Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency in Croatia between 1995 and 2006

Abstract

Aims: To evaluate the incidence, gender, symptoms and age at diagnosis of patients with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency in Croatia. Methods: Data were collected retrospectively for all classical CAH patients born or electively aborted following prenatal diagnosis between January 1, 1995 and December 31, 2006 and were compared with the data of a previously conducted study evaluating CAH patients discovered between 1964 and 1984. Results: During a 12-year period 34 classical CAH patients were born. There were 20 salt-wasting (SW; 12 female/8 male) and 14 simple-virilizing (SV; 7 female/7 male) patients. If 3 female, electively aborted fetuses were added, there would be a total of 37 CAH patients. With 532,942 live births and 34 CAH patients born over this period, the incidence of classical CAH was estimated at 1:15,574 or 1:14,403 if the 3 electively aborted fetuses were included. The lower incidence of SW boys compared to SW girls (8:12) and similar number of SW and SV boys (8:7) indicate that a substantial proportion of SW boys die unrecognized. Owing to better healthcare, the diagnosis was established significantly earlier in SW and SV girls compared to the period of 1964–1984 (p < 0.003). During 1995–2006, none of the patients died following the diagnosis of CAH and there was no erroneous sex assignment. Conclusion: Despite improvements in healthcare, the diagnosis of CAH in Croatia is still delayed and some of the patients go unrecognized or die. Therefore, the results of our study support the need to introduce newborn screening.

Association of HLA alleles and haplotypes with CYP21A2 gene p. V282L mutation in the Croatian population

“…A significant linkage between the p.V282L mutation and the HLA‐A*33:01‐B*14:02‐DRB1*01:02 haplotype observed in our study is in concordance with previously reported results from other studies .…”

“…Linkage disequilibrium has been demonstrated to exist between particular HLA‐A, ‐B, and ‐DRB1 alleles or haplotypes and CYP21A2 mutations . The p.V282L mutation has been reported to be associated with the HLA‐B14 antigen and ‐DR1 antigen among patients with NC form of the disease , while some other studies reported on the association with a single HLA antigen, but a combination of those HLA specificities have not been reported before .…”

No evidence of an increase in early infant mortality from congenital adrenal hyperplasia in the absence of screening

“…A Welsh cohort from 1966–77 had a significant excess of females34 whereas a case series from Birmingham found an increased prevalence of females overall, from 1958–85 but not from 1970–85, coinciding with the introduction of 17-OHP assays and appointment of a paediatric endocrinologist 13. The reduction in mortality rates over time in recognised CAH suggests that healthcare has improved and there is better awareness of CAH 14 19 35 36. Serum electrolyte analysis is widely available and perhaps more readily performed in vomiting neonates than during the period of the Welsh study.…”

Steroid 11-beta hydroxylase deficiency caused by compound heterozygosity for a novel mutation in intron 7 (IVS 7 DS+4A to G) in one CYP11B1 allele and R448H in exon 8 in the other

“…In the recent study on CAH due to 21-OHD carried out in Croatia incidence was estimated to be 1:14,403, but incidence of 11β-OHD (which accounts for 3-8% of overall CAH cases in other population) in Croatia is unknown [3]. Besides previously reported two brothers with 11β-OHD [4], one more male patient (unpublished) is registered in Croatia.…”