MON-155 A Patient with Acquired Generalized Lipodystrophy (AGL, Lawrence Syndrome) in Association with CTLA-4 Haploinsufficiency

Abstract

Acquired generalized lipodystrophy (AGL) is a rare disease which develops during early childhood and adolescence, characterized by selective loss of adipose tissue from large regions of the body. Diabetes mellitus with insulin resistance, hepatomegaly, and hypertriglyceridemia develop as a result of the fat loss. In addition to the symptoms associated with fat loss, patients with the autoimmune variety of AGL (Type 2) present with multiple autoimmune diseases. Recently a case of AGL with multiple autoimmune diseases was reported to harbor a mutation in the AIRE gene. Here we report a heterozygous variant (c.4_5insGTTGG, p.Ala2GlyfsTer14) resulting in haploinsufficiency in the immune checkpoint protein CTLA-4, identified in a patient with AGL and accompanying complex autoimmune cluster. The patient was born term with a normal spontaneous vaginal delivery and no complications. At age 6 months, she developed failure to thrive followed by type 1 diabetes and hypertriglyceridemia by ages 2 and 4 years, respectively, and was diagnosed with AGL. Her childhood clinical course was further complicated by poor weight gain despite adequate calorie intake, hepatomegaly with massive splenomegaly and chronic severe diarrhea (onset age 8 years). Her family history is notable for type 1 diabetes in her maternal uncle, type 1 diabetes, recurrent infections, cytopenias, and a mildly hypocellular bone marrow in her maternal cousin, hypothyroidism in her mother and maternal grandfather, and Addison's disease in her maternal grandfather. She presented to Michigan Medicine in acute liver failure and severe jaundice at the age of 14 years. She had mixed inflammatory hepatitis on liver biopsy. With supportive care, her condition improved, but it was noted that she had autoimmune enteropathy and Coombs-positive hemolytic anemia with thrombotic microangiopathy and subsequently developed nephrotic syndrome and progressive kidney insufficiency. Her lipodystrophy related abnormalities included severe insulin resistance (280 units /day with body weight: 41 lbs, hbA1c: 10.7), acanthosis nigricans and severe hypertriglyceridemia (varying between 600 to 6000 mg/dL) and hypertrophic cardiomyopathy. Recombinant metreleptin therapy was utilized during a 9-month hospitalization in 2016, but the patient could not sustain daily injections as an outpatient. Despite aggressive treatment of her kidney disease with specific immune therapies, her kidney disease and her enteropathy progressed. She is currently on hemodialysis, IVIG therapy, and abatacept, vedolizumab, and pentamidine. In conclusion, we report the novel association of CTLA-4 haploinsufficiency and concurrent presence of AGL and providing evidence that AGL can occur within the spectrum of immune dysregulation syndromes, opening the door to investigating these pathways as an etiology for an autoimmune variety of AGL.