2.1. 3$-HSD-Deficient NCAH
NCAH resulting from 3P-HSD deficiency has been purportedly diagnosed in 1-15% of children with premature pubarche (3,4) and a variable frequency of females with hirsutism and menstrual disorders with pubertal or postpubertal onset (5-7). In these early studies, patients were presumed to suffer from 3 P-HSD-deficient NCAH if they demonstrated a pregnenolone (PREG), 17-hydroxy-pregnenolone (17-HPREG), dehydroepiandrosterone (DHEA), and/or androstenediol (ADIOL) peak value, or a PREG:P4, 17-HPREG:17-HP, DHEA:A4, or ADIOL:testosterone ratio above the 90th or 95th percentile of normal during acute adrenocorticotropic hormone (ACTH)-(1-24) stimulation testing (5,7-9). However, when compared to those used for diagnosing 21-OH-deficient NCAH (see Subsection 126.96.36.199.), these criteria appear to be exceedingly lax, particularly since it is well documented that the adrenal cortex is overactive in a significant proportion of individuals with polycystic ovary syndrome (PCOS) (10).
Only the study of individuals with a confirmed mutation of the 3P-HSD gene can yield an accurate assessment of the endocrinological features and diagnostic criteria of the disorder. Two types of 3P-HSD genes, type I and II, have been reported (HSD3B1 and HSD3B2, respectively). Although both encode for gonadal enzymes, the HSD3B1 primarily determines extra-adrenal enzymatic activity and the HSD3B2 encodes for the intra-adrenal 3P-HSD protein. Consequently, 3P-HSD-deficiency CAH (and presumably NCAH) results from mutations of HSD3B2. However, several studies of hirsute females and children with premature pubarche presumed to have 3P-HSD-deficient NCAH by the previously published hormonal criteria have been unable to confirm the diagnosis upon molecular analysis of HSD3B2 (11-14). In fact, Pang and colleagues have nicely demonstrated that the majority of patients with an exaggerated 17-HPREG response to ACTH stimulation primarily suffer from PCOS (15).
To date, patients with molecularly proven defects of HSD3B2 (and no mutation of HSD3B1) have had stimulated 17-HPREG values that were at least 20-50 standard deviations greater than age-matched controls (i.e., in adult women >90 ng/mL), and all have presented in childhood (14). Excluding children diagnosed at birth or those with ambiguous genitalia, these studies suggested that 3 P-HSD-deficient NCAH could be present in children with premature pubarche when the 17-HPREG level was 95.8 ng/mL or more (294 nmol/L), 54 standard deviations (SD) or more above Tanner II pubic hair stage-matched control mean level; and in adults when the 17-HPREG levels were greater than 94.2 ng/mL (289 nmol/L), equivalent to or greater than21 SD above the normal mean level (14).
Consequently, the number of patients with true, genetically verifiable, 3 P-HSD-deficient NCAH appears to be extremely small, if at all. In a prospective study of 86 consecutive patients with either hirsutism and/or hyperandrogenic oligomenorrhea, none demonstrated an ACTH-stimu-lated 17-HPREG value greater than threefold the upper normal limit (~15 ng/mL), nowhere close to the values found in patients with genetically confirmed type II 3P-HSD gene defects (8). In fact, as yet no patient with genetically proven 3 P-HSD-deficient NCAH presenting in adulthood has been observed. In view of the limited number of patients with genetically confirmed 3 P-HSD-deficient NCAH diagnosed to date, it is difficult, if not impossible, to make any kind of accurate statement regarding their clinical features, pathophysiology, or diagnostic scheme at this time.
Investigators have suggested that some hyperandrogenic women suffer from 11-OH-deficient NCAH (16-19). However, it should be stressed that the same diagnostic uncertainties noted for 3P-HSD-deficient NCAH are found in the study of 11-OH (i.e., P450c11)-deficient NCAH. P450c11 is encoded by CYP11B1, a gene located on chromosome 8q21-22 in tandem with the CYP11B2 gene, which encodes for aldosterone synthase (20). Deficiency of 11-OH results from mutations in CYP11B1, and patients with both alleles encoding inactive enzymes have 11-OH-deficient CAH.
To confirm the diagnosis of 11-OH-deficient NCAH and potentially develop diagnostic criteria, we genotyped five patients with presumed 11-OH-deficient NCAH (21). Three were children (two females and one male) who presented with advanced bone age, accelerated growth, acne, and precocious adrenarche. Two of these were found to have mutations of both CYP11B1 alleles, defects that affected enzymatic expression in vitro. One of these two individuals had an 11-deoxycortisol level after ACTH stimulation of 41 ng/mL (upper normal limit of controls was <8 ng/mL), the other had a urinary tetrahydro-11-deoxycortisol level of 1690 ^g/24 hours (upper normal limit of controls was less than 50 ^g/24 hours). No mutations of the coding regions or intron/exon boundaries of the CYP11B1 genes in the third child could be detected. In addition, we studied two adult hyperandrogenic women with presumed 11-OH-deficient NCAH, neither of which had mutations of their CYP11B1 genes (21). These last two patients had ACTH-stimulated 11-deoxycortisol levels of 22 and 24 ng/ mL and were the only women with 11-deoxycortisol values threefold greater than the normal limit discovered during a study of 260 consecutive hyperandrogenic patients (19).
In conclusion, 11-OH-deficient NCAH is an extremely rare cause of adult hyperandrogenism, if it exists at all. Patients with 11-OH-deficient NCAH appear to have 11-deoxycortisol values (either after ACTH stimulation or as urinary metabolite) that are at least fivefold the upper normal limit, although the number of patients studied is insufficient to arrive at any firm conclusion.
2.3. 21-Hydroxylase-Deficient NCAH 2.3.1. Pathophysiology of 21-OH-Deficient NCAH
The pathophysiology of 21-OH-deficient NCAH must be considered from both a genetic and an endocrinological perspective.
188.8.131.52. Genetic Pathophysiology of 21-OH-Deficient NCAH
Cytochrome P450c21 is responsible for adrenal 21-OH activity, catalyzing the conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol, and progesterone (P4) to deoxycorticosterone (20). The gene encoding for P450c21 (CYP21) exists in tandem with a pseudogene (CYP21P). Each gene has 10 exons and 9 introns, although CYP21P has 88 mutations that render it nontranscribable. These genes are located in tandem with the human leukocyte antigen (HLA) locus on chromosome 6 next to the gene for the fourth component of complement (C4) and a gene for the extracellular matrix protein called tenascin-x (X) (22). The genes for CYP21, C4, and X are all duplicated, such that there are C4A and C4B, CYP21 and CYP21P, and XA and XB pairs. Both C4 genes are actively transcribed, whereas CYP21P and XA are inactive.
To date, approx 100 different CYP21 mutations have been reported (23-31), mostly point mutations, alhough small deletions and complete gene deletions and small insertions have also been described. Approximately 17 mutations account for about 95% of all of affected alleles (Table 1). The majority are primarily derived from the intergenic recombination of DNA sequences between the CYP21 gene and the highly homologous CYP21P (a process termed gene conversion), while the remaining are spontaneous mutations. Occasionally, patients may demonstrate multiple mutations of their CYP21 alleles.
Initially CAH and NCAH were not thought to share genetic defects because the severity of the disorders is so different. However, with the genotyping of increasing numbers of affected patients it has become clear that most individuals with NCAH and CAH are "compound heterozygotes" carrying different genetic mutations on each CYP21 allele (Fig. 1). In fact, approximately two-thirds of NCAH patients are compound heterozygotes (10), carrying a gene defect encoding for a mutation resulting in severe defects in P450c21 function (<2% wild-type activity) on one allele, whereas the other carries a mutation that determines a mild defect in the enzyme (i.e., 20-50% of wild-type activity) (Table 1).
Common Mutations of CYP21 Resulting in 21-Hydroxylase (21-OH)-Deficient Nonclassic Adrenal Hyperplasia (NCAH) and Salt-Wasting (SW-CAH) and Simple Virilizing (SV-CAH) Classic Adrenal Hyperplasia
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