AARSKOG SYNDROME, AUTOSOMAL DOMINANT
-AARSKOG SYNDROME, AUTOSOMAL DOMINANT
Hyperandrogenism due to cortisone reductase deficiency
-AARSKOG SYNDROME, AUTOSOMAL DOMINANT
-Rare endocrine disease
-Rare genetic disease
-Rare gynecologic or obstetric disease
Comment:
Cortisone reductase deficiency (CRD) is characterized by a failure to regenerate cortisol from cortisone via 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess (PMID:18628520).
Cortisone reductase deficiency (CRD) results from a failure to regenerate the active glucocorticoid cortisol from cortisone via the enzyme 11-beta-hydroxysteroid dehydrogenase (HSD11B1; 600713). The oxoreductase activity of 11-beta-HSD requires the NADPH-regenerating enzyme hexose-6-phosphate dehydrogenase (H6PD; 138090) within the endoplasmic ...Cortisone reductase deficiency (CRD) results from a failure to regenerate the active glucocorticoid cortisol from cortisone via the enzyme 11-beta-hydroxysteroid dehydrogenase (HSD11B1; 600713). The oxoreductase activity of 11-beta-HSD requires the NADPH-regenerating enzyme hexose-6-phosphate dehydrogenase (H6PD; 138090) within the endoplasmic reticulum. Lack of cortisol regeneration stimulates ACTH-mediated adrenal hyperandrogenism, with males manifesting in early life with precocious pseudopuberty and females presenting in midlife with hirsutism, oligomenorrhea, and infertility. Biochemically, CRD is diagnosed through the assessment of urinary cortisol and cortisone metabolites and consists of measuring the tetrahydrocortisol (THF) plus 5-alpha-THF/tetrahydrocortisone (THE) ratio, which in CRD patients is typically less than 0.1 (reference range, 0.7 to 1.2) (summary by Lavery et al., 2008). - Genetic Heterogeneity of Cortisone Reductase Deficiency CORTRD2 (614662) is caused by mutation in the HSD11B1 gene (600713) on chromosome 1q32-q41
A syndrome consistent with type I 11-beta-hydroxysteroid dehydrogenase (HSD11B1) deficiency had been described in 3 female patients, 2 of whom were sibs (Taylor et al., 1984; Phillipou and Higgins, 1985; Savage et al., 1991; Phillipov et al., 1996). The ...A syndrome consistent with type I 11-beta-hydroxysteroid dehydrogenase (HSD11B1) deficiency had been described in 3 female patients, 2 of whom were sibs (Taylor et al., 1984; Phillipou and Higgins, 1985; Savage et al., 1991; Phillipov et al., 1996). The ratio of metabolites of cortisol to those of cortisone was very low in these patients. In addition, 5-beta-reduced metabolites (see SRD5B1; 604741) of cortisol and cortisone were excreted in preference to 5-alpha-reduced metabolites (see SRD5A1; 184753). Because of enhanced peripheral clearance of cortisol, there was less negative feedback suppression of ACTH-dependent steroids, and the patients presented with features of adrenal androgen excess. Nikkila et al. (1993) found no mutation in the coding region of the HSD11B1 gene in one of these patients. In the absence of a confirmed defect in the HSD11B1 gene, Phillipov et al. (1996) termed the syndrome 'apparent cortisone reductase deficiency.' Jamieson et al. (1999) studied a 36-year-old woman with oligomenorrhea, hirsutism, and acne. She was plethoric and overweight with central fat distribution. Plasma cortisol was normal, but her adrenal glands were enlarged on CT scan. Urinary tetrahydrocortisone excretion rate was consistently high, raising the possibility of HSD11B1 deficiency. In addition, 5-beta reduction of cortisol and cortisone was markedly enhanced. The levels of all cortisol metabolites were suppressed normally with dexamethasone, but conversion of oral cortisone acetate to plasma cortisol was delayed and subnormal compared with that of healthy subjects. This was accompanied by a larger than normal increase in plasma cortisone concentration. Thus, the defect appeared to be in HSD11B1 activity and not in 5-beta-reductase activity. Three close relatives of the subject showed no comparable abnormalities, and analysis of the coding region and exon/intron boundaries of the subject's HSD11B1 gene revealed no differences from the consensus sequence. Jamieson et al. (1999) suggested that the defect may lie outside the coding region, or that some other inherited or acquired defect may lead to inhibition of this enzyme system. Biason-Lauber et al. (2000) reported a 55-year-old woman with oligomenorrhea, androgenetic alopecia, slight hirsutism, and infertility, who had mildly elevated blood pressure but normal lipid profile and fasting glucose and insulin levels. CT scan of the abdomen revealed bilateral adrenal hyperplasia and masses in both ovaries, and the patient underwent bilateral adnexectomy with the diagnosis of cystic teratomas. Postoperative urinary steroid analysis showed a decreased THF/THE ratio, and plasma cortisol was repeatedly elevated with exogenous sources excluded. Mass spectrometry demonstrated that the tetrahydro metabolites were mainly cortisone-derived, whereas the metabolites not reduced in the A ring were mostly cortisol derivatives, a constellation of findings consistent with CRD. Biason-Lauber et al. (2000) stated that this was the fifth reported case of apparent cortisone reductase deficiency (ACRD). Lavery et al. (2008) restudied 4 patients with ACRD, including the woman of Scottish descent originally reported by Jamieson et al. (1999) and studied by Draper et al. (2003), the woman reported by Biason-Lauber et al. (2000), and the Indo-Asian woman and boy of Polish descent studied by Draper et al. (2003). In all 4 cases, the THF plus 5-alpha-THF/THE ratios were lower than those in than age- and sex-specific reference cohorts. The ratio of urinary cortols to cortolones, which reflects secondary metabolism of cortisol and cortisone, respectively, was also low in these patients, and metabolites of cortisol were low to normal, whereas the metabolites of cortisone were extremely elevated compared to age- and sex-specific reference cohorts; these findings were consistent with a block in HSD11B1-mediated cortisone-to-cortisol conversion. The adult female patients demonstrated a clearly elevated cortisol secretion rate, whereas that of the young male case was in the upper limit of the reference range
In the woman of Scottish descent with CRD studied by Jamieson et al. (1999) and in 2 other patients, Draper et al. (2003) found triallelic digenic inheritance of mutations in the HSD11B1 (600713.0001) and H6PD (138090.0001; 138090.0002) genes. ...In the woman of Scottish descent with CRD studied by Jamieson et al. (1999) and in 2 other patients, Draper et al. (2003) found triallelic digenic inheritance of mutations in the HSD11B1 (600713.0001) and H6PD (138090.0001; 138090.0002) genes. Noting that large-scale population-based studies from 3 centers (Draper et al., 2006; Smit et al., 2007; White, 2005) had shown that the variants found by Draper et al. (2003) were polymorphisms rather than disease-causing mutations, Lavery et al. (2008) restudied 4 patients with ACRD, including the woman of Scottish descent originally reported by Jamieson et al. (1999), the woman reported by Biason-Lauber et al. (2000), and the Indo-Asian woman and boy of Polish descent studied by Draper et al. (2003). Lavery et al. (2008) detected no mutations or sequence variants in the HSD11B1 gene. Sequencing the H6PD gene revealed 4 novel mutations and 1 previously reported mutation in homozygous or compound heterozygous state (138090.0003-138090.0006 and 138090.0001, respectively) in all 4 patients. Expression and activity assays demonstrated loss of function for all 5 mutations, which were not found in 120 control chromosomes. Lavery et al. (2008) concluded that CRD can be explained solely by inactivation of the H6PD gene and stated that in the earlier study by Draper et al. (2003), these mutations in H6PD were either missed or presumed to be silent and thus of no relevance