Corticosterone Methyloxidase Type Ii Deficiency

A number sign (#) is used with this entry because corticosterone methyloxidase type II deficiency (CMO II deficiency) is caused by mutation in the CYP11B2 gene (124080).

Description

CMO type II deficiency is an autosomal recessive disorder caused by a defect in the final biochemical step of aldosterone biosynthesis, the 18-hydroxylation of 18-hydroxycorticosterone (18-OHB) to aldosterone. This enzymatic defect results in decreased aldosterone and salt-wasting associated with an increased serum ratio of 18-OHB to aldosterone. 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).

The CYP11B2 gene product also catalyzes an earlier step in aldosterone biosynthesis: the 18-hydroxylation of corticosterone to 18-OHB. A defect in that enzymatic step results in CMO type I deficiency (204300), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal (Portrat-Doyen et al., 1998).

Clinical Features

Royer et al. (1961) and Ulick et al. (1964) first reported a familial salt-losing disorder due to a defect in aldosterone biosynthesis apparent in the neonatal period.

David et al. (1968) reported 2 infant Puerto Rican sibs with growth retardation associated with aldosterone deficiency. The clinical manifestations were subtle; 1 infant had transient abnormalities in serum electrolytes. The enzymatic defect was in the final conversion of 18-hydroxycorticosterone to aldosterone. Rappaport et al. (1968) observed 2 brothers with a salt-losing syndrome due to decreased aldosterone. The authors postulated a defect in 18-OH-dehydrogenase. Spontaneous improvement occurred.

Rosler et al. (1973, 1977) reported a syndrome of profound salt wastage in 12 children from 8 Iranian Jewish families. Most families came from a relatively isolated community in Isfahan, Iran, with a high incidence of consanguinity; 3 of the families were related. Symptoms began at a few weeks of age and the external genitalia were normal. The children responded to heavy supplements of salt in their diet and to exogenous salt-retaining steroids. Aldosterone deficiency was due to an inborn error involving the terminal portion of the biosynthetic pathway and characterized by marked overproduction of 18-hydroxycorticosterone relative to aldosterone. The ratio, normally less than 3.0, was often greater than 100 in untreated patients with the defect. Plasma aldosterone was not a reliable index since some patients had normal serum levels at the expense of marked elevation in plasma renin activity and overproduction of precursors. Further analysis suggested autosomal recessive inheritance in these families (Cohen et al., 1977).

Ulick (1976) suggested that the disorder characterized by an increased 18-hydroxycorticosterone to aldosterone ratio be termed 'type 2 corticosterone methyloxidase defect.' Hyperkalemia, hyponatremia and metabolic acidosis in the neonate, failure to thrive in infancy, or retardation of growth during early childhood are the usual features. The authors suggested that the defective gene in CMO type II deficiency has a greater fitness than that for 21-hydroxylase deficiency (201910) because it is less life-threatening to the infant and probably does not impair reproduction in untreated females.

Veldhuis et al. (1980) reported a North American family with CMO type II deficiency ascertained through a male infant with profound salt wasting and marked reduction in serum and urinary aldosterone levels despite striking hyperreninemia. Concurrent elevations in plasma and urinary levels of 18-hydroxysteroids localized the defect to CMO II. Salt replacement, but not hydrocortisone, ameliorated the clinical and metabolic abnormalities. Six other relatives were affected in an autosomal recessive pattern. The severity of clinical manifestations was inversely correlated with age, showing apparent amelioration in adulthood. Veldhuis et al. (1980) noted that detection of the disorder could be difficult because it may present in infancy merely as failure to thrive and growth retardation. Unexplained hyperkalemia may be the main diagnostic clue in adults; lethal hyperkalemia may occur with salt depletion.

Lee et al. (1986) studied 2 sibs with CMO type II deficiency. The serum ratio of 18-OHB to aldosterone was greatly elevated and declined to normal with mineralocorticoid replacement. However, linear growth was deficient after cessation of mineralocorticoid therapy despite maintenance of normal serum electrolytes. Increased ratios in both parents suggested a means for carrier detection. The authors suggested that the ratio could also be used as an indicator of adequacy of mineralocorticoid replacement. Lee et al. (1986) stated that about 25 patients had been reported.

Hauffa et al. (1991) reported 2 boys, born of consanguineous Hungarian gypsy parents, with CMO type II. Both presented with infection-triggered, life-threatening salt loss and hyperkalemia. Laboratory studies showed increased plasma 18-OHB. In 1 of the brothers, in whom the diagnosis was established at the age of 1 year, treatment with 9-alpha-fluorocortisol was successful.

Picco et al. (1992) described CMO II deficiency as a cause of recurrent dehydration and severe failure to thrive in the first 3 months of life, associated with mild hyponatremia and hyperkalemia. The diagnosis was suggested by an elevated ratio of plasma renin to serum aldosterone and subsequently confirmed by an elevated ratio of serum 18-hydroxycorticosterone to aldosterone. Treatment with 9-alpha-fluorohydroxycortisone was successful.

Mapping

Using the restriction endonuclease MspI, Globerman et al. (1988) identified a unique DNA fragment within or near the CYP11B1 gene on chromosome 8 that cosegregated with CMO II deficiency in 6 affected families of Iranian Jewish origin. However, the authors noted that 11-hydroxylase activity was not affected by the putative mutation, suggesting that CMO II deficiency and 11-hydroxylase deficiency (202010) are distinct disorders and may be caused by different mutations in a single gene for a multifunctional enzyme.

Mayerova et al. (1991) used MspI restriction enzyme analysis to exclude a mutation in the CYP11B1 gene in a German family with CMO II deficiency.

Molecular Genetics

In affected individuals from 7 Jewish Iranian families with CMO II deficiency, Pascoe et al. (1992) identified homozygosity for 2 mutations in the CYP11B2 gene (R181W and V386A; 124080.0001). Eight asymptomatic individuals were homozygous for R181W alone and 3 asymptomatic individuals were homozygous for V386A alone, suggesting that both substitutions were necessary to cause the disorder. The families had previously been reported by Rosler et al. (1973, 1977), Cohen et al. (1977), and Globerman et al. (1988).

In a patient with CMO type II deficiency reported by Hauffa et al. (1991), Peter et al. (1998) identified a homozygous mutation in the CYP11B2 gene (124080.0007).