open access: Nature Reviews: Key Advances in Medicine

gene that encodes steroid 11β-hydroxylase
and is regulated by adrenocorticotropic
hor mone (ACTH)—and coding sequences
from CYP11B2—a gene that encodes aldosterone
synthase and is primarily regulated
by angiotensin II. Expression of this hybrid
gene leads to ACTH-regulated aldo sterone
overproduction. 2 Glucocorticoids, in small
doses, suppress hybrid gene expression
and ameliorate primary aldosteronism and
hypertension. Because wild-type CYP11B1
is expressed in the zona fasciculata (ZF)
of the adrenal cortex, so is the hybrid gene
(Figure 1). Thus, aberrant aldosterone synthase
activity, normally restricted to the
zona glomerulosa (ZG), occurs in the ZF. In
contrast to the ZG, which lacks the steroid
17α-hydroxylase enzyme necessary for the
formation of cortisol precursors, cortisol is
available as a substrate for aldosterone synthase
in the ZF. Hence, cortisol is converted
into the ‘hybrid steroids’ 18-hydroxycortisol
and 18-oxocortisol, the levels of which are
elevated in patients with FH-I. 2
The second recognized form of familial
hyperaldosteronism (FH-II) is neither
gluco corticoid-suppressible nor associ ated
with the hybrid gene mutation. 3 Approximately
30% of patients with FH-II have
uni lateral forms of primary aldosteronism
(mostly due to an aldosterone-producing
ade noma [APA]), with the remainder
being bilateral (due to bilateral adrenal
hyper plasia [BAH]). The genetic basis of
FH-II remains uncertain and is almost certainly
hetero geneous; several families have
demon strated linkage of FH-II with a locus
at chromosome 7p22. 3
In 2011, Mulatero and colleagues assessed
prevalence rates of familial hyper aldo steronism
among 300 patients consecutively
diag nosed with primary aldosteronism,
after exclud ing those suspected or diagnosed
as having a form of familial primary
aldo steronism. 4 Hybrid gene testing yielded
only two (0.7%) patients with FH-I. Of
the remaining 298 study participants, 199
had relatives available for and consenting
to bio chemical screening by aldosterone–
renin ratio (ARR) testing and, where positive,
definitive confirmation or exclusion
of primary aldo steronism by saline infusion
testing. This analysis revealed that 12
patients had at least one affected relative,
result ing in a preva lence of FH-II of at least
6% (almost 10-fold that of FH-I). The prevalence
could be higher, as another 54 patients
were classified as having ‘uncertain’ status,
either because not all family members
with hypertension underwent ARR testing
or because testing of family members
was inconclusive. 4
In a major breakthrough towards further
understanding the genetic basis of primary
aldosteronism, Choi and col leagues
reported somatic mutations (Gly151Arg and
Leu168Arg) in KCNJ5, which encodes an
inwardly-rectifying K + channel, in eight of 22
patients with APA. 5 A third, germline mutation
in KCNJ5 (Thr158Ala) had pre viously
been identified in affected members of a
US family with a new familial form of primary
aldosteronism (FH-III). 6 The affected
father and two daughters demon strated
very severe primary aldo steronism, with
childhood-onset hyper tension, hypo kalemia
and markedly elevated aldosterone and
sup pressed renin levels. As in patients with
FH-I, 18-hydroxycortisol and 18- oxocortisol
levels were elevated, albeit to a greater
degree. How ever, the primary aldosteronism
was not glucocorticoid-suppressible, and
the hybrid gene mutation was not present.
Resected adrenal glands showed marked,
diffuse hyperplasia of the ZF, with the combined
weight of both adrenal glands in one
daughter reaching 81 g (normal