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Familial partial lipodystrophy, Dunnigan type
A rare, genetic lipodystrophy 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
Familial partial lipodystrophy, Dunnigan type (FPLD2) is the most frequent form of familial partial lipodystrophy (FPLD) for which the prevalence is estimated at less than 1/100,000 in Europe; although, this is likely an underestimate.
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 monoallelic or biallelic LMNA pathogenic variants are rarely found, and are more frequently associated with atypical forms of lipodystrophies, associated or not 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, and with transient elastography if a fatty liver disease is suspected. 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 FPLD as well as Cushing syndrome, type 2 diabetes, metabolic syndrome and acquired lipodystrophy.
Prenatal diagnosis could be discussed in families with a known disease causing mutation.
FPLD2 is inherited in an autosomal dominant manner; where there is an affected parent, the risk of disease transmission is 50%.
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. The orphan drug metreleptin is authorized under exceptional circumstances in Europe for the treatment of metabolic complications of partial forms of lipodystrophies, in adults and children above the age of 12 years, where standard treatments have failed. Further studies are required to investigate the benefits and risks of treatment. 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)