Severe Aldosterone Synthase Deficiency in a 9-Day-Old Lebanese Boy: The Importance of Functional Studies to Establish Pathogenicity of Seemingly Benign Variants in <i>CYP11B2</i>

Abstract

<b><i>Introduction:</i></b> Aldosterone synthase deficiency is a rare autosomal recessive disease characterized by vomiting, dehydration, salt wasting, life-threatening hyperkalemia in infancy, followed by failure to thrive. It results from pathogenic variants in <i>CYP11B2</i>. <b><i>Case Presentation:</i></b> A boy, born in Montreal to Lebanese parents who are first cousins, was referred at 9 days of life for severe dehydration. A diagnosis of primary adrenal insufficiency was made, and treatment was started with fludrocortisone and hydrocortisone. Exome sequencing revealed a homozygous variant p.(Asn201Asp)(N201D) in <i>CYP11B2</i>. In silico, this variant was considered benign, but in vitro functional expression studies established it caused the severe aldosterone deficiency. It ended the diagnostic odyssey and allowed to safely stop hydrocortisone replacement. <b><i>Conclusion:</i></b> If a gene variant co-segregates with a phenotype, in vitro functional studies are required even if in silico studies are negative.