Cortisone Reductase Deficiency 2

A number sign (#) is used with this entry because of evidence that cortisone reductase deficiency-2 (CORTRD2) is caused by heterozygous mutation in the HSD11B1 gene (600713) on chromosome 1q32.

Description

Cortisone reductase deficiency (CRD) is a disorder in which there is a failure to regenerate the active glucocorticoid cortisol from cortisone via the enzyme 11-beta-hydroxysteroid dehydrogenase, encoded by the HSD11B1 gene. Purified 11-beta-HSD acts readily as a dehydrogenase, inactivating cortisol to cortisone; however, in the presence of a high NADPH/NADP+ ratio, generated in vivo through the activity of microsomal hexose-6-phosphate dehydrogenase (H6PD; 138090), 11-beta-HSD switches to ketoreductase activity and generates active glucocorticoid. Lack of cortisol regeneration stimulates ACTH-mediated adrenal hyperandrogenism, with males manifesting in early life with precocious pseudopuberty and females presenting later with hirsutism, oligomenorrhea, and infertility. Biochemically, CRD is diagnosed through the assessment of urinary cortisol and cortisone metabolites and consists of measuring the ratio of tetrahydrocortisol (THF) plus 5-alpha-THF to tetrahydrocortisone (THE), which in CRD patients is typically less than 0.1 (reference range, 0.7 to 1.2) (summary by Lawson et al., 2011).

For a discussion of genetic heterogeneity of cortisone reductase deficiency, see CORTRD1 (604931).

Clinical Features

Lawson et al. (2011) studied 2 unrelated boys who presented at 8 years and 13 years of age, respectively, with hyperandrogenism and premature pseudopuberty with biochemical features of cortisone reductase deficiency. The 8-year-old boy had premature pubarche and advanced bone age, whereas the 13-year-old boy had recent-onset obesity with clinical signs suggestive of insulin resistance (acanthosis nigricans) and hyperandrogenemia. Measurement of urinary cortisone and cortisol metabolites revealed abnormally low THF plus 5-alpha-THF/THE ratios in both patients; the cortols-to-cortolone ratio, which reflects the secondary metabolism of cortisol and cortisone, was also low compared to age- and sex-specific reference values. Absolute levels of cortisol metabolites were low to normal, but those of cortisone metabolites were very high, consistent with a blockage in 11-beta-HSD1 (HSD11B1; 600713)-mediated cortisone-to-cortisol conversion. Analysis of family members revealed that both boys' mothers had urine biochemistry identical to those of their offspring, whereas the fathers had normal values. Calculated cortisol secretion rates, based on summation of all cortisol and cortisone metabolites, appeared to be increased in the boys and their mothers, but levels for the fathers were within the reference range. Androgen metabolite excretion levels were markedly elevated in both boys and were in the upper range of normal or higher in their mothers, whereas excretion in the fathers was normal.

Molecular Genetics

In 2 young boys with a mild form of cortisone reductase deficiency, in whom no mutations were detected in the H6PD gene (138090), Lawson et al. (2011) identified heterozygosity for different missense mutations in the HSD11B1 gene (600713.0002 and 600713.0003). The mutations were inherited from their mothers, who had similar biochemical profiles.