Background. Craniopharyngiomas are benign but locally invasive tumours of the sellar region that arise from ectopic embryonic remnants of Rathke's pouch, affecting both children (adamantinomatous type -aCP) and adults (papillary type -pCP) and associated with significant morbidity.Objective. To study the clinical presentation of CRF as well as the posttreatment evolution of craniopharyngioma in children versus adults in a large mixed cohort.Material and methods. We performed a retrospective review of CRF patients evaluated in the National Institute of Endocrinology in Bucharest between 1990 and 2016.Results. A total of 107 patients (72 adults, 35 children) with a mean follow-up of 6.2 years were included. The presenting symptoms were mostly headache, visual impairment, symptoms of hypopituitarism, diabetes insipidus. Some symptoms or hormonal abnormalities were significantly more prevalent in the children group (p<0.05): nausea/ vomiting (47.8% vs 16.7%), photophobia (21.7% vs 5.6%), diabetes insipidus(28.5% vs 8.3%), GH deficiency (68.8% vs 17.1%). Impaired visual acuity (67.6%of cases) or visual fields (71.4%) were more frequent in adults compared to children (44.1%; 51.6%). The tumor dimensions were similar in both groups (3.05± 1.05 cm in children; 2.7± 1.07 cm in adults). Massive suprasellar extension reaching the third ventricle was frequently present in all cases. All cases underwent surgery but only a minority of those not cured received postoperative adjuvant radiotherapy. Frequent postoperative complications were: aggravation of the endocrine deficit (>80% of cases in both groups needed chronic replacement therapy), central diabetes insipidus (68.2% children, 34.3% of adults).Conclusions. Despite similar tumor dimensions and extension compared to adults, craniopharyngioma in children is more frequently associated with signs of intracranial pressure. The results and complications of treatment are similar in adults and children.

Branched chain amino acids (BCAA) are essential elements of the human diet, which display increased plasma levels in obesity and regained particular interest as potential biomarkers for development of diabetes. To define determinants of insulin resistance (IR) we investigated 73 genes involved in BCAA metabolism or regulation by fine-scale haplotype mapping in two European populations with metabolic syndrome. French and Romanians (n = 465) were genotyped for SNPs (Affymetrix) and enriched by imputation (BEAGLE 4.1) at 1000 genome project density. Initial association hits detected by sliding window were refined (HAPLOVIEW 3.1 and PHASE 2.1) and correlated to homeostasis model assessment (HOMAIR) index, in vivo insulin sensitivity (SI) and BCAA plasma levels (ANOVA). Four genomic regions were associated with IR located downstream of MUT, AACS, SLC6A15 and PRKCA genes (P between 9.3 and 3.7 x 10−5). Inferred haplotypes up to 13 SNPs length were associated with IR (e.g. MUT gene with P < 4.9 x 10−5; Bonferroni 1.3 x 10−3) and synergistic to HOMAIR. SNPs in the same regions were also associated with one order of magnitude lower P values (e.g. rs20167284 in the MUT gene with P < 1.27 x 10−4) and replicated in Mediterranean samples (n = 832). In French, influential haplotypes (OR > 2.0) were correlated with in vivo insulin sensitivity (1/SI) except for SLC6A15 gene. Association of these genes with BCAA levels was variable, but influential haplotypes confirmed implication of MUT from BCAA metabolism as well as a role of regulatory genes (AACS and PRKCA) and suggested potential changes in transcriptional activity. These data drive attention towards new regulatory regions involved in IR in relation with BCAA and show the ability of haplotypes in phased DNA to detect signals complimentary to SNPs, which may be useful in designing genetic markers for clinical applications in ethnic populations.

BACKgROUND: somatostatin analogs (ssA) are now considered standard therapy for acromegaly, as primary or adjunctive treatment after pituitary surgery. OBJeCTIve: To evaluate the efficacy of ssA and the effect of dose escalation in non-operated patients with acromegaly as compared to patients treated after pituitary surgery in a Romanian tertiary care center. DesIgN: Retrospective study of 73 consecutively evaluated patients with acromegaly treated with ssA, divided into 2 groups: 11 patients (4M/7f, 21-62 years) with primary treatment and 62 patients (22M/40f, 21-68 years) treated after surgery. They received Octreotide LAR 20-30 mg i.m./28 days or Lanreotide sR 30 mg i.m./14/10/7 days. Random serum growth hormone (GH) was measured using IRMA, sensitivity 0.2-0.01 μg/L IGF-1 was measured using different assays and compared with ULN for age and sex. RESULTS: Overall, random GH ≤2.5 μg/L was attained in 39 patients (53.4%) and optimal GH ≤1 ng/mL) in 30 patients (41%), while normal IGF-1 was recorded in 22/72 patients (30.5%). The final random GH ≤2.5 μg/L was achieved in 27.2% of non-operated patients (3/11) as compared with 58% (36/62) of patients treated medically after pituitary surgery, p<0.05. escalation of doses of ssA applied in 43 patients improved the number of controlled patients by 5 (12.1%, p=0.059) and the number of optimally controlled patients by 9.7%. Of the 8 patients who switched from Lanreotide to Octreotide, 2 patients achieved gh normalization. CONCLUsION: The rate of biochemical control via ssA treatment in patients with acromegaly could be improved by rise of the ssA dose or by debulking surgery. Occasionally, substituting one ssA for another may be of benefit.

Recent studies have suggested that calpain-10 (CAPN10) gene polymorphisms play a role in the susceptibility to polycystic ovary syndrome (PCOS). The aim of the present study was to evaluate the possible association between three single nucleotide polymorphisms (SNPs) in CAPN10 gene: UCSNP-43 (rs3792267), UCSNP-19 (rs3842570), and UCSNP-63 (rs5030952) and PCOS in Tunisian cases and control women. Study subjects included 127 women with PCOS (mean age 29.8 ± 4.7 year) and 150 healthy women (mean age 33.5 ± 5.6 year). CAPN10 genotyping was carried-out by direct PCR and PCR-RFLP. Linkage disequilibrium pattern in the genomic region explored was determined by HAPLOVIEW 4.2 while reconstruction of haplotypes was done using PHASE 2.1. The phylogenetic distribution of haplotypes in the population was determined by ARLEQUIN 2.000. Six haplotypes were observed. None of SNPs associated with PCOS or its components while the haplotype H4 associated with the phenotype PCOS-obese (P < 0.025). Moreover the pair of haplotypes H1/H4 strongly associated with high blood-pressure (OR = 14.4, P < 0.012). This work confirms the association of CAPN10 gene with metabolic components in PCOS and highlights the role of haplotypes as strong and efficient genetic markers.

Branched-chained amino acids (BCAA) are essential dietary components for humans and can act as potential biomarkers for diabetes development. To efficiently estimate dietary intake, we developed a BCAA database for 1331 food items found in the French Centre d’Information sur la Qualité des Aliments (CIQUAL) food table by compiling BCAA content from international tables, published measurements, or by food similarity as well as by calculating 267 items from Greek, Turkish, Romanian, and Moroccan mixed dishes. The database embedded in MEDIPAD software capable of registering 24 h of dietary recalls (24HDR) with clinical and genetic data was evaluated based on archived 24HDR of the Saint Pierre Institute (France) from 2957 subjects, which indicated a BCAA content up to 4.2 g/100 g of food and differences among normal weight and obese subjects across BCAA quartiles. We also evaluated the database of 119 interviews of Romanians, Turkish and Albanians in Greece (27–65 years) during the MEDIGENE program, which indicated mean BCAA intake of 13.84 and 12.91 g/day in males and females, respectively, comparable to other studies. The MEDIPAD is user-friendly, multilingual, and secure software and with the BCAA database is suitable for conducting nutritional assessment in the Mediterranean area with particular facilities for food administration.

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Insulin resistance (InsR) characterizes the metabolic syndrome (MetS) for which many genes were involved by GWAS. To further explore genetic susceptibility involving rare SNPs with major effect we genotyped patients from MEDIGENE collection using Affymetrix MEDISCOPE chip. Screening of French, Romanians and Albanians in Italy and Greece (n = 605) for metabolic pathways detected a new SNP associated with MetS in exon 3/4 of ATF5 (activating transcription factor 5) gene (Chr19q13.33). Genuine association was completed by imputation (BEAGLE4.1) at 1000 Genome Project adding new 6 SNPs and submitted to sliding window (SW) procedure for haplotypes detection. The strong association signal was found for rs61742136 with MetS (P &lt; 1.8x10-7, Bonferroni 2.7x10-6, OR 9.37, 95% CI[3.3-26.8]), InsR (P &lt; 0.00049, OR 3.4, 95% CI[1.7-8.4]) and with HOMA index (P &lt; 0.023). Among MetS components, the strongest association concerned high blood pressure (HBP) (P &lt; 2.1x 10-4, OR 4.8, 95% CI[1.8-12.4]) while HDL, TG and obesity were associated with OR &lt; 3. In women, MetS association signal was much stronger with OR 10.9, 95% CI[3.2-36.6] (P &lt; 8.5x10-7). SW detected associated haplotypes between 3 to 8 SNPs, the best value being that of ATGGGGTC haplotype with OR 12.2, 95% CI[3.2-46.65] (P &lt; 1.98 x10-7, Bonferroni 1.13x10-5). Association of rs61742136 was replicated in MEDIGENE cohort (n = 948) with MetS, albeit with P &lt; 2.0x10-3 (Bonferroni 0.026) and solely with low HDL (P &lt; 0.05). Other SNPs were associated with HBP (rs75273180 and rs1152230 with P &lt; 0.03 and 0.04, respectively) and with potential interactions in Haploreg V4 database. Overall fixation index (Fst = 0.001) indicates a minimal differentiation suggesting adaptive selection in Mediterranean populations. This is a first time report of implication of ATF5 in MetS and gives a new insight on its pathogenesis in view of this CREB valine/leucine zipper transcriptional factor in stress-induced anti-apoptosis or neuroprotective effects. Disclosure S. Haydar: None. F. Grigorescu: None. C. Lautier: None. C. Normand: None. J. Hadi: None. M. Vintila: None. M. Gheorghiu: None. A. Fountas: None. A. Tsatsoulis: None. A. Copola: None. D. Lauro: None. D. Ylli: None. A. Ylli: None. L. Brugnara: None. F. Hanzu: None. R. Gomis: None.