*3.2. Familial Hyperaldosteronism Type II*

Familial hyperaldosteronism type II (FH type II) was first described by Stowasser et al. [15] in a kindred with an autosomal dominant form of PA. Other kindreds were subsequently described and a linkage with a locus on chromosome 7p22 was reported in some but not all families but sequencing the entire linked locus did not identify the genetic cause [16]. In 2018, Scholl et al. [17] identified the genetic variant responsible in the original kindred with FH type II described by Michael Stowasser as a heterozygous variant of the *CLCN2* gene that caused early-onset primary aldosteronism and hypertension often with hypokalaemia. *CLCN2* encodes CIC-2, a homodimer voltage-gated chloride channel expressed in the adrenal gland predominantly in the ZG [17]. In the original family with FH type II, eight individuals were carriers of the *CLCN2* mutation (resulting in the CIC-2 p.Arg172Gln substitution) and of these, seven tested positive with a screening test for primary aldosteronism (elevated aldosterone-to-renin ratio). One carrier for the CIC-2 p.Arg172Gln variant had a normal aldosterone-to-renin ratio, and therefore did not have primary aldosteronism, indicating an incomplete penetrance of the allele. Scholl et al. found the p.Arg172Gln substitution in an additional kindred and two further cases of p.Arg172Gln mutations (1 occurring de novo) in 2 unrelated patients with early-onset PA [17] as well as other *CLCN2* variants encoding 4 different mutations in CIC-2 (a de novo p.Met22Lys mutation, p.Tyr26Asn, p.Ser865Arg and p.Lys362del). At the same time, Fernandes-Rosa et al., reported a de novo heterozygous p.Gly24Asp mutation in the CIC-2 chloride channel associated with PA [18]. Electrophysiological recordings showed that the mutated CIC-2 channels display modified gating resulting in increased chloride efflux compared with wild-type CIC-2 channels. The increased chloride efflux leads to depolarization of adrenocortical cells, activation of voltage-dependent Ca2+ channels, Ca2+ influx, increased *CYP11B2* gene expression and aldosterone production.
