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Background: Receptor for advanced glycation end- products (RAGE) is a multiligand receptor up- regulated at sites of inflammation, especially in tissues with accelerated advanced glycation end-products formation. It is additionally stimulated by RAGE ligands S100A12 and HMGB1 released from recruited immune cells thus perpetuating the inflammatory process with a potential role in the development of type 1 diabetes as well as in development in diabetes complications. Expression of RAGE molecules and its ligands has not been evaluated in new-onset diabetic patients, and data on their role in diabetes development are still scarce. Aim: To assess gene expression for RAGE, S100A12 and HMGB1 in peripheral blood mononuclear cells (PBMC) and plasma concentration of truncated receptor sRAGE and CRP in patients suffering from new-onset type 1 diabetes (NT1D), in patients with disease duration of more than five years (T1D) and in healthy controls. Subjects and Methods: We included 35 NT1D patients (47.5% female, age 10.7+/-3.0 years), 36 T1D patients (47.2% female, age 16.3+/-5.6 years), and 36 healthy controls (55.6% female, age 16.2+/-6.9 years). Gene expression for RAGE, S100A12, and HMGB1 was quantified using qPCR, and sRAGE level was measured by ELISA. CRP was measured by routine laboratory method. Results: The PBMC s100A12 gene expression (in arbitrary units, AU) was significantly lower in NT1D patients compared to controls (mean ±SD (95%CI) = 1.22±0.81 (0.94-1.51) v.s. 2.62 (2.01-3.23), p=0.040) and compared to T1D (3.07±3, 10 (2.02- 4.12), Poster Category 1 Horm Res Paediatr 2019 ; 91(suppl 1):1–682 DOI: 10.1159/000501868 145 p=0.002). HMBG (AU) expression was also lower in NT1D when compared to controls (0.73±0.63 (0.51- 0.95) v.s. 1.91 (0.97-1.42), p=0.031) with no difference when compared to T1D. There was no difference between groups neither in RAGE gene expression nor in plasma sRAGE levels. NT1D also showed higher CRP (mg/dL) levels when compared to control group (2, 32±4, 15 (0, 77-3, 87) v.s. 0, 62±0, 95 (0, 27-0, 96), p=0.023). Conclusion: Our findings might suggest the role of s100A12 and HMGB1 in type 1 diabetes development. However, we expected increased expression of these molecules in the setting of enhanced inflammation as suggested by higher CRP levels. We speculate that s100A12 and HMGB1 expression might be restricted to sites of inflammation harvesting PBMC expressing these genes from peripheral blood. Comparison between gene and protein expression in peripheral blood as well as between circulation and affected tissues should be performed in order to explain the contribution of these molecules to the development of diabetes

Introduction: Oncocytomas are rare epithelial tumors that can be found in various tissues such as kidney, salivary and endocrine glands. Adrenocortical oncocytomas (AON) are very rare tumors with around 160 patients described in the literature. Generally they are regarded as benign and mostly hormonally nonfunctional. When hormonally active, these tumors produce adrenal steroids resulting in various clinical presentations such as virilization, feminization, and Cushing or Conn syndrome. Until now, only 8 pediatric patients with functional adrenocortical oncocytomas (FAON) have been described in literature. Case Report: We report on a 15.5 year old girl referred for secondary amenorrhea lasting 8 months. Slowly progressive virilization was reported for almost 2 years. At presentation she had deep voice, acne, hirsutism (Ferriman-Gallwey score 22), clitoromegaly and atrophic breasts. Blood pressure was normal. Initial laboratory findings revealed marked hyperandrogenemia: testosterone 17.7 nmol/L (ref. 0.4-1.7), androstenedione 21.8 nmol/L (ref. 1-12), DHEAs 26.8 umol/L (ref. 2- 10), with suppressed LH 0.1 IU/L, FSH 0.3 IU/L and estradiol 92 pmol/L. Serum and urinary cortisol as well as aldosterone and plasma renin activity were normal. Abdominal CT scan showed right adrenal gland mass measuring 4 cm in diameter. Subsequently laparoscopic right adrenalectomy with lymphadenectomy was performed. Pathohistological diagnosis revealed oncocytic adrenocortical tumor with benign characteristics according to Wieneke criteria and Bisceglia classification. Adrenal androgen levels normalized completely after the surgery and the girl regained menstruation 1.5 month following tumor extirpation. Conclusion: In conclusion, AONs are very rare tumors with yet unidentified pathogenesis and potential risk factors for their development. They are mostly discovered in adults, but can also be found in children. There is no specific age distribution in children with FAON. Unlike adults, all children with FAON presented with right sided adrenal mass and very strong female preponderance (8/9). Most of the patients with FAON (7/9), including our, presented with symptoms of androgen excess. All but one were pathohistologically classified as benign at the time of diagnosis. Follow-up time ranged from 1- 84 months in children with FAON. None of them had signs of disease recurrence at that time. Due to extreme rarity of this tumor in children and no clear evidence regarding its’ true potential, long-term follow-up of these children should be recommended. Since there are no specific guidelines regarding management of these patients, knowledge assembled from individual cases would provide better understanding.

Introducton: Klinefelter syndrome (KS) describes the phenotype of the most common sex chromosome abnormality in humans. About 80% of KS patients have 47, XXY karyotype, while rest of the patients can have mosaicism or other numeric or structural sex chromosome abnormalities. Tall stature is one of the hallmarks of KS and it is thought to be due to supernumerary X chromosome leading to SHOX gene overdosage. Deletion of SHOX gene, on the contrary, has been related to impaired growth in patients with Leri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia and Turner syndrome, but also in some cases of idiopathic short stature. Case Report: The proband is 14.6 year old boy evaluated for obesity (height 170.6 cm, + 0.4 SDS, weight 91.5 kg, +2.41 SDS, BMI 31.4 kg/m2, + 2.19 SDS). At examination he had penis buried in fat tissue, with testes size Prader 4-5, pubic hair Tanner 3 and adipomastia with enlarged areolas. His laboratory finding revealed elevated gonadotropins (LH 11.9 lU/L, ref. 0.2-5 ; FSH 25.5 lU/L, ref. 1.2-5.8 ; testosterone 7.9 nmol/l, ref. 3-27) and subsequently KS was suspected. The karyotyping revealed 46, XXY/46, XY mosaicism with one derivated X chromosome and 3.5% 46, XY cells (mos 47, X, der(X)del(Xp)dup(Xq)(Xq28- Xq27.2::Xp22.32- Xq28), Y/ 46, XY). Further cytogenetic analysis with FISH proved deletion of pseudoautosomal region 1 of X chromosome including SHOX gene. Proband was in custody of his grandmother (on father’s side), so his parents were invited for further genetic evaluation. His father has 46, XY, normal male karyotype and normal phenotype. His mother is disproportionately short (height 155 cm, – 1.3 SDS, arm span 152 cm) and has phenotypic features of LWD (mesomelic limb shortening, Madelung deformity). Her karyotyping revealed complex rearrangement of one X chromosome with duplicated Xq27.2-qter, deleted Xp22.32 region and subsequent one SHOX deletion (46, X, der(X)del(Xp)dup(Xq)(Xq28- Xq27.2::Xp22.32Xq28). Conclusion: To the best of our knowledge this is the first report of the patient with KS born to the mother with LWD. Although tall stature would be expected, SHOX gene deletion might have contributed to normal stature of our patient. In KS patients carrying complex chromosomal rearrangements, detailed cytogenetic evaluation is indicated in patient and his parents. This might explain spectrum of phenotypes in patient, detect unrecognized disease in parents and provide correct genetic counseling regarding possibility of transmitting monogenic disorders in further parental pregnancies or in case of option for proband’s fertility preservation.

Objective – The aim was to report a case of a 17-year-old girl with marked virilization and secondary amenorrhea due to androgen producing Sertoli-Leydig cell tumor (SLCT). We also provided a brief review of the literature with insight into clinical picture, pathological features and treatment of patients with this rare tumor. Case report − We present a 17-year-old girl with SLCT, who developed clinical symptoms of severe virilization. The tumor secreted testosterone and alpha fetoprotein (AFP). The imaging revealed tumor of the right ovary which histologically corresponded to intermediate-grade SLCT with low mitotic rate. Furthermore, it was stage IA according to International Federation of Gynecology and Obstetrics. Laparoscopic right salpingo-oophorectomy was preformed, resulting in regression of virilization symptoms and normalization of serum testosterone and AFP levels. Conclusion − Due to rarity of SLCT in children and adolescents, gathering information from available case reports is necessary to establish guidelines regarding optimal management, including type of surgery and adjuvant chemotherapy. New knowledge regarding related diseases in SLCT survivors emphasize the need for long-term follow up of these patients.

This study included 161 patients: 92 patients had type 1 diabetes (T1D) while 69 patients had a combination of T1D and autoimmune thyroiditis, the so-called autoimmune polyglandular syndrome type 3 variant (APS3v). Those patients, as well as 93 controls, were typed for HLA-DRB1 and -DQB1 genes to assess their possible contribution to the development/protection of T1D with/without autoimmune thyroiditis. Both HLA-DRB1*04 and - DRB1*03 frequencies were significantly higher among T1D and APS3v patients than in controls. The frequencies of HLA-DRB1*11 and -DRB1*15 were lower among T1D patients, while HLA-DRB1*07 and -DRB1*11 occurred significantly less frequently among APS3v patients in comparison to controls. HLA-DQB1*03:01 and -DQB1*03:02 were associated with a higher risk of developing T1D and APS3v ; HLA-DQB1*02 was significantly more present among APS3v patients while HLA-DQB1*03:03 was observed with a significantly lower frequency only among T1D patients. HLA-DRB1*03~DQB1*02 and HLA- DRB1*04~DQB1*03:02 were associated with both diseases. The higher frequency of HLA- DRB1*03/DRB1*03 among APS3v patients was the only significant difference in genotype frequency when compared to T1D patients, while high risk (HLA- DRB1*03/DRB1*04) and medium risk genotypes for T1D (HLA-DRB1*04/DRB1*04) occurred with similar frequencies in both patient groups. Although some the results point toward shared genetic susceptibility of T1D and APS3v, observed differences in both susceptible/protective HLA profiles indicate the necessity of further studies in order to elucidate the pathogenesis of these diseases.

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.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: Resistance to thyroid hormone (RTH) is primarily dominantly inherited and characterized by reduced organ responsiveness to thyroid hormone with elevated serum iodothyronines and unsuppressed TSH levels. It is most frequently caused by thyroid hormone receptor beta (THRB) gene mutations. We report a child and her mother with de-novo missense mutation in the THRB gene (H435Y) traced to a mutation in ancestral germline. Case study: A 7.5-yr-old girl presented with goiter. Parents report nervousness poor weight gain despite good appetite and occasional palpitations. Her weight was 24.9 kg (50 c.), height 138.3 cm (>95 c), heart rate 81/min, palpable goiter and warm and wet skin. Serum iodothyronines were elevated with a normal TSH suggesting RTH (Figure 1). There was perceptive hearing loss at 30dB. Her mother presented at age 12 years with symptoms of hyperthyroidism ; paroxysmal supraventricular tachycardia and goiter. Diagnosis of Graves’ disease, despite unsuppressed TSH suggesting RTH, led to antithyroid drug treatment, followed by thyroidectomy at the age of 14 years and subsequently levothyroxine therapy. Sequencing of the THRB gene revealed a single nucleotide substitution producing the missense mutation H435Y in both proband and her mother. Genotyping of the maternal grand parents revealed that the mutation in the mother originated de-novo in the THRB allele inherited from the maternal grand mother (Figure 1). Conclusion: We present the occurrence of RTH in two generations caused by THRB H435Y traced to a de-novo mutation in an ancestral allele. To our knowledge this is the first report of a THRB gene mutation in Croatia.

Homozygous familial hypercholesterolemia (FH) is a rare autosomal dominant disorder caused by mutations in the low-density-lipoprotein (LDL) receptor gene. It occurs with a frequency of approximately 1 per million persons world-wide. Clinically, homozygous FH is associated with extremely elevated levels of LDL cholesterol and cutaneous xanthomas that develop in early childhood. These children are at risk of extremely early coronary events and death from myocardial infarction caused by premature generalized atherosclerosis. Their medical treatment is very complex, associated with various problems and complications. We describe a 3-year-old boy with clinical signs of homozygous FH (elevated LDL-cholesterol levels and xanthomas). Heterozygous hypercholesterolemia was found in his parents and some other family members. The boy has been treated with simvastatin and atorvastatin, but without reaching the treatment goals. LDL apheresis is planned as the treatment of choice for homozygous children with FH.