Genotype Is Associated to the Degree of Virilization in Patients With Classic Congenital Adrenal Hyperplasia

Abstract

Background: Molecular defects of CYP21A2 consistently decrease 21-hydroxylase activity and result in a variable expression of disease severity in patients with congenital adrenal hyperplasia (CAH).Aim: The genotype and biochemical findings were examined in an attempt to reveal any association to the degree of virilization in classic CAH patients.Methods: The study included 18 CAH patients with complete characterization of CYP21A2 mutations and were sorted based on the severity of the inherited mutations and the expected percentage of 21-hydroxylase enzyme activity.Results: Eleven out of the 18 patients manifested the SW form with the remaining seven exhibiting the SV form. The most frequent genetic defect in the classic salt-wasting (SW) and simple virilising (SV) forms was the IVS2-13A/C>G (36.1%) mutation, followed by delEX1-3 (19.4%) and p.Ile172Asn (19.4%). Four patients, who shared a combination of two mutations belonging to the most severe type, manifested only the SW form. Four out of five patients who shared homozygosity in the IVS2-13A/C>G mutation, demonstrated the SW form and only one demonstrated the SV form. All four patients who shared the p.Ile172Asn mutation, either in the homozygous or compound heterozygous state, manifested the SV form. Interestingly, a female neonate with SW, bearing the IVS2-13A/C>G/Large del, exhibited complete male virilisation (Prader 5). The remaining four affected female new-borns also exhibited the SW form, with two of them virilised as Prader 3 and the other two as Prader 4. Virilisation with clitoromegaly was also observed in one female, who presented premature adrenarche and carried the least severe p.Pro30Leu mutation.Conclusion: The frequency of the underlying mutations in our patients, with the classic form of CAH, varies but were quite similar to the ones reported in the Mediterranean region. Therefore, the identification of severe CYP21A2 defects in Cypriot patients and their comparison with the incidence and severity in different populations, will create a valuable diagnostic tool for genetic counseling in the classic form of CAH.

The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis

“…Eight out of nine patients in mutation group A exhibited the classical SW form and one presented the SV form. All four patients in group B had the SV form in accordance with the genotype p.Ile172Asn [18]. The majority of patients (85.0 %) categorized as group C exhibited the NC-CAH form with predominance in females (71.7 %) (▶Table 1).…”

“…Group B included patients homozygous for a less severe (p.Ile172Asn) or com-pound heterozygous with mutations from null or A group mutations, where the residual enzyme activity in in vitro expression experiments is about 2 % [29]. Patients in the null, A, and B groups were described in detail in a recent publication by our group [18]. Group C contained patients who were homozygous for p.Val-281Leu, or compound heterozygotes with p.Pro30Leu, DelEx1-3, p.Gln318stop, p.Pro482Ser, p.Val304Met, p.Met283Val, cluster E6, 30 kb del, and p.Pro453Ser.…”

“…Since 2007 our group has extensively studied the genetic implication of CYP21A2 in Cypriot patients with CAH. These included the true carrier frequency in the general population of Cyprus [10], the genotype-phenotype association with the various forms of CAH [14][15][16][17][18], the impact of heterozygosity in female patients with hyperandrogenemia [19,20], and the implication of variants in the untranslated 5′UTR region of the CYP21A2 gene [21]. In the present update, we present the molecular genetic features of the disease in patients of Cypriot descent over the last 11 years.…”

Primary Adrenocortical Insufficiency Case Series in the Neonatal Period: Genetic Etiologies Are More Common Than Expected

“…Currently, a general correlation between genotype and phenotype of CAH has been established, but the mutation phenotype does not always correlate precisely the genotype and phenotype ( 16 ). The most frequent genetic defect in classic form of CAH is IVS2-13A/C>G (36.1%), followed by deletion of exon 1–3 (19.4%), which both lead to extremely low enzyme activity ( 17 ). The combination of mutations IVS2-13A/C>G or c.955C>T (exon 8) with a large deletion has been associated with the most severe salt-wasting phenotype ( 18 – 20 ).…”

“…The combination of mutations IVS2-13A/C>G or c.955C>T (exon 8) with a large deletion has been associated with the most severe salt-wasting phenotype ( 18 – 20 ). The combination of c.955C>T (exon 8) with c.1069C>T (exon 8) has also been associated with salt-wasting phenotype ( 17 ). An 8-bp deletion in exon 3, reported as 706_713del8bp in this study, caused a nonsense mutation in exon 3 and was associated with salt wasting ( 17 ).…”