Attila Tar

Novel sequence variation of AIRE and detection of interferon-ω 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‐ω serum concentration with APS I and other multi‐organ autoimmune diseases.

Testicular development in an SRY-negative 46,XX individual harboring a distal Xp deletion

A case of a true hermaphrodite presenting with a karyotype of 46,X,del(X)(p21.1→pter) is described. The testis-determining gene, SRY, was not detected in DNA prepared from either peripheral blood lymphocytes or from a gonad biopsy. The patient also presented with a series of discrete somatic abnormalities, including abnormal skin and retinal pigmentation, and mental retardation. The extent of the Xp deletion was mapped by Southern blotting. X chromosome replication studies of lymphoblast cells prepared from the patient indicated that the deleted X chromosome was inactivated in all cells examined. It is suggested that the phenotype of the patient is caused by the unmasking of a recessive allele(s) on the grossly intact X chromosome. The relationship between the Xp deletion, the intersex phenotype, and the possible role of an Xp locus involved in human sex determination is discussed.

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.

Hypertelorism and hypospadias associated with a de novo apparently balanced translocation between 8q22.3-23 and 20p13

A de novo apparently balanced translocation involving chromosomes 8 and 20 was found in a 14-year-old boy with minor anomalies, mild skeletal abnormalities and ambiguous external genitalia including perineoscrotal hypospadias, rudimentary fused labioscrotal folds, bilateral cryptorchidism, and small penis. The karyotype was 46,XY, t(8;20)(q22.3-23;p13). No signs of other conditions known to be associated with structural anomalies of either chromosome 8 or 20 were present and incomplete masculinisation of the external genitalia appears to be the main component of the phenotype. Clinical and biological studies showed apparently normal testicular function in utero and after birth. Examinations excluded 5 alpha-reductase deficiency or a block in any enzymatic steps of testosterone, glucocorticoid and mineralocorticoid biosynthesis. Coding sequences of the sex-determining gene (SRY) and androgen receptor gene (AR) were found to be identical to those of a normal male excluding their role in the cause of the present condition. Since several other reports describe the association of hypospadias and hypertelorism with deletions or translocations involving 8q, we suggest that a locus necessary for male sex differentiation is located at distal 8q.

[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].

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.

[Results of ENDORSE-2-HUNGARIA study. Repeated assessment of the prevalence of venous thromboembolism risk and prophylaxis in acute hospital care setting].

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.

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.

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.

[Pure 46,XY gonadal dysgenesis].

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.

A SHOX géndeletio előfordulása 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.Absztrakt: Bevezetes: A SHOX gen izolalt haploinsufficientiaja az alacsonynovest okozo monogenes elvaltozasok leggyakoribb oka. A gen heterozigota elterese az idiopathias alacsonynovessel (ISS) diagnosztizalt betegek 2–15%-aban, Leri–Weill-dyschondrosteosis szindroma (LWS) 50–90%-aban, valamint a Turner-szindromaban szenvedők csaknem 100%-aban igazolhato. Celkitűzes: A SHOX gen haploinsufficientiaja gyakorisaganak meghatarozasa ISS-sel es LWS-sel diagnosztizalt, valamint Turner-fenotipusu, de normalis karyotypussal rendelkező betegek (TF) koreben, valamint beazonositani a SHOX genelteresre jellemző dysmorphias jeleket. Modszer: Osszesen 144 betegben kerult sor a SHOX gen haploinsufficientia-vizsgalatara multiplex ligatios proba Amplifikacio (MLPA) modszerrel. A betegek klinikai adatai (auxologiai parameterek, csontrendszeri rendellenessegek, dysmorphias tunetek) es a pozitiv genotipus kozotti osszefuggeseket statisztikai modszerekkel elemeztek. Eredmenyek: A vizsgalt 144 betegből 11 (7,6%) eseteben igazol...