Congenital Hyperreninemic Hypoaldosteronism Unlinked to the Aldosterone Synthase (CYP11B2) Gene

Abstract

Isolated hyperreninemic hypoaldosteronism presenting in infancy is usually caused by mutations in the CYP11B2 gene encoding aldosterone synthase. We studied five patients in four unrelated kindreds with hyperreninemic hypoaldosteronism, in whom we were unable to find such mutations. All presented in infancy with failure to thrive, hyponatremia, hyperkalemia, markedly elevated plasma renin activity, and low or inappropriately normal aldosterone levels. All had normal cortisol levels and no signs or symptoms of congenital adrenal hyperplasia. All responded to fludrocortisone treatment. There were no mutations detected in exons or splice junctions of CYP11B2. Linkage of the disorder to CYP11B2 was studied in two unrelated consanguineous patients and in an affected sib pair. The consanguineous patients were each heterozygous for at least one of three polymorphic microsatellite markers near CYP11B2, excluding linkage to CYP11B2. However, linkage of the disease to CYP11B2 could not be excluded in the affected sib pair. Genes involved in the regulation of aldosterone biosynthesis, including those encoding angiotensinogen, angiotensin-converting enzyme, and the AT1 angiotensin II receptor were similarly excluded from linkage. These results demonstrate the existence of an inherited form of hyperreninemic hypoaldosteronism distinct from aldosterone synthase deficiency. The affected gene(s) remain to be determined.

Rare causes of acute hyperkalemia in the 1st week of life

“…Selective HA is usually (but not always) caused by a mutation in the gene encoding the enzyme aldosterone synthase, leading to two distinct types of aldosterone synthase deficiency, types I and II [2,18]. The biochemical difference between the two types is that 18-hydroxycorticosterone (18OH-B, an aldosterone precursor) is deficient in type I but overproduced in type II [2].…”

Congenital hyperreninemic hypoaldosteronism due to aldosterone synthase deficiency type I in a Portuguese patient – Case report and review of literature

“…Although most cases of AS deficiency reported a mutation on the CYPB11B2 gene, this condition has recently been associated with cases of patients with clinically and biochemically presumed AS deficiency with no identified mutations on the CYP11B2 gene, emphasising a bigger heterogeneity and possible other mechanisms associated with the disease -mutations in genes encoding other renin-aldosterone system components (such as angiotensinogen, angiotensinconverting enzymes and angiotensin II-receptor) or other regulatory genes of AS function. Encouraging the report of cases not linked to the CYPB11B2 gene mutations is important precisely to estimate the proportion of patients without positive genetic analysis and contribute to a broad comprehension of the molecular basis of the condition (6,9).…”

“…Typically, the disease manifests in the first weeks of life with nausea, vomiting, feeding problems and failure to thrive in the neonatal period. Isolated aldosterone deficiency is associated with neonatal salt-wasting syndrome resulting in hyponatremia, hyperkalaemia, metabolic acidosis and marked elevated renin with low or unappropriated normal aldosterone levels (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Usually, clinical severity improves with age and patients are frequently asymptomatic during adulthood despite not having mineralocorticoid therapy (16).…”

Neonatal salt‐wasting and 11 β‐hydroxylase deficiency in a child carrying a homozygous deletion hybrid CYP11B2 (aldosterone synthase)–CYP11B1 (11 β‐hydroxylase)

“…This homozygous chimeric genotype in a non‐consanguineous family is a rare finding. Because microsatellite typing has proven useful for documenting consanguinity in an apparently non‐consanguineous family with a homozygous rare allele of 21‐OHD (22), the polymorphic microsatellite D8S1704 (23) was analyzed. Two different alleles (163 and 167 pb) were detected in the present patient, but recombinant events separating both, the indirect marker and the mutant gene, may not be discarded.…”