SAT-087 Familial Generalized Lipodystrophy in Two Siblings Due to Homozygous p.Arg545His LMNA Mutation

Abstract

Background: Homozygous mutations in lamin A/C (LMNA) gene are extremely rare and have been reported to cause mandibuloacral dysplasia type A, Emery-Dreifuss muscular dystrophy-3, Charcot-Marie-Tooth axonal neuropathy type 2B1, progeroid syndrome and severe familial partial lipodystrophy. We report a novel syndrome of familial generalized lipodystrophy due to homozygous p.Arg545His LMNA mutation in two sisters. Clinical Cases: The proband, a 18.5-year-old Hispanic female, was diagnosed with speech delay at age 4 years; and developed lipodystrophy and acanthosis nigricans at age 10. She was diagnosed with diabetes and elevated serum aspartate and alanine aminotransferases at 11 years of age; and extreme hypertriglyceridemia (serum triglycerides >10,000 mg/dL), xanthomas and three episodes of acute pancreatitis at 14 years of age. Her liver biopsy showed hepatocytes with pleomorphic and enlarged mitochondria and variably enlarged glycogenated nuclei, with macro-vesicular and micro-vesicular steatosis in 2% of hepatocytes. At age 16, she had severe metabolic abnormalities despite low fat diet, metformin 1000 mg, insulin > 600 units, fish oil 4 g, gemfibrozil 600 mg, and lisinopril 10 mg per day. Subcutaneous metreleptin 2.5 mg/d was initiated which improved glycemic control, liver enzymes and triglycerides, with no further episode of acute pancreatitis. She currently takes metreleptin and insulin 140 units daily. She recently developed right hydrosalpinx, 1.8 cm posterior uterine fibroids, and 2.1 cm endometriosis. Her 17-year-old sister had speech delay in infancy, and recurrent pyelonephritis, and lost sc fat in early childhood. She developed hypothyroidism, elevated transaminases, and diabetes at age 10, 14, and 16 years, respectively. She had one episode of acute pancreatitis and an incidental 6.8 cm ovarian cyst was found at age 16 years. Both of them have generalized loss of sc fat, more from the extremities than from the trunk, thin lips with perioral pigmentation, dry skin, short 5th finger with clindodactyly, and bilateral ankle contractures. The proband also had bilateral knee contractures. They have no acro-osteolysis, buffalo hump, double chin, myopathy or neuropathy. Whole exome sequencing of both the patients revealed homozygous mutation chr1:156107470G>A, p.Arg545His (rs142191737, minor allele frequency 0.000038 in Latinos) in LMNA (http://gnomad.broadinstitute.org). The mother and a younger brother are both heterozygous for p.Arg545His variant and are healthy without any lipodystrophy. Conclusions: Homozygous p.Arg545His LMNA mutation results in a novel syndrome of childhood-onset familial generalized lipodystrophy with early onset diabetes, hypertriglyceridemia, and hepatic steatosis, speech delay and joint contractures. Metreleptin therapy may be helpful in improving metabolic derangements.