1q22) encoding the nuclear intermediate filaments A-type lamins. Typical forms of FPLD2 are mainly due to heterozygous substitutions at the 482nd codon of the gene (p.R482W/Q or L mutation). Other mutations can lead to atypical lipodystrophies, more frequently associated with other laminopathic phenotypes (muscular and/or cardiac dystrophies, accelerated aging).
Diagnosis is made by clinical examination, analysis of fat distribution by imaging (MRI, CT-scan and whole-body dual-energy X-ray absorptiometry) and evaluation of metabolic status (hypertriglyceridemia, low levels of high density lipoprotein (HDL)-cholesterol in the blood, hyperinsulinemia, altered glucose tolerance, low circulating levels of leptin and adiponectin). Body mass index is usually normal. Liver enzyme levels should be measured and ultrasonography of liver should be performed. Cardiovascular investigations are needed to search for rhythm and conduction disturbances, and early atherosclerosis. Molecular genetic testing confirms diagnosis.
Differential diagnoses include other forms of FLPD as well as Cushing syndrome (see these terms), type 2 diabetes, metabolic syndrome and acquired lipodystrophy.
Prenatal diagnosis is possible in families with a known disease causing mutation.
FPLD2 is inherited in an autosomal dominant manner and genetic counseling is warranted.
Management and treatment
Treatment consists of correcting metabolic abnormalities and managing complications. Monitoring diet (reduced intake of dietary fats and carbohydrates) and maintaining daily physical activity can improve the metabolic complications of lipodystrophy. Insulin sensitizers (mainly metformin) and lipid-lowering drugs (statins, or fibrates in case of major hypertriglyceridemia) can also be helpful. Diabetes may require other non-specific treatments, along with insulin. Treatment with metreleptin has resulted in regression of hepatic steatosis and an improvement in metabolic homeostasis, but is only approved in Japan and for the treatment of generalized forms of lipodystrophies in the US (and through compassionate programs in other countries). Regular cardiac monitoring is recommended. Ethinylestradiol should be avoided in women with FPLD2. Plastic surgery can help some patients.
Prognosis is linked to the severity of associated comorbidities (diabetes, pancreatitis, cardiovascular diseases).
- Clinical practice guidelines
- English (2016)