A 15-yr-old woman presented with abdominal distension and an elevated blood glucose level. She was born at full term with a birth weight of 2.7 kg by c-section delivery. Hyperpigmentation of her skin developed 10 months from birth. She attained menarche at the age of 13 yr, and this was followed by an irregular period. She developed diabetes mellitus at the age of 13 yr and began diabetic treatment with oral hyperglycemic agents (sulfonylurea, metformin, voglibose). Yet she didn't achieve good glycemic control despite using oral hypoglycemic agents. On admission, her random plasma glucose was measured by the glucose oxidase method using a Hitachi Modular D2400 (Roche, Tokyo, Japan) and the serum cholesterol, triglycerides, high-density lipoprotein cholesterol and chemistry were tested using a Hitachi Modular D2400 (Roche, Tokyo, Japan). Her fasting plasma glucose (13.2 mmol/liter), triglyceride (14.9 mmol/liter), alanine aminotransferase (87 U/L), and aspartate aminotransferase levels (70 U/L) were all increased. She had severe hepatomegaly on the MR imaging. Microvesicular and macrovesicular changes and perivenular fibrosis were noted on the liver biopsy. On examination, she looked older than her age group and she had the bird-like face with a beaked nose (Fig. 1A and 1B). The skin over the hands and feet was atrophic with prominent superficial veins (Fig. 1C). She had thin, spindle-shaped fingers with mild flexion contractures of the distal and proximal interphalangeal joints and elbow joints (Fig. 1C). She had a small mandible and a small mouth (Fig. 1B). There was hyperpigmented skin covering the neck, trunk and upper extremities (Fig. 1D). She had generalized loss of subcutaneous fat over the face, neck, upper chest area, hips, and extremities (Fig. 1A and 1C). The lateral quadriceps were prominent bilaterally. There was no graying, but there was thinning of scalp hair and diminution of hair over her eyebrows and over her upper and lower extremities. The liver was palpable 5 cm below the right costal margin, and the spleen was not palpable. She didn't have cataract or any abnormality in fundus exam. Doppler echocardiography did not show concentric left ventricular hypertrophy, increased left ventricular pressures, aortic or mitral regurgitation, or calcification of the posterior annulus. The whole-body fat and regional fat in the head, trunk and upper and lower extremities were determined by performing dual-energy X-ray absorptiometry (DEXA) scanning (GE Lunar [Madison, WI] instruments). The proportion of fat in the individual lesions as well as that of the whole body was calculated as a percentage of the body mass. She had markedly reduced body fat with generalized lipodystrophy. The body fat with using DEXA was estimated to be 6.5% of the total body mass. Whole body MRI studies confirmed markedly decreased subcutaneous fat, abdominal fat and intrathoracic fat (Fig. 2). MRI studies were performed using a 3 Tesla imaging device (GE Signa Exite 3.0 HD T) at the trunk (chest, abdomen) and the peripheral (biceps, triceps, forearm, thigh, and calf) limbs. Her grandmother was diagnosed with diabetes mellitus at 72 yr old, but her parents, brother and sister did not have any history of diabetes or cardiovascular disease. Her parents, brother, and younger sister didn't have an abnormal appearance of their faces, extremities, skin and etc. We did not find abnormal finding in their medical histories.

Primary fibroblasts from skin biopsy samples were grown on Dulbecco's modified Eagle's medium (DMEM, Gibco Lab, NY, USA) and they were fixed in phosphate buffered saline (PBS) that contained 4% formaldehyde for 30 minutes at 4℃. The cells were made permeable by incubating them in 0.1% Triton X-100 for 15 min at room temperature and then they were blocked for nonspecific binding by incubation with monoclonal anti-lamin antibody (antibody H-110 at a 1:100 dilution in blocking buffer; Santa Cruz Biotechnology, Santa Cruz, CA.) for 60 min at 37℃. The primary antibody was removed, and the coverslip was washed with PBS and then incubated with the secondary antibody conjugated with FITC-conjugated goat anti-rabbit IgG antibody for 120 min at room temperature. After washing, the coverslips were mounted using commercial mounting medium for fluorescent microscopy (Aqua Poly/ Mount; Polysciences, Inc., Warrington, PA.), and the slides were examined using an AxioCam MRc5 microscope (Carl Zeiss USA, Thornwood, NY). The skin fibroblasts from this patient were from the 7th passage. Indirect immunofluorescent studies revealed normal localization of the lamin A/C protein in the nuclear envelope in the affected subject. The captured images of the nuclei showed abnormal nuclear morphology. Several deformed nuclei, multilobulations, nuclear membrane invagination and nuclear hypertrophy were observed in this patient (Fig. 3).

We found the exonic sequence associated with the T506del and it was 25.374 Kb of genomic DNA. The nucleotide numbering started with the adenine of the first ATG codon for lamin A/C. We found a T deletion in exon 2 in the LMNA gene that resulted in altered amino acid sequence from codon 169 to stop codon (Fig. 4). Although G507del was found in LMNA gene of her mother and sister, they didn't have any phenotype of premature aging or lipodystrophy. The exonic sequence of the LMNA gene of her father and brother had the same sequence compared with other normal persons. The exonic sequence of the LMNA gene of each person is shown in Figure 4.