Reporting a Novel Homozygous Variant in the HSD11B2 Gene: Reclassifying the Variant Using Sherloc Refinement: A Case Report Study

 Apparent mineralocorticoid excess (AME) is an autosomal recessive disorder resulting from a deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) caused by mutations in the HSD11B2 gene. The mutated gene affects the enzyme activity which results in the rising of cortisol that can be associated with hypokalemia, severe low-renin mineralocorticoid, hypertension, and sodium retention. Few genetic variants, almost 40, have been reported in this gene and more genetic studies are necessary. In this study, we aim to investigate an Iranian patient suspected of being affected by AME.

 A 2.5-year-old girl from consanguineous parents was referred to Ali Asghar Children’s Hospital. She was born prematurely with a birth weight of 2.20 kg. Her chief complaint was fever, failure to thrive, polydipsia and polyuria. The initial diagnosis was cystic fibrosis (CF), but the results of the sweat test were normal. Other differential diagnoses were apparent mineralocorticoid excess syndrome type 2, Liddle syndrome, and Bartter syndrome type2. Biochemical tests performed on the patient’s free urine showed a high ratio, almost 12, of cortisol to cortisone. Whole exome sequencing (WES) was performed to find out the causative gene.

 WES showed a novel homozygous variant in the 11βHSD2 gene. According to the American College of Medical Genetics and Genomics (ACMG) guideline, it was a vindicated uncertain significance (VUS), but using Sherloc refinement suggested that this transversion mutation is most likely to be pathogenic.