#604931
ICD+
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| CORTISONE REDUCTASE DEFICIENCY | ||||||||||||||||||||||||
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| 11-BETA-HYDROXYSTEROID DEHYDROGENASE, TYPE I, DEFICIENCY OF HSD11B1 DEFICIENCY | ||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||
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| A number sign (#) is used with this entry because this disorder has been shown to demonstrate a triallelic digenic pattern of inheritance involving mutations in the HSD11B1 (600713) and H6PD (138090) genes. 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. In the patient studied by Jamieson et al. (1999) and in 2 other patients, Draper et al. (2003) showed triallelic digenic inheritance of the phenotype caused by mutation in the HSD11B1 (600713.0001) and H6PD (138090.0001; 138090.0002) genes. Because the phenotype of cortisone reductase deficiency resembles that of polycystic ovary syndrome (PCOS; 184700), San Millan et al. (2005) investigated the R453Q variant of H6PD (138090.0002) and the 83557insA variant of HSD11B1 (see 600713.0001) in 116 patients with PCOS and 76 nonhyperandrogenic controls. Four controls and 5 patients presented 3 of 4 mutant alleles in H6PD R453Q and HSD11B1 83557insA, which is the genotype observed in some subjects with CRD. Estimates of 11-beta-HSD oxoreductase activity were measured in 6 of these 9 women, ruling out CRD. Patients homozygous for the R453 allele, which was more frequent in PCOS patients, presented with increased cortisol and 17-hydroxyprogesterone levels compared with carriers of Q453 alleles; these differences were not observed in controls. HSD11B1 83557insA genotypes were not associated with PCOS and did not influence any phenotypic variable. San Millan et al. (2005) concluded that digenic triallelic genotypes of the H6PD R453Q variant and HSD11B1 83557insA mutation do not always cause CRD. They also suggested that the H6PD R453Q variant is associated with PCOS and might influence its phenotype by influencing adrenal activity. | ||||||||||||||||||||||||
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