Anita Špehar Uroić

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.

Primary hypothyroidism and nipple hypoplasia in a girl with Wolcott–Rallison syndrome

Wolcott–Rallison syndrome (WRS), caused by mutation in the EIF2AK3 gene encoding the PERK enzyme, is the most common cause of permanent neonatal diabetes mellitus (PNDM) in consanguineous families and isolated populations. Besides PNDM, it also includes skeletal abnormalities, liver and renal dysfunction, and other inconsistently present features. We present two siblings, who are WRS patients, and are Albanians from Kosovo born to unrelated parents. The older sister presented with PNDM, exocrine pancreatic insufficiency, short stature, microcephaly, normocytic anemia, delay in speech development, skeletal abnormalities, primary hypothyroidism, and hypoplastic nipples. Sequencing of the EIF2AK3 gene identified a homozygous mutation R902X in exon 13. The younger brother was diagnosed with PNDM and died from hepatic failure suggesting that he has been suffering from WRS as well. Including one previously reported patient from Kosovo carrying the same homozygous mutation, there are three WRS patients from this very small, ethnically homogenous region suggesting founder effect in this population. Conclusion: We postulate that thyroid hypoplasia with primary subclinical hypothyroidism already reported in two WRS patients and nipple hypoplasia could also be the phenotypic reflection of the mutation of pleiotropic EIF2AK3 gene in secretory cells.

Five patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (one with associated neuroblastoma) discovered in three generations of one family.

Background: Most patients with 21-hydroxylase deficiency (21-OHD) are compound heterozygous carriers. Their phenotype usually reflects a less severe allelic mutation, although discordance between the genotype and the phenotype has been observed. Case Report: We present 5 patients with congenital adrenal hyperplasia (CAH) due to 21-OHD belonging to the 3 generations of the same family (grandmother, parents and their 2 children). As each patient carries at least one mild mutation of the CYP21 gene, their genotypes correspond to nonclassical CAH. The propositus is the older brother, who is compound heterozygous with a mild and severe CYP21 mutation (P30L/R356W). In spite of one mild CYP21 mutation, he presented with the clinical picture of a simple virilizing form of 21-OHD and required glucocorticoid replacement therapy from the age of 4. Both probands’ parents are compound heterozygous carriers of different CYP21 gene mutations causing various degrees of enzymatic activity impairment, which explains the different genotypes and phenotypes in their offspring. The probands’ mother, besides the nonclassical 21-OHD, also had neuroblastoma of the adrenal gland. Conclusion: The potential discordance between the genotype and the phenotype in some patients with CAH is emphasized. The existence of a mild CYP21 mutation P30L in a compound heterozygous with CAH might be associated with progressive virilization requiring glucocorticoid therapy from early childhood. The occurrence of neuroblastoma with 21-OHD may support the hypothesis that an impairment in the synthesis and secretion of glucocorticoids may play role in the development and functioning of the adrenal medulla.

Glycosyltransferase B4GALNT1 and type 1 diabetes in Croatian population: clinical investigation.

OBJECTIVES Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by destruction of pancreatic beta cells. Gangliosides are thought to be a target of a variety of anti-islet autoantibodies. The formation of gangliosides is catalyzed by addition of sugar residues to complex glycoconjugate molecules by glycosyltransferases. Beta-1,4-N-acetyl-galactosaminyl transferase 1 is the enzyme involved in the synthesis of asialo, a, b and c-series gangliosides and it is coded by B4GALNT1 gene. DESIGN AND METHODS We genotyped 2 B4GALNT1 tagSNPs, designed to capture 100% of common variation in the region, in 202 families and 199 controls from the Croatian population. RESULTS Transmission disequilibrium test and case-control analysis did not detect an association of B4GALNT1 gene with T1DM. CONCLUSIONS Expression of gangliosides requires coordinated work of many genes. There is enough evidence showing that gangliosides are plausible contributors to T1DM pathological processes and, therefore, future studies on different glycosyltransferase genes are necessary.