Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children.

Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified heterozygous frameshift mutations in NR2F2, encoding COUP-TF2, in three children. One carried a c.103_109delGGCGCCC (p.Gly35Argfs∗75) mutation, while two others carried a c.97_103delCCGCCCG (p.Pro33Alafs∗77) mutation. In two of three children the mutation was de novo. All three children presented with congenital heart disease (CHD), one child with congenital diaphragmatic hernia (CDH), and two children with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The three children had androgen production, virilization of external genitalia, and biochemical or histological evidence of testicular tissue. We demonstrate a highly significant association between the NR2F2 loss-of-function mutations and this syndromic form of DSD (p = 2.44 × 10-8). We show that COUP-TF2 is highly abundant in a FOXL2-negative stromal cell population of the fetal human ovary. In contrast to the mouse, these data establish COUP-TF2 as a human "pro-ovary" and "anti-testis" sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent functions in mouse and human biology.

[The prevalence of SHOX gene deletion in children with idiopathic short stature. A multicentric study]. / A SHOX géndeletio elofordulása idiopáthiás alacsonynövésben. Multicentrikus tanulmány.

INTRODUCTION: The isolated haploinsufficiency of the SHOX gene is one of the most common cause of short stature determined by monogenic mutations. The heterozygous deviation of the gene can be detected in 2-15% of patients with idiopathic short stature (ISS), in 50-90% of patients with Leri-Weill dyschondrosteosis syndrome (LWS), and in almost 100% of patients with Turner syndrome. AIM: The aim of our study was to evaluate the frequency of SHOX gene haploinsufficiency in children with ISS, LWS and in patients having Turner syndrome phenotype (TF), but normal karyotype, and to identify the dysmorphic signs characteristic for SHOX gene deficiency. METHOD: A total of 144 patients were included in the study. Multiplex Ligation-dependent Probe Amplification (MLPA) method was used to identify the SHOX gene haploinsufficiency. The relationships between clinical data (axiological parameters, skeletal disorders, dysmorphic signs) and genotype were analyzed by statistical methods. RESULTS: 11 (7.6%) of the 144 patients showed SHOX gene deficiency with female dominance (8/11, 81% female). The SHOX positive patients had a significantly higher BMI (in 5/11 vs. 20/133 cases, p<0.02) and presented more frequent dysmorphic signs (9/11vs 62/133, p = 0.02). Madelung deformity of the upper limbs was also significantly more frequent among the SHOX positive patients (4/11, i.e. 36%, vs. 14/133, i.e. 10%, p = 0.0066). There were no statistically significant differences between the mean age, mean height and auxological measurements (sitting height/height, arm span/height) between the two groups of patients. CONCLUSIONS: The occurrence of SHOX gene haploinsufficiency observed in our population corresponds to the literature data. In SHOX positive patients, in addition to short stature, the dysmorphic signs have a positive predictive value for SHOX gene alterations. However, the SHOX deletion detected in a patient with idiopathic short stature without dysmorphic signs suggest that SHOX deletion analysis can be recommended in patients with ISS. Orv Hetil. 2017; 158(34): 1351-1356.

[Actual questions about the prevention of venous thromboembolism in cancer patients receiving chemotherapy]. / A kórházi és az ambuláns kemoterápiában részesülo onkológiai betegek vénásthromboembolia-profilaxisának aktuális kérdései.

Cancer patients have a 2-7 fold increased risk of venous thromboembolism compared with the general population and, since 1990, this is associated with significant morbidity and mortality. This review summarizes the current knowledge on venous thromboembolism and cancer. Notably, the risk of venous thromboembolism varies depending on the type and stage of cancer. For instance, pancreatic and brain cancer patients have a higher risk of venous thromboembolism than breast and prostate cancer patients. Moreover, patients with metastatic disease have a higher risk than those with localized tumors. Tumor-derived procoagulant factors, cytokines and growth factors may directly and indirectly enhance venous thromboembolism. Chemotherapy produces ~6,5 fold increase in venous thromboembolism incidence in cancer patients compared to the general population. Prevention of this complication is challenging. The authors review the development of guidelines concerning venous thromboembolism prevention in hospitalized and also in ambulatory cancer patients treated with chemotherapy. Current guidelines recommend the use of low-molecular-weight heparin. Understanding the underlying mechanisms may allow the development of new therapies to safely prevent venous thromboembolism in cancer patients.

[Pure 46,XY gonadal dysgenesis]. / 46,XY tiszta gonáddiszgenezis.

The authors report a rare case of pure 46,XY gonadal dysgenesis (Swyer syndrome). Swyer syndrome is associated with 46,XY karyotype, primary amenorrhea as well as the presence of female internal genital tract and bilateral streak gonads in a phenotypic female. The genetic background of this syndrome includes mutations of several genes involved in the testis differentiation cascade. Mutation of the SRY gene accounts for only 10-15% of all 46,XY gonadal dysgenesis cases while the majority cases may be linked to other deficient genes involved in the sex differentiation pathway. The patient was a 16-year-old female who was referred for endocrinological evaluation because of primary amenorrhea. Physical examination revealed a phenotypic female, height 166 cm, weight: 56.5 kg, breast and pubic hair development were Tanner I. and II, respectively. She had female external genitalia. Pelvic magnetic resonance imaging showed a hypoplastic uterus and ovaries at both sides measuring 5×10 mm in size. Chromosomal analysis revealed 46,XY karyotype. Analysis of the SRY and SF1 genes showed no mutations. Serum follicle-stimulating hormone and luteinizing hormone were elevated. Serum tumor marker concentrations were normal. Prophylactic bilateral gonadectomy was performed and histological examination showed bilateral streak gonads. Hormone replacement therapy produced development of secondary sexual characters and 1.5 years after treatment the patient had menarche. Authors conclude that karyotype analysis should be performed in adolescent with primary amenorrhea. After establishment of the diagnosis, dysgenetic gonads should be removed because of the high risk of gonadal neoplasia.

[Questionnaire for assessing the risk of venous thromboembolism in hospitalized surgical and non-surgical patients in the 4th Hungarian antithrombotic guideline entitled "Risk reduction and treatment of venous thromboembolism"]. / Vénásthromboembolia-kockázati kérdôív kórházban kezelt sebészeti és nem sebészeti betegek részére "A thromboemboliák kockázatának csökkentése és kezelése" címu, 4. magyar antithromboticus irányelvben.

A large proportion of hospitalized surgical and medical patients are at risk for venous thromboembolism. Depending on the type of surgical intervention, venous thrombosis develops in 15-60% of surgical patients without prophylaxis. Although venous thromboembolism is most often considered to be associated with recent surgery or trauma, 50 to 70% of symptomatic thromboembolic events and 70 to 80% of fatal pulmonary embolisms occur in nonsurgical patients. International and national registries show that the majority of at-risk surgical patients actually received the appropriate thromboembolic prophylaxis. However, despite of international and national recommendations, prophylaxis was not provided for a large proportion of at-risk medical patients. The rate of medical patients receiving prophylaxis should be increased, and appropriate thrombosis prophylaxis should be offered to at-risk medical patients. The thrombosis risk assessment is an important tool to identify patients at increased risk for venous thromboembolism, to simplify decision making on prophylaxis administration, and to improve the adherence to guidelines. When the risk is recognized, if there is no contraindication, prophylaxis should be ordered. The 4th Hungarian Antithrombotic Guideline entitled "Risk reduction and treatment of thromboembolism" calls attention to the importance of risk assessment and for the first time it includes and recommends risk assessment models for hospitalized surgical and medical patients. The risk assessment models are presented and the evidence based data for the different risk factors included in these models are reviewed.

[Results of ENDORSE-2-HUNGARIA study. Repeated assessment of the prevalence of venous thromboembolism risk and prophylaxis in acute hospital care setting]. / Az ENDORSE-2-HUNGARIA vizsgálat eredményei. Az akut kórházi betegek vénásthromboembolia-kockázatának és -profilaxisának ismételt hazai felmérése.

ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study in 2006, was a multinational cross-sectional survey designed to assess the prevalence of venous thromboembolism (VTE) risk in the acute hospital care setting, and to determine the proportion of at-risk patients who receive appropriate prophylaxis. From the 358 randomly selected hospitals across 32 countries in the global registry, 9 Hungarian centers were included. According to the Hungarian results, the use of appropriate prophylaxis was more common in surgical patients but much less common in medical patients comparing to the worldwide average. ENDORSE 2-HUNGARY was a local survey to compare the prophylactic habits after two years and two months time period. In both surveys, the 2004 American College of Chest Physicians (ACCP) evidence-based consensus guidelines were used to assess venous thromboembolism risk and to determine whether patients were receiving recommended prophylaxis. The one day survey ENDORSE 2-HUNGARY was repeated beside seven already audited hospitals, and in two newly recruited hospitals. A total of 886 patients were assessed for thrombosis risk on the basis of hospital chart review. Of these patients 59.0% (N=523) were judged at risk for VTE, including 100% (N=327) surgical and 35.1% (N=196) medical patients. 67.9% (N=355) of the total at-risk patients received ACCP-recommended VTE prophylaxis. Among surgical patients, 84.4% (N=276) received recommended prophylaxis compared with 40.3% (N=79) of medical patients. Results of the ENDORSE in 2006 and 2009 were compared, as well. The rate of appropriate prophylaxis use in at-risk patients did not changed significantly in surgical patients, however, a significant, 43.9% increase was found in medical patients (p=0.002), that proves the success of lectures presenting the facts and focusing to increase medical prophylaxis during the time period between the two studies. 59.7% of at-risk medical patients and 15.6% of surgical patients were unprotected against thrombosis in 2009. We should further increase the rate of at-risk patients receiving appropriate prophylaxis. We should reinforce the rationale for the increase of awareness of VTE risk in hospitalized medical patients, and to enhance the prophylaxis practice among healthcare professionals.

Novel sequence variation of AIRE and detection of interferon-omega antibodies in early infancy.

OBJECTIVE: Autoimmune polyendocrine syndrome type I (APS I) is a rare primary immunodeficiency disorder characterized by chronic mucocutaneous candidiasis, multi-organ autoimmunity and ectodermal dysplasia. Autoantibodies to parathyroid and adrenal glands and type I interferons (IFN) are hallmarks of APS I, which results from mutations in the autoimmune regulator (AIRE) gene. We wished to study clinical, immunological and genetic features of APS I in Hungarian patients, and to correlate anti-IFN-omega serum concentration with APS I and other multi-organ autoimmune diseases. DESIGN: Detailed analysis of patients with APS I and multi-organ autoimmune diseases. PATIENTS: Seven patients with APS I and 11 patients with multi-organ autoimmune diseases were studied. MEASUREMENTS: Mutational analysis was performed by bidirectional sequencing of AIRE. Antibodies against IFN-omega and endocrine organ-specific autoantigens were studied with radioimmunoassay. RFLP was performed by digestion of DNA with Hin6I restriction enzyme. RESULTS: AIRE sequence analysis revealed homozygous c.769C>T mutations in three patients and compound heterozygous sequence variants (c.769C>T/c.44_66dup26bp; c.769C>T/c.965_977del13bp; c.769C>T/c.1344delC) in four patients with APS I. All the six live patients tested had markedly elevated IFN-omega antibodies, which were not found in heterozygous siblings or parents. One of the identified patients was negative for antibodies against IFN-omega at 6 weeks of age, but became positive at 7 months. At age 1, he is still without symptoms of the disease. In contrast to patients with APS I, no AIRE mutation or elevation of IFN-omega antibodies were detected in patients with multi-organ autoimmune diseases. CONCLUSION: This is the first overview of patients diagnosed with APS I in Hungary. A novel c.1344delC mutation in AIRE was detected. Anti-IFN-omega antibodies seem to appear very early in life and are helpful to differentiate APS I from other multi-organ autoimmune diseases.

Mutations in the TSPYL1 gene associated with 46,XY disorder of sex development and male infertility.

We screened 100 individuals with anomalies of testicular development or function for mutations in the TSPYL1 gene. A 46,XY female with complete gonadal dysgenesis carried a p.K320R mutation in the highly conserved NAP domain, and a 46,XY male with idiopathic azoospermia harbored a p.R89H mutation, and this data supports the hypothesis that mutations in TSPYL1 may contribute to anomalies of testicular development/function.

[Results of ENDORSE study in Hungary. Multinational, cross-sectional study to assess the prevalence of venous thromboembolism risk and prophylaxis in acute hospital care setting]. / Az ENDORSE vizsgálat magyarországi eredményei: az akut kórházi betegek vénásthromboembolia-kockázatának és -profilaxisának nemzetközi, keresztmetszeti felmérése.

Information about the risk of venous thromboembolism and prophylactic practices around the world is limited. ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study is a multinational cross-sectional survey designed to assess the prevalence of venous thromboembolism (VTE) risk in the acute hospital care setting, and to determine the proportion of at-risk patients who receive appropriate prophylaxis. All hospital inpatients aged 40 years or above admitted to a medical ward, or those aged 18 years or above admitted to a surgical ward, in 358 randomly selected hospitals across 32 countries were assessed for risk of VTE on the basis of hospital chart review. The 2004 American College of Chest Physicians evidence-based consensus guidelines were used to assess venous thromboembolism risk and to determine whether patients were receiving recommended prophylaxis. Nine Hungarian centers were included in the international survey, and a total of 1300 patients were assessed for thrombosis risk in Hungary. Of these patients 39.9% (N=519) were judged at risk for VTE, including 58.2% (N=253) surgical and 30.8% (N=266) medical patients. 56.6% (N=294) of the total at-risk patients received ACCP-recommended VTE prophylaxis. Among major surgery patients 86.6% (N=219) received recommended prophylaxis compared with 28.2% (N=75) of medical patients. In Hungary more than two-thirds of at-risk hospitalized medical patients did not receive appropriate prophylaxis. ENDORSE results reinforced that a large proportion of hospitalized surgical and medical patients are at risk for VTE worldwide as well as in Hungary. The rate of at-risk patients receiving appropriate prophylaxis should be urgently increased.

[Safety profile of NO-SPA]. / A NO-SPA mellékhatásprofilja.

The aim of the safety analysis performed by Chinoin Drug Safety Unit was to summarise the safety profile of NO-SPA (drotaverine hydrochloride), the Hungarian spasmolytic well known in Hungary and abroad. Authors collected the safety data from clinical studies between 1964-1998 for the determination of the adverse event frequency. Based on the data of 12111 patients treated with NO-SPA in 37 clinical trials 0.9% frequency of adverse events was found. The value indicates uncommon (0.1-1%) adverse event frequency according to the criteria for frequency categories. The benefit-risk ratio of NO-SPA is favourable, since the therapeutic effect does not include frequent adverse reaction occurrence.