Monogenic and Polygenic Models Detected in Steroid 21-Hydroxylase Deficiency-Related Paediatric Hyperandrogenism

Abstract

Aims: Hyperandrogenism, although mostly due to polygenic interactions, is monogenic for some enzymatic adrenal deficiencies. This study evaluates mono- and biallelic 21-hydroxylase deficiency (21OHD)-related hyperandrogenism in pediatric patients. Sensitizing and protective polymorphisms were investigated in carriers and cryptic forms of 21OHD. Methods: The study involved a monogenic analysis of CYP21A2 in patients (375 nonclassical 21OHD [NC21OHD] children; 306 hyperandrogenic 21OHD carriers, n = 306) and a polygenic association study (CAPN10-UCSNP44, PON1-108, TNFR2-M196R, IGF2-ApaI and IRS1-G972R polymorphisms) of 170 hyperandrogenic carriers plus 277 family members (control groups). The metabolic marker 17OH progesterone defined the degree of deficiency; clinical expressivity was determined by pediatric endocrinologists. Results: The group of 21OHD carriers manifesting hyperandrogenism was enriched in the CAPN-UCSNP44 rare variant in homozygosity (4.9 vs. 0.4%, NCBI data for the general population; p = 0.004). In our patients and controls, contrasting distributions were observed for this and another polymorphism, TNFR2-196R. In a recessive model, their rare variants were more frequently detected among the forms with high (p = 0.048) and low (p = 0.034) expressivity respectively. Conclusions: 21OHD-related pediatric hyperandrogenism follows monogenic and polygenic models. The opposite behaviors in terms of clinical expressivity detected for CAPN-UCSNP44 and TNFR2-M196R rare variants suggest these variants to be sensitizing and protective factors respectively in adrenal hyperandrogenism.

Molecular Diagnosis of Steroid 21-Hydroxylase Deficiency: A Practical Approach

“…A proper threshold for 17-OHP values is difficult to define since some carriers are prone to present a hyperandrogenism similar to that shown in NCF ( 56 , 85 , 90 – 92 ). Genotyped carriers inside fully characterized segregated families are useful to achieve this goal ( 56 , 91 ). Compound heterozygosity with severe alleles in NCF may be suspected based on 17-OHP levels ( Figure 2A and Supplementary Table 3 ) ( 56 , 63 ) conversely to what happen with carriers of severe vs. mild variants.…”

“…The cut-offs for maximum predictive values are represented by small, empty squares in the Figures. (2B) [From Ezquieta et al., ( 91 )] Diagram of a hypothetical interaction between protective and sensitizing factors modulating the clinical expressivity of 21-OHD-related hyperandrogenism. CAPN10-UCSNP44C and TNFR2-R196 are proposed in this study to be sensitizing and protective factors, respectively.…”

“…Monogenic and polygenic models in paediatric hyperandrogenism due to 21-OHD have been detected ( 91 )( Figure 2B ), being carriers (monoallelic) with hyperandrogenism the counterpart of cryptic forms (biallelic alterations) without clinical expression. Considering the important contribution of the “back door” pathway to circulating levels of the potent androgen 11-ketotestosterone in CAH ( 93 , 94 ), investigation of gene variants coding for the enzymes involved seems interesting.…”

“…The biochemical marker 21-deoxicortisol detects carriers ( 10 , 40 , 95 ), although only molecular analyses are able to discriminate carriers of severe alleles. Individuals with hyperandrogenism and moderately elevated post-ACTH 17-OHP levels (not reaching the NCF threshold) may take benefit from CYP21A2 analyses since alterations are more frequent in these patients ( 91 ) ( Supplementary Table 2 ).…”

Prevalence and Clinical Outcome of CYP21A2 Gene Mutations in Patients with Nonfunctional Adrenal Incidentalomas

“…Furthermore V281L and P30L were reported in 4 % of Austrian-Yugoslavic nonbiased subjects [26]. Ezquieta et al estimated carrier frequency of V281L in Spain at 7.5 % in 300 neonates [27] and 7.8 % in the group of 102 life partners of analyzed CAH subjects [28]. To the best of our knowledge, there are no Polish data published evaluating the prevalence of CYP21A2 gene mutations either in general or in CAH patients populations.…”