Nevena Krnić

Incidence of type 1 diabetes mellitus in 0 to 14‐yr‐old children in Croatia – 2004 to 2012 study

The incidence of type 1 diabetes mellitus (T1DM) among children and adolescents increased during the last 50 yr. The T1DM incidence in Croatia was 8.87/100.000/yr over 1995–2003, with an annual increase of 9%, which placed Croatia among countries with moderate risk for T1DM.

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

Aims: To evaluate the incidence, gender, symptoms and age at diagnosis among 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 01.01.1995 and 31.12.2006 and were compared with the data of the 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 females/8 males) and 14 simple virilizing (SV) patients (7 females/7 males). If 3 female fetuses, electively aborted, were added, that would be a total of 37 CAH patients. With 532,942 live births and 34 CAH patients born over this period, incidence of classical CAH was estimated to 1:15,574 or 1:14,403 if 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 substantial proportion of SW boys die unrecognized. Owing to better health care, 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 of improvement in health care, diagnosis of CAH in Croatia is still delayed and some of the patients go unrecognized or die. Therefore, we think that the results of our study support the need for the introduction of newborn screening.

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

The CYP21A2 mutations that are in linkage disequilibrium with particular HLA‐A, ‐B, ‐DRB1 alleles/haplotypes, cause deficiency of the 21‐hydroxylase enzyme (21‐OHD) and account for the majority of congenital adrenal hyperplasia (CAH) cases. The aim of this study was to investigate those associations with the p.V282L mutation linked to the non‐classical (NC) form of CAH among Croatians. The study included parents of patients with the NC form of CAH, positive for the p.V282L mutation (N = 55) and cadaveric donor samples (N = 231). All subjects were HLA‐A, ‐B, and ‐DRB1 typed and tested for the presence of the p.V282L mutation. Among parents of patients, 92.73% of subjects were positive for the B*14:02 allele and almost half of them carried the HLA‐A*33:01‐B*14:02‐DRB1*01:02 haplotype. Among cadaveric samples 77 out of 96 subjects positive for the B*14:02 allele had the p.V282L mutation. Among them, 37 were positive for the HLA‐A*33:01‐B*14:02‐DRB1*01:02 haplotype, 23 had the HLA‐A*33:01‐B*14:02‐DRB1*03:01 haplotype, 8 had the B*14:02‐DRB1*01:02 combination and 5 were carrying the HLA‐A*68:02‐B*14:02‐DRB1*13:03 haplotype. Only 4 of these subjects were positive for the B*14:02 allele. HLA‐B*14:02 was the only single allele with association that reached statistically significant P value (RR = 12.00; P = 0.0024). Haplotypes B*14:02‐DRB1*01:02 (P < 0.001) and HLA‐A*68:02‐B*14:02‐DRB1*13:03 (P < 0.001) as well as HLA‐A*33:01‐B*14:02‐DRB1*01:02 and HLA‐A*33:01‐B*14:02‐DRB1*03:01 showed high relative risks (RR = 45.00, RR = 41.63 and RR = 36.96, respectively). Our data support the previously documented association of the HLA‐A*33:01‐B*14:02‐DRB1*01:02 haplotype with the p.V282L mutation, but also point out a high frequency of the p.V282L mutation among Croatians with HLA‐A*33:01‐B*14:02‐DRB1*03:01 and HLA‐A*68:02‐B*14:02‐DRB1*13:03 haplotypes.