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CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

CORTICOSTERONE METHYLOXIDASE TYPE I DEFICIENCY

Alternative titles; symbolsCMO I DEFICIENCYALDOSTERONE DEFICIENCY IHYPERRENINEMIC HYPOALDOSTERONISM, FAMILIAL, 1; FHHA1AALDOSTERONE DEFICIENCY DUE TO DEFECT IN S...

Alternative titles; symbols

  • CMO I DEFICIENCY
  • ALDOSTERONE DEFICIENCY I
  • HYPERRENINEMIC HYPOALDOSTERONISM, FAMILIAL, 1; FHHA1A
  • ALDOSTERONE DEFICIENCY DUE TO DEFECT IN STEROID 18-HYDROXYLASE
  • 18-HYDROXYLASE DEFICIENCY
  • STEROID 18-HYDROXYLASE DEFICIENCY

▼ Description
CMO type I deficiency is an autosomal recessive disorder caused by a defect in the penultimate biochemical step of aldosterone biosynthesis, the 18-hydroxylation of corticosterone (B) to 18-hydroxycorticosterone (18-OHB). This enzymatic defect results in decreased aldosterone and salt-wasting. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal. These patients have an increased ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998).

The CYP11B2 gene product also catalyzes the final step in aldosterone biosynthesis: the 18-oxidation of 18-OHB to aldosterone. A defect in that enzymatic step results in CMO type II deficiency (610600), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO II deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18-OHB. These patients have a low ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998).

▼ Clinical Features
Visser and Cost (1964) and Degenhart et al. (1966) reported 3 Dutch infants, from a large consanguineous family, who presented in early infancy with dehydration, failure to thrive, poor feeding, vomiting, and intermittent fever. Laboratory studies showed hyponatremia and hyperkalemia, consistent with salt-wasting. Urinary aldosterone was undetectable and corticosterone and 11-deoxycorticosterone were increased. Total urinary excretion of 17-ketosteroids, 17-ketogenic steroids, and 17-hydroxycorticosteroids was normal. Mineralocorticoid (deoxycorticosterone acetate) supplementation was successful. Postmortem examination of 1 affected infant who died of infection showed grossly normal adrenals, but microscopic examination showed poor development of the zona glomerulosa and hyperplasia of the juxtaglomerular apparatus. The findings suggested a metabolic defect affecting biosynthesis of aldosterone at the step between corticosterone and aldosterone. All 6 parents of the 3 patients shared a great-grandparental ancestral couple in common.

In a follow-up of the family reported by Visser and Cost (1964), Peter et al. (1997) found decreased plasma levels of aldosterone and 18-OH-corticosterone and increased plasma corticosterone and 11-deoxycorticosterone. Cortisol and its precursors were in the normal range. The findings were consistent with a defect in 18-hydroxylation of corticosterone, thus confirming the diagnosis of CMO type I deficiency.

Drop et al. (1982) knew of 6 reported cases.

Kayes-Wandover et al. (2001) reported a 47-year-old man who first presented with CMO type I deficiency after developing hyperkalemia in preparation for a barium enema. Past medical history was notable for failure to thrive in infancy. Laboratory analysis showed increased serum renin with low serum and urinary levels of aldosterone, increased urinary corticosterone, and decreased urinary 18-hydroxycorticosterone.

▼ Molecular Genetics
In 3 Amish patients with CMO type I deficiency, Mitsuuchi et al. (1993) identified a homozygous 5-bp deletion in the CYP11B2 gene (124080.0003).

In 2 individuals with CMO I deficiency reported by Visser and Cost (1964), Peter et al. (1997) identified a homozygous mutation in the CYP11B2 gene (124080.0006). All 4 unaffected parents were heterozygous for the mutation.

In a man who presented in middle age with CMO type I deficiency, Kayes-Wandover et al. (2001) identified a homozygous 6-bp duplication in the CYP11B2 gene (124080.0009).

Tags: 8q24.3