ESPE2022 Poster Category 1 Adrenals and HPA Axis (52 abstracts)
Identification of a novel CYP11B2 variant in a family with varying degrees of aldosterone synthase deficiency
Mark Garrelfs 1 , Tuula Rinne 2 , Jacquelien Hillebrand 3 , Peter Lauffer 1 , Merijn Bijlsma 4 , Hedi Claahsen-van der Grinten 5 , Nicole de Leeuw 2 , Martijn Finken 1 , Joost Rotteveel 1 , Nitash Zwaveling-Soonawala 1 , Max Nieuwdorp 6 , Paul van Trotsenburg 1 & Christiaan Mooij 1
1Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam and Vrije Universiteit, Amsterdam, Netherlands; 2Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; 3Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam University Medical Centers, University of Amsterdam and Vrije Universiteit, Amsterdam, Netherlands; 4Department of Pediatrics, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam and Vrije Universiteit, Amsterdam, Netherlands; 5Department of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands; 6Department of Endocrinology, Amsterdam University Medical Centers, University of Amsterdam and Vrije Universiteit, Amsterdam, Netherlands
Background: Isolated aldosterone synthase deficiency is a rare autosomal recessive disorder caused by pathogenic variants in CYP11B2. To date, more than forty different pathogenic variants in the CYP11B2 gene causing isolated aldosterone synthase deficiency have been identified. We report on a novel pathogenic CYP11B2 variant.
Case report: The second child (male) of consanguineous, healthy parents, presented shortly after birth with severe signs of aldosterone deficiency. Initial biochemical analysis showed hyponatremia, hyperkalemia and metabolic acidosis. After ruling out glucocorticoid deficiency with a cosyntropin stimulation test, isolated mineralocorticoid deficiency or pseudohypoaldosteronism was suspected. Additional biochemical work-up revealed hyperreninemic hypoaldosteronism and clearly elevated aldosterone precursors, confirming the biochemical diagnosis of isolated aldosterone synthase deficiency.
Genetic analysis: Initial genetic analysis revealed a novel heterozygous variant of unknown significance in exon 3 of the CYP11B2 gene Chr8:NM_000498.3:c.400G>A p.(Gly134Arg). The heterozygous variant seemed an insufficient explanation for the observed phenotype of our patient. Because the variant was located in a large region of homozygosity, another set of primers was designed which led to the discovery that the c.400G>A variant was in fact present in the homozygous state. The initially used primers had also recognized and amplified the highly homologous region of the CYB11B1 gene, leading to false negative results. Segregation analysis on the patients asymptomatic parents and sister revealed that the mother and sister were heterozygous carriers but, surprisingly, the patient’s father appeared homozygous for the novel CYP11B2 variant. Biochemical evaluation of the father indicated subclinical enzyme impairment, characterized by low aldosterone and elevated aldosterone precursors.
In silico analysis: To gather more arguments for pathogenicity of the c.400G>A variant, in silico analyses were performed. Gly at position 134 is highly conserved across species and appears to be an exposed residue in the Cytochrome P450 domain of CYP11B2. The variant is predicted to be deleterious by multiple pathogenicity prediction methods. Protein modelling using PyMOL predicted that p.(Gly134Arg) has a positively charged appendicle in close proximity to the putative steroid product egress route, which probably influences protein-substrate dynamics. These findings support the pathogenicity of the reported novel homozygous CYP11B2 variant.
Conclusion: We report on a novel variant in CYP11B2 associated with varying degrees of isolated aldosterone synthase deficiency in the same family. Initial genetic analysis was complicated by homology of the CYP11B2 and CYP11B1 genes. In silico analyses, including protein modelling, provided additional evidence for pathogenicity of this novel variant.
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