Abstract: PUB175
Rare Heterozygous CFH Variant in Sporadic Case of Atypical Hemolytic Uremic Syndrome (aHUS) Initially Presenting with Severe Hypertension
Session Information
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Tran Thuy, Huong Quynh, Kansai Medical University, Second Department of Internal Medicine, Renal Division, Hirakata, Osaka, Japan
- Ueda, Hiroko, Kansai Medical University, Second Department of Internal Medicine, Renal Division, Hirakata, Osaka, Japan
- Pham, Xuyen Thi, Kansai Medical University, Department of Cardiovascular Surgery, Hirakata, Osaka, Japan
- Kato, Noritoshi, Nagoya University Graduate School of Medicine, Department of Nephrology, Nagoya, Aichi, Japan
- Maruyama, Shoichi, Nagoya University Graduate School of Medicine, Department of Nephrology, Nagoya, Aichi, Japan
- Tsukaguchi, Hiroyasu, Kansai Medical University, Second Department of Internal Medicine, Renal Division, Hirakata, Osaka, Japan
Introduction
Atypical hemolytic-uraemic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal failure in the absence of Shiga toxin A. aHUS is induced by dysregulation of the alternative complement pathway leading to complement-mediated kidney injury. The dysregulation clinically becomes overt in association with environmental triggers and genetic predisposition. We present a sporadic aHUS case with CFH variant who initially manifested hypertensive crisis in his middle age.
Case Description
A 40-year-old man first presented with renal dysfunction (eGFR 10 ml/min/1.73m2), hypertensive emergency, and cardiomyopathy. He had hematological features of thrombotic microangiopathy (TMA), but showed normal levels of C3 and C4. Antibody for complement factor H (CFH) was negative. His TMA manifestation was relieved by antihypertensive medication. Four months later, however, the TMA recurred after enterocolitis. Plasmapheresis effectively improved hypertension and thrombocytopenia. Genetic testing revealed a rare heterozygous p.Cys659Arg variant in the CFH gene, a variant of uncertain significance (VUS) by ACMG criteria. Structurally, p.Cys659Arg variant impairs the conserved Cys residue forming the 11th short consensus repeats in the mid-region.
Discussion
The CFH represents the most prevalent cause of sporadic aHUS (15% to 20%). Screening the CFH gene is particularly important because CFH variants are associated with a poor prognosis, about 50% of whom progress to the End Stage Renal Disease (ESRD). Genetic testing for aHUS will improve patient outcomes by making earlier diagnosis of aHUS, guiding personalized medicine, e.g. eculizumab, facilitating genetic counseling, and preventing recurrence of TMA in renal allografts. Functional assay and variant data sharing are necessary to accurately validate the pathogenicity of variants.