J Clin Res Pediatr Endocrinol. Ahead of Print: JCRPE-76588 | DOI: 10.4274/jcrpe.galenos.2022.2022-3-4

Identification of a Novel CYP11B2 Variant in a Family with Varying Degrees of Aldosterone Synthase Deficiency

Mark R. Garrelfs¹, Tuula Rinne², Jacquelien J. Hillebrand³, Peter Lauffer¹, Merijn W. Bijlsma⁴, Hedi L. Claahsen-van Der Grinten⁵, Nicole De Leeuw², Martijn J.J. Finken¹, Joost Rotteveel¹, Nitash Zwaveling-soonawala¹, Max Nieuwdorp⁶, A.S. Paul van Trotsenburg¹, Christiaan F. Mooij^1
1Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam and Vrije Universiteit, Amsterdam, the Netherlands.
²Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
³Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam University Medical Centers, University of Amsterdam and Vrije Universiteit, Amsterdam, the Netherlands
⁴Department of Pediatrics, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam and Vrije Universiteit, Amsterdam, the Netherlands
⁵Department of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
⁶Department of Endocrinology, Amsterdam University Medical Centers, University of Amsterdam and Vrije Universiteit, Amsterdam, The Netherlands.

Isolated aldosterone synthase deficiency is a rare autosomal recessive disorder caused by pathogenic variants in CYP11B2, resulting in impaired aldosterone synthesis. We report on a neonate with isolated aldosterone synthase deficiency caused by a novel homozygous CYP11B2 variant Chr8: NM_000498.3: c.400G>A p.(Gly134Arg). The patient presented shortly after birth with severe signs of aldosterone deficiency. Interestingly, segregation analysis revealed that the patient’s asymptomatic father was also homozygous for the CYP11B2 variant. Biochemical evaluation of the father indicated subclinical enzyme impairment, characterized by elevated aldosterone precursors. Apparently, this homozygous variant led to different clinical phenotypes in two affected relatives. In this manuscript we elaborate on the performed biochemical and genetic work-up and describe potential pitfalls of CYP11B2 sequencing due to its homology to CYP11B1.

Keywords: Aldosterone Synthase, Mineralocorticoid, CYB11B2, Hypoaldosteronism

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