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Diabetic ketoacidosis (DKA) is the leading cause of mortality in a type 1 diabetic mellitus (T1DM) in pediatric population. The prevalence of the DKA in the developed world ranges from 15% to 61% and in Croatia it is 33 to 36%. In the past few decades in Europe there have been no significant changes in the prevalence of DKA in patients with newly T1DM. In the previous preventive program known as the “Parma campaign”, which was conducted between 1991 and 1998 and reduced the prevalence of DKA from the initial 78% to the cumulative prevalence during the campaign of 12.5%. The aim of the prevention program was to reduce the prevalence of DKA in the Southern part of Croatia in children and adolescents with newly diagnosed T1DM.

The aim of this study was to investigate the relationship between pre-pregnancy body mass index (BMI) and fasting blood glucose level in pregnancy on the anthropometry of newborns. The sample consisted of 171 healthy pregnant women and their newborns from the Croatian Islands' Birth Cohort Study. Peripheral blood of pregnant women was taken in the second trimester and fasting glucose values >5.1 mmol/l were considered elevated. Anthropometric variables (body weight, height and waist circumference) were measured according to the International Biological Program. Pre- pregnancy BMI and fasting glucose levels during pregnancy were significantly positively correlated (p

Uvod: Kod djece i adolescenata se uz epidemiju debljine uočava porast incidencije ne samo dijabetesa tipa 1 i 2, već i novog fenotipa tzv. „dvostrukog, hibridnog ili 1, 5 dijabetesa” koji ima elemente i tipa 1 i tipa 2. To su debeli bolesnici s inzulinskom rezistencijom, hiperinzulinemijom i prisutnim autoantitijelima na antigene beta stanica gušterače. Ključnu patogenetsku ulogu u hibridnom dijabetesu možemo objasniti i teorijom akceleracije prema kojoj porast tjelesne mase dovodi do inzulinske rezistencije i slabljenja kontrole glikemije. Porast glikemije ubrzava apoptozu beta stanice, direktno ili poticanjem imunološkog odgovora u genetički sklonih osoba. Cilj: Prikazati kako dokazano stanje debljine, inzulinske rezistencije i hiperinzulinemije prethode razvoju autoimunosti na beta stanicu i potrebu određivanja antitijela na stanice pankreasa prije konačne dijagnoze dijabetesa tipa 2 kod svih pretilih adolescenata. Metode i ispitanici: Podatci su prikupljeni iz medicinske dokumentacije bolesnika praćenih kroz petogodišnje razdoblje u Klinici za dječje bolesti Split. Od 155-ero novotkrivenih bolesnika s dijagnozom dijabetesa izdvojili smo troje koji se uklapaju u dijagnozu dijabetesa tipa 1, 5. Rezultati: Prvom bolesniku u kronološkoj dobi (CA) od 11, 1 godina s indeksom tjelesne mase (ITM) iznad 95. centile za dob (ITM-SDS +3, 67) i manifestacijom dijabetesa: GUP (23, 4 mmol/L), inzulin natašte (41, 05 mIU/L),  C peptid na prijmu i natašte (1, 4 - 0, 86), HbA1c (7, 76%), uz naknadno pridošla pozitivna antitijela ICA (4, 0) i IA-2 (>400 IU/mL). Nakon 10 mjeseci uočava se pad C peptida natašte (0, 13). Postaje mikroalbuminuričan (Alb. > 300 mg/dan). Nakon 2, 8 godina uočava se daljni C peptida natašte uz prisutna pozitivna antitijela ICA (2, 5), IA2 (293), GAD (1143), uz pad ITM- SDS-a (3, 67 na 2, 04). Drugom bolesniku u CA 12, 47 godina dokazan je teški stupanj debljine (ITM-SDS 3, 08), hiperglikemija natašte (5, 9 mmol/L), inzulin na tašte (16, 9 mIU/L), povišen HOMA-R (4, 43). U kronološkoj dobi od 16, 05 godina imao je patološki OGTT test, Hb1Ac 7, 0%, C peptid natašte 0, 45, ITM- SDS je bio u padu na +2, 41, ICA (4, 0) i IA-2 (> 400) antitijela su bila pozitivna. Treća je preuhranjena bolesnica (ITM-SDS 1, 71 ili 95, 7 c.) kod koje smo u CA 12, 61 godina postavili dijagnozu poremećene tolerancije glukoze uz stanje inzulinske rezistencije (IR) i hiperinzulinemije. U CA 14, 3 godina bila je eutrofi čna, imala je „dijabetički oblik krivulje“ tijekom OGTT-a i povišeni HbA1c na 6, 1%, nije imala više hiperinzulinemiju i IR, IVGTT je bio patološki, a biljezi autoimunosti na beta stanicu (ICA, GADA, IA-2) bili su pozitivni. Rasprava/zaključak: Debljina u mladih osoba povezana je s povećanom učestalošću autoimunosti na beta stanicu te bi kod svakog pojedinačnog slučaja u onih s hiperglikemijskim sindromom i ITM iznad 95. centile za dob, trebalo razmatrati i entitet tzv. duplog, hibridnog ili 1, 5 dijabetesa.

The main goal of this study was to test the association of pre-pregnancy body mass index (BMI) and fasting glucose level in pregnancy on birth size of newborns. The sample consisted of 177 healthy pregnant woman and their newborns from the islands (Hvar and Brač) and the mainland (Split- Dalmatian County) who are participants in the Croatian Islands Birth cohort Study (CRIBS). Anthropometric variables (body weight, height and waist circumference) were measured according to the International Biological Program. Peripheral blood of pregnant women was taken between 22nd and 26th week of gestation, and fasting glucose values >5.1 mmol/L were considered elevated. Statistical analyses were done by SPSS10.0 for Windows. There was a significant positive correlation between pre-pregnancy BMI and fasting glucose levels during pregnancy as well as between pre- pregnancy BMI and birth weight, length, and head circumference of the newborns. Hyperglycemic women gave birth to significantly heavier newborn girls then normoglycemic women (p

Uvod: APECED (engl. Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy) ili autoimuni poliglandularni sindrom tip 1 rijetka je autosomno recesivna bolest koja uključuje široku mogućnost kombinacija autoimunosne destrukcije, prvenstveno endokrinog tkiva, kroničnu površinsku kandidijazu i ektodermnu distrofi ju. Višestruke mutacije gena AIRE (engl. AutoImmune REgulatory gene), smještenog na kromosomu 21q 22, 3 koji kodira sintezu proteina APECED, transkripcijskog regulatora, odgovorne su za nastanak APECED-a. Dijagnoza APECED-a postavlja se: 1.) klinički, na osnovi prisutnosti dvaju od triju velikih znakova (mukokutana kandidijaza - MK, hipoparatireoidizam - HP i Adissonova bolest - AB) ; 2.) imunološki, na osnovi pozitivnih protutijela protiv tip I. interferona omega i alfa (IFN-ω i IFN-α) koji se mogu detektirati dugo vremena prije pojave organ-specifi čnih protutijela, 3.) genetički, na osnovi mutacije gena AIRE. Klasična trijada (MK+HP+AB) razvije se u 2/3 bolesnika, a neki imaju i više od deset komponenata APECED-a. MK se kao prvi znak pojavljuje u 75-93% slučajeva, obično već u dojenačkom razdoblju. Zatim se pojavljuje HP, najčešće između četvrte i pete godine, a AB u školskoj dobi. Prije klasične trijade mogu se javiti periodična groznica s osipom, keratokonjuktivitis, autoimuni hepatitis, gastrointestinalna disfunkcija, alopecija i vitiligo. Cilj: Opisat će se naši bolesnici kao dokaz tvrdnji da je korelacija genotip - fenotip kompleksna, što sugerira da i neki drugi genetički i okolišni faktori utječu na kliničku prezentaciju i progresiju bolesti. Metode i ispitanici: Prikazat ćemo sedmero naših bolesnika, kojima je genskom analizom dokazana mutacija R257X u egzonu 6 gena AIRE. Rezultati: Troje od sedmero naših bolesnika imaju četiri endokrinopatije, dvoje ima tri endokrinopatije, jedan od njih s dijabetesom tip 1 umro je u 18. godini u stanju teške hipoglikemije. Dosad jedan bolesnik ima dvanaest znakova, dvoje imaju deset, dvoje devet, jedan tri znaka, dok jedan ima dva znaka sindroma. Neendokrine manifestacije su prolazne, dok su endokrine trajna stanja. Rasprava/zaključak: Slijed glavnih sastavnica sindroma kod naših bolesnika je relativno konzistentan. Izdvajamo onihodistrofi ju kao prvu neendokrinu manifestaciju kod troje od sedmero bolesnika. Kod svih je bolesnika dokazana mutacija R257X u egzonu 6 gena AIRE, koja se navodi kao najčešća u populaciji srednjoeuropske regije.

Thyroid antibodies against thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) are key markers of Hashimoto’s thyroiditis (HT). To explore genetic background of thyroid antibodies, we performed the first genome-wide association study (GWAS) of thyroid antibodies levels in 405 HT patients. GWAS analyses on TgAb and TPOAb levels were performed separately on a set of 6 007 542 genetic variants using GEMMA. To identify genetic variants that predispose to both thyroid antibodies, we additionally performed a bivariate analysis using MultiABEL. We detected two suggestively associated genetic variants with TgAb, rs6972286 close to ANKRD7 and LSM8 (P=2.34×10-7 ) and rs756763 inside CA10 (P=6.05×10-7 ) ; one with TPOAb, rs12507813 between TRIM61 and TRIM60 (P=4.95×10-7 ) ; and three with both antibodies (bivariate analysis), rs13190616 inside RP11- 138J23.1 (P=2.01×10-6 ), rs561030786 close to DUBR (P=7.33×10-6 ) and rs12713034 inside FSHR (P=7.66×10-6 ). All identified genomic regions have a substantial literature record of involvement with female-related traits, immunemediated diseases and personality traits that are all characterized by increased thyroid antibody levels. Our findings demonstrate the existence of genetic overlap between thyroid autoimmunity in HT and several non-thyroid diseases characterized by the presence of thyroid antibodies. We also suggest that genetic variants that regulate antibody levels may differ between HT patients and individuals with normal thyroid function.

Uvod: Klasična galaktozemija je autosomno recesivni poremećaj metabolizma galaktoze, uzrokovan mutacijom gena GALT, što rezultira nedostatnom aktivnošću enzima galaktoza-1-fosfat uridiltransferaze (GALT). Bolest se najčešće prezentira u novorođenačkoj dobi, nakon unosa laktoze (disaharid glukoze i galaktoze), sa žuticom, kataraktom, netolerancijom obroka, nenapredovanjem u tjelesnoj masi, hipotonijom, hipoglikemijom, hepatomegalijom, hepatocelularnim oštećenjem, renalnom tubularnom disfunkcijom te sklonošću sepsi, osobito onoj uzrokovanoj s E. coli. Cilj: Prikazat ćemo dva bolesnika s klasičnom galaktozemijom i prolaznom tercijarnom hipotireozom. Metode i ispitanici: Podatke smo izvadili iz povijesti bolesti dvaju bolesnika s klasičnom galaktozemijom liječenih na Klinici za ženske bolesti i porode te na Klinici za dječje bolesti KBC-a Split. Rezultati: Prvi bolesnik je muško novorođenče hospitalizirano u osmom danu života zbog hiperbilirubinemije i nenapredovanja u tjelesnoj masi, uz hepatomegaliju. Liječen je infuzijama glukoza- elektrolitnih otopina, fototerapijom te antibioticima parenteralno. Četvrtog dana boravka uz direktnu hiperbilirubinemiju uočava se porast transaminaza (AST i ALT). Petnaestoga dana boravka postao je letargičan, uz daljnje povećanje jetre te početni ascites. Reduktivne supstance u urinu su bile pozitivne. Zbog sumnje na galaktozemiju započeta je dijeta bez galaktoze, a djetetovo opće stanje se brzo popravilo. Dijagnoza je potvrđena nalazom visoke koncentracije galaktoza-1-fosfata u eritrocitima i odsutnom aktivnošću GALT enzima u eritrocitima. Molekularnom analizom gena GALT dokazano je da je bolesnik složeni heterozigot za Q188R/K285N mutacije. Tijekom prvog tjedna boravka nađe se nizak T3 i T4, uz normalan TSH. Testom TRH je dokazana tercijarna hipotireoza. Započeta je supstitucijska terapija levotiroksinom, koja je nakon dva mjeseca ukinuta. Drugi bolesnik je muško nedonošče koje od drugog dana života ima indirektnu hiperbilirubinemiju. Petog dana života zabilježena je hipoglikemija. Zbog pogoršanja kliničkog stanja uvode se antibiotici s kojima ne dolazi do poboljšanja. Klinički je novorođenče sve lošijeg općeg stanja, slabije spontane motorike i hipotono, uz nalaze koji upućuju na jetrenu leziju. U urinu su pozitivne reduktivne supstance, a GALT aktivnost u eritrocitima je 0%. Započne se dijeta bez galaktoze, na što se djetetovo opće stanje postupno popravlja, uz i dalje prisutnu hipotoniju. Obradom se dokaže tercijarna hipotireoza. Uvedemo supstitucijsku terapiju levotiroksinom, koja se provodila tri mjeseca. Molekularnom analizom gena GALT dokazano je da je bolesnik složeni heterozigot za Q188R/R33C mutacije, pri čemu je R33C dosad neopisana mutacija. Rasprava/zaključak: U novorođenčadi s dijagnosticiranom klasičnom galaktozemijom potrebno je kontrolirati hormone štitnjače s obzirom na opisane slučajeve prolazne tercijarne hipotireoze koja iziskuje supstitucijsku terapiju.

Uvod: Pretilost je jedan od najvećih javnozdravstvenih problema danas u populaciji djece i adolescenata. Inzulinska rezistencija (IR) je jedan od glavnih patofi zioloških mehanizama u stvaranju metaboličkih poremećaja u pretilosti. Metformin je registriran za liječenje šećerne bolesti tip 2 u djece starije od 10 godina, te je pokazano da pozitivno utječe na indeks tjelesne mase (ITM). Cilj: Prikazati utjecaj metformina na metaboličke parametre i ITM Z score nakon godinu dana liječenja. Metode i ispitanici: Retrospektivno je analizirano 62-je pretilih ispitanika s IR- om iz baze podataka Klinike za dječje bolesti KBC-a Split. Pretilost je defi nirana ITM Z score > 2, 00, a IR je defi niran HOMA-R indeksom > 3, 16 i/ili vrijednost inzulina u bilo kojoj točki proširenog OGTT > 150 μU/mL. Ispitanici su liječeni metforminom u dozi od 500 mg do 2000 mg na dan. Svim ispitanicima obavljena su antropometrijska mjerenja (tjelesna visina, tjelesna masa, te su izračunati ITM i ITM Z score), i laboratorijske analize (OGTT test s inzulinom u pet točaka, lipidogram), prije terapije i nakon godinu dana. Procjena IR-a izraču nata je uz pomoć indeksa HOMA-R i QUICKI, koji u obzir uzimaju bazalne vrijednosti glukoze i inzulina, te uz pomoć Matsuda indeksa koji u obzir uzima sve vrijednosti glukoze i inzulina iz OGTT testa u pet točaka. Rezultati: Prosječna dob ispitanika iznosila je 11, 2 ± 2, 9 godina, 25 (40, 3%) su dječaci, a 37 (59, 7%) djevojčice. Nakon jedne godine liječenja s metforminom pronađeno je značajno smanjene ITM (27, 51 ± 2, 14 vs. 24, 23 ± 3, 58 kg/m2, p < 0, 001), ITM Z score (2, 77 ± 0, 49 vs. 1, 94 ± 0, 68, p < 0, 001), prosječne glukoze u svih pet točaka iz OGTT (6, 62 ± 0, 88 vs. 6, 21 ± 0, 96 mmol/L, p = 0, 004), prosječnog inzulina u svih pet točaka iz OGTT (138, 11 ± 73, 5 vs. 80, 49 ± 56, 39 μU/mL, p < 0, 001), triglicerida (1, 26 ± 0, 69 vs. 0, 98 ± 0, 45mmol/L, p < 0, 001), HDL (1, 15 ± 0, 24 vs. 1, 26 ± 0, 27mmol/L, p < 0, 001), te indeksa HOMA-R (5, 36 ± 3, 41 vs. 3, 13± 1, 75, p < 0, 001), QUICKI (0, 31 ± 0, 02 vs. 0, 33 ± 0, 03, p < 0, 001) i Matsuda (1, 93 ± 0, 76 vs. 3, 75 ± 2, 05, p < 0, 001). Rasprava/zaključak: Rezultati ovog istraživanja upućuju na pozitivan utjecaj metformina u liječenju pretile djece i adolescenata s inzulinskom rezistencijom. Nakon godine dana liječenja metforminom pronadjeno je značajno poboljšanje metaboličkih parametara i ITM Z score. Potrebna su dodatna istraživanja koja bi pratila dugoročne učinke metformina na pretilu djecu i adolescente.

Homocysteine is an amino acid involved in several key metabolic processes. In the general population hyperhomocysteinaemia is an indicator of vascular disease, while in normal pregnancy homocysteine blood levels falls. The objective of this study was to examine associations of homocisteine in pregnant women with possible predisposing factors (older age, smoking status, physical inactivity, hypertension), pregnancy outcomes (preterm birth, small/normal/large for gestational age) and newborns` anthropometry (measures z- standardized according to WHO). Fasting homocisteine concentration, taken between 22nd and 26th week of gestation, were determined in 116 women, participants in the CRoatian Islands` Birth Cohort Study (CRIBS). Homocisteine below than referent range (3.4- 20.4 µmol/L) was determined in 19 women (16.4%) while its concentration in others was within the referent range. None of the investigated predisposing factors was significantly associated with predicting homocisteine level, nor were pregnancy outcomes. Newborns of mothers with homocisteine

Hashimoto’s thyroiditis (HT) is the most common autoimmune thyroid disorder defined as a chronic inflammation of the thyroid gland. It is characterized by the infiltration of lymphocytes and progressive destruction of thyroid tissue. Another distinguished feature of HT is the presence of elevated thyroid autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb). The aim of this study was to explore the genetic background of HT-associated traits, namely thyroid volume and thyroid antibodies, in HT patients by genome-wide association analysis (GWAS). The study included 430 HT patients recruited at the University Hospital Split (Croatia). Diagnosis of HT patients was based on clinical findings and laboratory parameters according to ETA recommendations and guidelines for Management of Subclinical Hypothyroidism. Participants were genotyped using the Illumina Infinium HumanCoreExome genotyping platform and imputed using the “1000 Genomes” reference panel and IMPUTE2 software. Association analysis of the resulting 8, 592, 875 genetic markers was performed using GEMMA software. Three analyzed traits were adjusted for covariates under standard linear regression model: thyroid volume was adjusted for gender, age, BSA, TSH, and levothyroxine therapy status whereas TPOAb and TgAb levels were adjusted for gender. Derived residuals were further included in the association analysis as a new phenotype for each trait under the linear mixed model, which accounts for population stratification and relatedness. We identified two genome-wide significant associations of intronic variants inside the AATF and CNDP1 genes (p=1.36×10-8, p=3.08×10-8, respectively) with thyroid volume. An additional genetic variant near the MIR8054 gene was suggestively associated with thyroid volume (p=2×10-7). No SNP reached genome-wide significance for thyroid antibodies ; however, we identified two suggestive associations of genetic variants near the FAM13A and TRIM61 genes with TPOAb levels (p=6.30×10-8, p=4.89×10-7, respectively) and two suggestive associations of genetic variants near GTF3AP6 and inside the CA10 gene with TgAb levels (p=2.27×10-7, p=6.48 ×10-7, respectively). Our most interesting signal resides within AATF (apoptosis antagonizing transcription factor), which is involved in the regulation of gene transcription and cell proliferation. Overexpression of this gene interferes with MAP3K12-induced apoptosis, whereas, inhibition of the same MAP3K12 activity is driven by MBIP, a gene that has already been associated with thyroid cancer and TSH level, giving further evidence of the biological relevance of this pathway in thyroid function. The second hit resides inside CNDP1 (carnosine dipeptidase 1), which is a human carnosinase mainly expressed in the central nervous system. In conclusion, our study identified novel, biologically interesting genes associated with thyroid volume and several suggested genes associated with thyroid antibodies in HT patients. These findings represent a good basis for further exploration of underlying genetics of HT determinants.

The intrauterine environment affects fetal growth and development. Healthy women with no history of chronic diseases, who concieved naturally and had singleton pregnancies have been participating in the CRoatian Islands` Birth Cohort Study (CRIBS), an ongoing project in the Eastern Adriatic, Croatia, aiming to assess the prevalence of risk factors for the Metabolic Syndrom. Fasting blood lipids (tot- Chol, Trig, HDL-Chol and LDL-Chol), glucose and homocysteine levels were determined in 94 pregnant women (taken between 22th and 26th week of gestation). We investigated their association with possible predisposing factors (age, gestational age, level of education, obesity and smoking status), newborns` anthropometric measures (weight, lenght and head circumference) and with adverse pregnancy outcomes (pre-eclampsia, preterm birth, small/large for gestational age). Among the blood lipids, the largest divergence was found in triglyceride levels (mean 4.2±1.1, range 0.9-11), with elevated values (>1.7 mmol/L) present in >75% of the examinees. Smokers, in comparison to non-smokers, had significantly lower HDL-Chol levels and women older than 30 years had significantly higher tot-Chol than younger ones. Women with higher mean glucose levels (but within the normal range) gave birth to children with significantly higher weight- at-birth z-standardized according to WHO, and women with low homocysteine levels (

Concentration of lipoprotein (a), Lp(a), an important part of the clinical biomarker profile for atherosclerosis, in blood plasma varies both between and among populations. The elevated Lp(a) level in pregnancy were recognized as a risk factor for thrombosis and/or pre-eclampsia, but the referent values for uneventful pregnancies are yet undefined. The objective of this study was to test the association of fasting Lp(a) levels, taken between 22nd and 26th week of gestation, with possible predisposing factors (older age, smoking status, physical inactivity, hypertension, gestational diabetes), pregnancy outcomes (preterm birth, small/normal/large for gestational age) and newborns` anthropometric measures in 113 women (age range 19.8-41.7 yrs, mean 30.6±4.6 yrs) from the CRoatian Islands` Birth Cohort Study (CRIBS). In these women, with no history of chronic disease prior to pregnancy, Lp(a) leves varied largely, from 1.0 mg/dl to 127.3 mg/dl (median 13.1 mg/dl), but most of the women (88.5%) had Lp(a) 35 yrs), smoking statuts (both current and ex-smokers) and hypertension in predicting Lp(a)≥50 mg/dL (p=0.017, Cox & Snell R2=0.162, Nagelkerke R2=0.333). Nor logistic, neither linear regression models used for the estimation of adjusted associations between Lp(a) and birth weight, length and head circumference, all z- standardized according to WHO, showed significant associations. In the CRIBS sample, elevated Lp(a) levels were not found to be a predictive biomarker for the pregnancy outcome and neonatal size.

The prevalence of Metabolic Syndrome (MetS) on Eastern Adriatic islands is higher than in neighboring mainland area. The CRoatian Islands` Birth Cohort Study (CRIBS) is an ongoing 3-year-project with an aim to assess the prevalence of known risk factors for MetS. The CRIBS sample consists of pregnant women from Dalmatian islands Brač and Hvar and nearby coastal town Split and its surroundings, who had no history of chronic diseases (particularly MetS), who conceived naturally and had singleton pregnancies, and their newborns. We tested the association of possible predisposing factors for MetS (age, smoking, prepregnancy BMI, fasting blood biochemical parameters) and newborns` anthropometric measures. In this preliminary sample (n=131, age range 19.8-41.7 yrs, mean 30.6±4.6 yrs), 28.3% of women reported smoking in pregnancy and 22.2% reported being exposed to passive smoking. 17.9% of all the women were overweight and 4.7% were obese. In comparison to underweight women (

The CRoatian Islands` Birth Cohort Study (CRIBS) is an ongoing project in Split-Dalmatia County (towns of Split and Solin, islands of Brač and Hvar), with an aim to assess the prevalence of variety of risk factors (biological, medical, epidemiological, environmental and psychosocial) for the Metabolic Syndrom (MetS) in the sample of up to 700 healthy pregnant women and their newborns. The project started in November 2015, and since February 2016 pregnant women have been enrolling in the study at several specialist gynecological practices. Here we present the preliminary results of the reproductive health characteristics (age at menarche, use of contraceptives before the pregnancy, age at primiparity) and the sociodemographic characteristics (place of residence, educational attainment, employment and financial status) of the first 50 pregnant women who decided to participate in the CRIBS study. The mean age at menarche of the CRIBS pregnant women was 12.92±1.19 yrs, and age at primiparity ranged from 19.15 yrs to 34.51 yrs (mean 25.51±4.07 yrs, p=ns between mainland and islands). Many enrolled women (82%) reported using no contraceptives before the pregnancy. In women who already had 2 or more children (n=7), the mean age difference between the offspring was 5.25±3.93 yrs (range 2.23-13.36 yrs). 94% of women reported being married or having a partner, who was in 87% of cases older than his wife/partner. 52% of pregnant women attained high level education, 70% were employed, 60% owned house/flat, and 90% perceived their financial status as average or better than average. This preliminary data show that pregnant women from the CRIBS study are on average younger at primiparity than the national mean is, use contraceptives very rarely, and, in spite of the significant percentage of unemployment, perceive that their financial status was good enough to raise a family.

Uvod: Gravesova bolest (GB) manifestira se šarolikim kliničkim znakovima hipermetaboličkog stanja. Katkad nije jednostavno razlikovati tireotoksikozu i GB, jer se klinički preklapaju. Odabir načina liječenja GB-a složen je proces. Rezultate praćenja i liječenja djece i adolescenata s GB-om dijagnosticiranih u razdoblju od 2002. do 2016. u Klinici za dječje bolesti KBC-a Split usporedili smo s iskustvima iz literature. Antitireoidni lijekovi (ATL) su prvi terapijski izbor. Prednost ATL-a u odnosu na radiojodnu terapiju (RAI) i tireoidektomiju je obnavljanje ravnoteže osi hipotalamus - hipofi za – štitnjača. Primjena ATL-a – propiltiouracila je od 2010. zabranjena zbog hepatotoksičnosti sa zatajenjem jetre. Remisija u pedijatrijskih bolesnika postiže se u manje od 30% slučajeva, a prediktivni faktori za postizanje remisije su dob, veličina strume i razina antitijela na TSH receptore. Metoda defi nitivnog zbrinjavanja trebala bi se razmotriti nakon najduže 24 mjeseca od manifestacije GB-a. RAI se predlaže nakon dobi od 10 godina, jer se na taj način smanjuje rizik razvoja malignih stanja. Tireoidektomija je indicirana kod izraženog GB-a i u bolesnika s većim volumenom štitnjače. Metode: Retrospektivna analiza podataka, pregled relevantne literature, služeći se PubMedom i drugim publiciranim materijalima. Rezultati: Na Klinici za dječje bolesti KBC Split u četrnaestogodišnjem razdoblju liječili smo 41-og bolesnika s GB-om. Remisiju smo uočili u 12/41 bolesnika (29, 2%) s GB- om, a relaps u 4/12 (30%). RAI je primijenjen u 3/41 (7, 5%) bolesnika, tireoidektomija u njih 13/41 (32%). Razgovor o prednostima i rizicima predloženih terapijskih izbora u bolesnika s GB-om je poželjan i nužan. Zaključak: Zapažanja u 14-godišnjem razdoblju su nas navela na odluku da moramo poticati roditelje bolesnika s GB-om na bržu odluku o defi nitivnom zbrinjavanju, posebno one s malom mogućnošću za postizanje remisije, one kod kojih se ATL-i primjenjuju duže od godine dana te bolesnike nakon prvog relapsa.

Anaplastični karcinom štitnjače je jedan od četiri najmalignija tumora u čovjeka. Pojavljuje se u jednog do dva bolesnika na milijun ljudi u godini dana. U djece je iznimno rijedak. 17-godišnja bolesnica primljena je u Kliniku za bolesti uha, nosa i grla i kirurgiju glave i vrata u KBC-u Split zbog operacije štitnjače. Ranije joj je nađen nagli porast čvora lijevog režnja štitnjače. Preoperacijska obrada je upućivala na benigan karakter promjena. Napravljena je operacija thyreoidectomia totalis cum dissectione colli regionis VI et VII. Intraoperacijski preparat lijevog režnja štitnjače je bio maligan. Potom se napravio i PET/CT. Nalaz je bio uredan. Bolesnica je upućena otorinolaringološko-onkološkom timu gdje se određuje adjuvantna radioterapija. Stadij bolesti prema TNM klasifi kaciji bio je IVa. Godinu dana nakon operacije bolesnica je dobro, nema znakova bolesti. Ovaj prikaz slučaja je prilog dosadašnjim rijetkim spoznajama o anaplastičnom karcinomu štitnjače u osoba mlađe životne dobi u svijetu.

thyroid hormone. It is usually caused by the mutations in the thyroid hormone receptor (TRβ) transmitted autosomal dominantly. Clinical presentation is variable. The cardinal features include: high serum concentration of free T4, T3, non suppressed (normal or high) serum TSH, absence of the usual symptoms and signs of thyreotoxicosis, and goiter. Case report: We describe the variety of clinical symptoms of female child which we were follow up from infancy to the age of three. Biochemical thyroid function tests showed persistent elevated serum T4, free T4, T3, free T3 and slighted elevated TSH. We confirmed our clinical diagnosis of genetic sequencing TRβ and found de novo mutation in one allele of the gene TRβ. This mutation involves a single nucleotide substitution (ad adenine for the normal guanine) at codon 322, which results in a replacement of the normal glycine with glutamic acid (G332E).This amino acid substitutions located in the hormone-binding domain resulting in the reduction of its affinity to the T3-ligand to only 2% of the normal receptor. Conclusion: Until now this rare mutation has been found in only two other families, but without evidence of clinical presentation. Here, we describe clinical feature of female child through three years which was depended of age.

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. Aim was to investigate incidence rates and trends of T1DM from 2004 to 2012 in 0 to 14-yr-old Croatian children, and to compare the results with previous studies in Croatia and other European countries. T1DM crude incidence rates are estimated for the entire group and three subgroups: 0-4, 5-9, and 10-14 yr. Standardized incidence is calculated using the method of direct standardization according to World Health Organization (WHO) standard world population. The incidence rates by gender, age groups, seasonality, and calendar year, and their interactions were analyzed using Poisson regression model. A total of 1066 cases were ascertained over 2004-2012. The standardized incidence was 17.23/100.000/yr (95% CI: 16.19- 18.26), with no significant differences in incidence rates or trends between boys and girls. Statistically significant annual increase of 5.87% (p < 0.001) was found for the whole group, and for the subgroups 5-9 yr (6.82% ; p < 0.001) and 10-14 yr (7.47% ; p < 0.001). In the youngest subgroup (0-4 yr), annual increase was lower (2.43% ; p = 0338) and not statistically significant. The incidence of childhood T1DM is increasing in Croatia, thus placing Croatia among countries with high risk for T1DM. The annual increment of 5.87% is considerably lower than 9.0% reported earlier, but still higher than the European average (3.9%). The increase in incidence ceased in youngest children.

Introduction. The incidence of type 1 diabetes mellitus (T1DM) has increased markedly during the last fifty years among children and adolescents, while mean age at diagnosis has decreased. It was studied in Croatian children and adolescents under the age of 15 years during the period from 1995 to 2003 when it was 8.87 per 100.000/person-years, which placed Croatia in a group of countries with moderate risk for T1DM according to WHO. Objectives. To determine incidence rates of T1DM in children and adolescents younger than 15 years in Croatia in the period from 2004 to 2009, to evaluate additional differences in incidence rates and trends and to compare them with results from the study that analysed the period of 1995 to 2003 in Croatia, and with data from other European countries. Patients and methodes. The number of newly diagnosed T1DM patients was achieved from registry that collects data from all pediatric departments in Croatia. The population data were obtained from Central Bureau of Statistics of the Republic of Croatia. T1DM crude incidence rates were estimated as a number of newly diagnosed patients per 100.000 persons per year, among all children aged 0 to 14 years, and in three age subgroups: 0 to 4, 5 to 9 and 10 to 14 years old. The method of direct standardization to WHO standard world population of less than 15 years of age was used for calculation of standardized incidence according to gender and as a whole group. Poisson regression model was used to analyse the incidence rates by gender, age, and calendar year, and their interactions. Results. During the period of six years 665 children (364 girls, 319 boys) aged 0 to 14 years were diagnosed for T1DM. The standardized incidence was 15.71 (95% CI 9.51-21.91) per 100 000/person-year. No significant difference in T1DM incidence was found between boys and girls (2 =2.83 ; p>0.05). The annual increase in incidence was 5.44% (95% CI 0.84-10.24) and was statistically significant (2 =5.087, p

Knowledge accumulated through genetic research of complex diseases emphasize that these diseases develop as a consequence of cumulative effects of polymorphisms in multiple genes. Many of these susceptibility genes overlap between various autoimmune diseases. The aim of this study was to determine whether four SNPs reported as risk variants in juvenile idiopathic arthritis (VTCN1 gene), sarcoidosis (ANXA11 gene), primary biliary cirrhosis (IL12RB gene) and celiac disease (LPP gene), are associated with susceptibility to type 1 diabetes mellitus (T1DM). We genotyped four SNPs (rs2358817, rs1049550, rs6679356, rs9865818) within VTCN1, ANXA11, IL12RB and LPP genes in 265 T1DM family trios in Croatian population. To test the association we performed transmission disequlibrium test (TDT) in all trios and stratified analysis in different age-of-onset groups. Transmission disequilibrium test did not detect an association of VTCN1, ANXA11, IL12RB and LPP gene polymorphisms with T1DM, but interesting trend in IL12RB2 rs6679356 minor allele C overtransmission in patients below 8 years was observed (p=0.075) and undertransmission in patients above 12 years of T1DM onset (p=0.063). We demonstrated that gene regions associated with several autoimmune diseases are not associated with T1DM. These results exclude investigated SNPs as possible common susceptibility loci between several autoimmune diseases and T1D in our sample set. We observed a trend towards overtransmission and undertransmission of IL12RB2 rs6679356 minor allele C in two groups of patients (below 8 years and above 12 years of T1DM onset, respectively) suggesting that common autoimmune loci might play different roles in disease development within different age groups.

Acute suppurative thyroiditis is a rare but potentially life threatening disease in children and adolescents, usually occurring as a complication of so-called pyriform sinus fistula. The left thyroid lobe is affected in 90% of cases. Common treatment is a combination of surgical and antibiotic therapy, although good results of less invasive therapeutic approaches have been reported recently from non-randomized studies. We describe three female pediatric patients with acute purulent thyroiditis treated at our Department during a 20-year period, without confirmed sinus pyriform fistula. Two patients had a process in the right lobe of the thyroid, and all of them were treated with antibiotics and surgical therapy.

Opisuje regionalne razlike u incidenciji i trendu incidencije te načinu kliničke prezentacije šećerne bolesti tipa1 u djece

Cilj. Odrediti incidenciju dijabetesa tip 1 (DT1) u djece i adolescenata u dobi 0-14 godina u Republici Hrvatskoj (RH) u razdoblju od 2004. do 2007. godine i usporediti je s incidencijom u razdoblju od 1995. do 2003. godine. Metode. Broj novooboljelih dobiven je iz baze podataka koja sadrži podatke o bolesnicima s dijabetesom iz svih pedijatrijskih odjela u RH, a broj djece dobiven je iz Državnog zavoda za statistiku RH. Godišnja stopa incidencije izračunata je kao broj novooboljelih na 100.000 djece i adolescenata u dobi od 0-14 godina, i podijeljena je prema dobnim skupinama od 0-4, 5-9 i 10-14 godina. Rezultati. Od 2004. do 2007. godine DT1 u RH otkriven je u 389 djece i adolescenata (206 djevojčica i 183 dječaka) mlađih od 15 godina (median 8, 9 godine, 0, 46 - 14, 9). Prosječna stopa incidencije u spomenutom razdoblju iznosila je 13, 8/100.000 (12, 9 - 14, 4). Nije nađena statistički značajna razlika u incidenciji bolesti među spolovima, kao ni u pojedinim godišnjim dobima. U studiji provedenoj od 1995. do 2003. godine srednji godišnji porast ukupne incidencije DT1 bio je 9% (od 7, 81 -1995. godine na 14, 8 - 2003. godine) i to najviše na račun dobne skupine od 0-4 godine (14%) u kojoj je incidencija bila najniža. U našoj studiji nije bilo porasta ukupne stope incidencije (slična je kao u zadnje tri godine prethodne studije ; 11-14, 8), no izjednačile su se incidencije među dobnim skupinama na račun nastavka trenda porasta incidencije u najmlađoj dobnoj skupini od 0-4 godine (slika 1). U dvije trećine svih bolesnika (66, 7%) dijagnoza je postavljena u pet centra (KBC Rebro 24, 7%, KBC Split 17, 0%, KB Rijeka 10, 0%, KB Sestre Milosrdnice 8, 4%, i KB Osijek 6, 8%), a u jedne trećine u preostalih četrnaest pedijatrijskih odjela. Zaključak. RH spada u skupinu zemalja s visokom incidencijom DT1 u djece i adolescenata u dobi od 0-14 godina (zemlje s godišnjom incidencijom od 10-19.99/100.000 prema WHO). Iako tijekom razdoblja istraživanja (2004-2007) nije zabilježen porast ukupne incidencije, uočen je daljnji porast incidencije bolesti u dobnoj skupini od 0-4 godine, što govori u prilog sve ranijoj pojavi bolesti.

Aim: The aim of this study was to determine the influence of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency on the appearance and the course of neonatal hyperbilirubinemia in Central Dalmatia region. Methods: The florescent spot test was used in the retrospective study to screen blood samples of 513 male children which had neonatal hyperbilirubinemia higher than 240µmol/L. Florescence reading was performed at the beginning and at the 5th, 10th and 20th minutes of incubation and was classified into three groups: bright florescence, weak florescence and no florescence. Samples with no florescence and weak florescence reading in 5th minute were quantitatively measured using spectrophotometric method. Results: Bright florescence in 5th, 10th, and 20th minute were present in 461 samples (90%). The rest 52 samples (10%) were quantitatively measured using spectrophotometric method and in 32 of them there were normal G-6-PD activity but 20 samples (3, 9%) were G-6-PD deficient. The average of hospitalization of the children with newborn jaundice and G-6-PD deficiency were 15, 8 days, and 9 days for the same children with normal G-6-PD activity. Conclusion: Prevalence rate of G-6-PD deficiency among newborns in Central Dalmatia region is significantly higher (p< 0, 001) compared to the prevalence rate among men in Central Dalmatia region (0, 75% in males). We can also conclude that G-6PD deficiency has an influence on a course of newborn jaundice. The children with newborn jaundice and G-6-PD deficiency have had a significantly longer hospitalization then children with neonatal hyperbilirubinemia and normal G-6-PD.

Childhood type 1 diabetes in Croatia: incidence and trends from 1995 to 2003

Osvrt na zbrinjavanje krnično bolesnog djeteta prema modelu zbrinjavanja djece sa šećernom bolešću u Klinici za pedijatriju, KBC Zagreb

Type 1 diabetes is an autoimmune disease characterised by destruction of pancreatic beta cells. It is influenced by environmental and genetic factors. TNF and LTA are cytokines with a wide range of inflammatory and immunomodulatory activities possibly related with type 1 diabetes. The aim of the present study was to evaluate the association of 11 TNF/LTA tag polymorphisms in 160 type 1 diabetes trio families from South Croatia. Investigated tag polymorphisms were designed to capture the majority (62%) of common variation in TNF/LTA gene region, based on the HapMap database. We observed overtransmision of allels from parents to affected child at four variants: rs909253, allele C, p=1.2x10-4, rs1041981, allele A, p=1.1x10-4, rs1800629 (G-308A), allele A, p=1.2x10-4 and rs361525 (G-238A), allele G, p=8.2x10-3. We also identified overtransmission of the rs1800629(G-308A)-rs361525 (G-238A) G-A haplotype, p=2.384x10-5. The present study found an association of TNF/LTA gene region with type 1 diabetes. A careful assessment of TNF/LTA variants adjusted for linkage disequilibrium with HLA loci is needed to further clarify the role of these genes in type 1 diabetes susceptibility.

Monosialo-ganglioside (GM2-1) can be found on the pancreatic beta cell membrane. GM2-1 has recently been shown to be target for ICA and GAD autoantibodies associated with type 1 diabetes mellitus (T1DM) development. Beta-1, 4-N acetyl- galactosaminyl transferase 1 (GalNAc-T) is the enzyme involved in the biosynthesis of GM2 gangliosides. GalNAc-T catalyzes the transfer of GalNAc into GM3 by beta-1, 4 linkage resulting in the synthesis of GM2. Enzyme beta-1, 4 GalNAc-T is coded with B4GALNT1 gene located on chromosome 12. The purpose of this study was to examine the relation of B4GALNT1 gene tag single nucleotide polymorphisms (tagSNP) with susceptibility to T1DM. Two analyzed B4GALNT1 tagSNP-s. rs1008314 and rs715930, capture 100% of B4GALNT1 common variation at the r2=0.8, based on the HapMap data. We performed case-control (213 patients and 199 control subjects) and family-based (202 families) studies in Croatian population. Case-control study did not observe an association with T1DM (rs1008314, p=0.3001 ; rs715930, p=0.5256). Also, transmission disequilibrium test did not detect any discrepancy from the expected minor allele transmission (rs1008314, p=0.6547 ; rs715930, p=0.4986) nor for the haplotype transmission from parents to affected child. This is the first ever reported association study to examine B4GALNT1 gene polymorphisms with T1DM. We did not find any evidence to support our hypothesis of B4GALNT1 T1DM association.