We report on a case of a 50-year-old female patient with primary hyperaldosteronism, in whom adrenal venous sampling was required to differentiate between unilateral and bilateral disease. Because of a history of severe allergy to iodinated contrast media, premedication with glucocorticoids was indicated. Exogenous glucocorticoids, however, can affect measurements of serum cortisol. To avoid this potential confounding effects on the cortisol assay, we decided to use dexamethasone instead of prednisolone or hydrocortisone. A high-dose adrenocorticotropin (ACTH) stimulation test with the simultaneous use of dexamethasone revealed an adequate adrenal cortisol response. ACTH-stimulated adrenal venous sampling showed reliable results, which provided a solid basis for further clinical decision-making.

Somatic mutations driving aldosterone production have been identified in approximately 90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided DNA sequencing approach. In the present study, using CYP11B2-guided whole-exome sequencing (WES) and targeted amplicon sequencing, we detected 2 somatic variants in CLCN2 in 2 APAs that were negative for currently known aldosterone-driver mutations. The CLCN2 gene encodes the voltage-gated chloride channel ClC-2. CLCN2 germline variants have previously been shown to cause familial hyperaldosteronism type II. Somatic mutations in CLCN2 were identified in 2 of 115 APAs, resulting in a prevalence of 1.74%. One of the CLCN2 somatic mutations (c.G71A,p.G24D) was identical to a previously described germline variant causing early-onset PA, but was present only as a somatic mutation. The second CLCN2 mutation, which affects the same region of the gene, has not been reported previously (c.64-2_74del). These findings prove that WES of CYP11B2-guided mutation-negative APAs can help determine rarer genetic causes of sporadic PA.

Bartter syndrome (BS) and Gitelman syndrome (GS) are renal tubular disorders affecting sodium, potassium, and chloride reabsorption. Clinical features include muscle cramps and weakness, in association with hypokalemia, hypochloremic metabolic alkalosis, and hyperreninemic hyperaldosteronism. Hypomagnesemia and hypocalciuria are typical of GS, while juxtaglomerular hyperplasia is characteristic of BS. GS is due to SLC12A3 variants, whereas BS is due to variants in SLC12A1, KCNJ1, CLCNKA, CLCNKB, BSND, MAGED2, or CASR. We had the opportunity to follow up one of the first reported cases of a salt-wasting tubulopathy, who based on clinical features was diagnosed with GS. The patient had presented at age 10 years with tetany precipitated by vomiting or diarrhea. She had hypokalemia, a hypochloremic metabolic alkalosis, hyponatremia, mild hypercalcemia, and normomagnesemia, and subsequently developed hypocalciuria and hypomagnesemia. A renal biopsy showed no evidence for juxtaglomerular hyperplasia. She developed chronic kidney failure at age 55 years, and ocular sclerochoroidal calcification, associated with BS and GS, at older than 65 years. Our aim was therefore to establish the genetic diagnosis in this patient using whole-genome sequencing (WGS). Leukocyte DNA was used for WGS analysis, and this revealed a homozygous c.226C > T (p.Arg76Ter) nonsense CLCNKB mutation, thereby establishing a diagnosis of BS type-3. WGS also identified 2 greater than 5-Mb regions of homozygosity that suggested likely mutational heterozygosity in her parents, who originated from a Greek island with fewer than 1500 inhabitants and may therefore have shared a common ancestor. Our results demonstrate the utility of WGS in establishing the correct diagnosis in renal tubular disorders with overlapping phenotypes.