Endocrine Abstracts

The predominant subtype of familial partial lipodystrophy (FPLD) is a rare autosomal dominant disease occurring in Arginine 482 codon of LMNA gene (FPLD subtype 2, also known as Dunnigan-type lipodystrophy). FPLD may also occur in patients harboring mutations in different exons of LMNA. We herein describe two unrelated patients referred to our Center for the suspicion of partial lipodystrophy and carrying two novel heterozygous LMNA variants. The first one is a 20-year-old woman who exhibited at physical examination an abnormal distribution of subcutaneous adipose tissue, characterized by the accumulation of fat in the neck and lipoatrophy in the lower limbs. Acanthosis nigricans was evident in the patient’s groin and armpits. Her body mass index was 27.3 kg/m². Biochemical blood tests showed combined hyperlipidemia (triglycerides 494 mg/dl; total-cholesterol 246 mg/dl; HDL-cholesterol 45 mg/dl; LDL-cholesterol 135 mg/dl). The oral glucose tolerance test revealed severe insulin resistance (fasting 36 mUI/ml; two-hours 386 mUI/l) and the abdominal ultrasound showed hepatic steatosis. Plasma leptin and high molecular weight adiponectin levels were 23.9 mg/l and 1.9 mg/ml, respectively. She was found to carry a novel heterozygous p.Asn195Tyr LMNA variant in exon 3. The second case, is a 45 years old woman with a history of PCOS and insulin resistance from adolescence, at physical examination she showed an accumulation of fat in the neck and lipoatrophy in the upper and lower limbs resembling the fat distribution pattern of FPLD2. Her body mass index was 23.1 kg/m². Biochemical blood tests showed increased triglycerides levels (260 mg/dl). The abdominal ultrasound demonstrated hepatic steatosis. Plasma leptin and high molecular weight adiponectin levels were 4.8 mg/l and 1.5 mg/ml, respectively. Genetic testing revealed a novel heterozygous p.Ser239Arg LMNA variant located in exon 4. Notably, in silico analysis indicated a predicted damaging role for both aminoacid substitutions. In conclusion, we identified two novel missense variants in the lamin gene associated with familial partial lipodystrophy (FPLD). These previously unrecognized variants in subjects presenting with partial lipodystrophy underscore the considerable phenotypic heterogeneity in LMNA pathogenic mutations and emphasizes the necessity of additional research to unravel their physiopathological relevance and therapeutic implications.