Context. A heterozygous missense mutation substituting arginine at position 133 to leucine in the lamin A/C protein has been reported in two young women with clinical features of short stature, bird-like facies and early onset of aging processes.

Objective. To carry out detailed phenotyping of these two women by evaluating the pattern of fat loss using anthropometry, dual energy x-ray absorptiometry (DEXA), and magnetic resonance imaging (MRI) and to study metabolic abnormalities in glucose and lipid metabolism.

Design. Descriptive Case Reports.

Setting. Referral Center.

Patients. Patient 1 was a 23-year-old African-American female with progeroid features. Patient 2 was a 24-year-old Caucasian female with generalized lipodystrophy, hypertriglyceridemia and severe insulin resistance diabetes who required over 200 U of insulin daily.

Interventions. None

Main Outcome Measures. Body fat distribution to characterize pattern of lipodystrophy and to study nuclear morphology abnormalities in skin fibroblasts.

Results. Patient 1 had normal body fat (27%) by DEXA. However, MRI revealed relative paucity of sc fat in the distal extremities, with preservation of sc truncal fat. She had impaired glucose tolerance and elevated post-prandial serum insulin levels. Patient 2 in contrast, had only 11.6% body fat as determined by DEXA and had generalized loss of sc and intra-abdominal fat on MRI. Skin fibroblasts from patient 2 showed marked abnormal nuclear morphology compared with those from patient 1. Despite the deranged nuclear morphology, the lamin A/C remained localized to the nuclear envelope and the nuclear DNA remained within the nucleus.

Conclusions. Atypical Werner's syndrome associated with Arg133Leu mutation in LMNA gene presents with a phenotypically heterogeneous disorder. Furthermore, the severity of metabolic complications seems to correlate with the extent of lipodystrophy.