[Diagnostic and therapeutic perspectives in RASopathies].

RASopathies are congenital diseases that manifest in childhood with symptoms and potential complications, typically associated with an elevated tumour predisposition risk. The heterogeneous symptoms involve mostly central nervous, cardiovascular, musculoskeletal systems and skin, and modified growth pattern. From molecular perspective, the function of a key protein involved in Ras signalling is impaired, leading to disrupted regulation of cell growth and division.

[Diagnostics and follow-up strategy for Silver–Russell syndrome based on a case report showing familial accumulation].

"Characterized by both intrauterine and postnatal growth retardation, and consequent small stature, Silver–Russell syndrome is associated with typical minor anomalies (relative macrocephalia, protruding forehead, downturned corners of mouth, micrognathia, low set ears, facial, skeletal and limb asymmetry) and findings involving mainly the endocrine system. The molecular background of the syndrome is complex, but it is most often caused by the involvement of critical regions of chromosome 11 and/or chromosome 7. Beside the molecular diagnosis, the Netchine–Harbison clinical scoring system aims to contribute to the successful diagnosis of Silver–Russell syndrome.

"Heat waves" experienced during larval life have species-specific consequences on life-history traits and sexual development in anuran amphibians.

Extreme temperatures during heat waves can induce mass-mortality events, but can also exert sublethal negative effects by compromising life-history traits and derailing sexual development. Ectothermic animals may, however, also benefit from increased temperatures via enhanced physiological performance and the suppression of cold-adapted pathogens. Therefore, it is crucial to address how the intensity and timing of naturally occurring or human-induced heat waves affect life-history traits and sexual development in amphibians, to predict future effects of climate change and to minimize risks arising from the application of elevated temperature in disease mitigation.

Sex reversal and ontogeny under climate change and chemical pollution: are there interactions between the effects of elevated temperature and a xenoestrogen on early development in agile frogs?

Anthropogenic environmental change poses a special threat to species in which genetic sex determination can be overwritten by the thermal and chemical environment. Endocrine disrupting chemicals as well as extreme temperatures can induce sex reversal in such species, with potentially wide-ranging consequences for fitness, demography, population viability and evolution. Despite accumulating evidence suggesting that chemical and thermal effects may interact in ecological contexts, little is known about their combined effects on sex reversal.

Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 () gene.

Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the testis-determining gene is present in many cases, the etiology is unknown in most -negative patients.

The importance of the multiplex ligation-dependent probe amplification in the identification of a novel two-exon deletion of the NR5A1 gene in a patient with 46,XY differences of sex development.

Gonadal dysgenesis (GD) is a rare cause of differences of sex development (DSD) with highly variable clinical and genetic conditions. Although identification of the causative genetic alterations can offer a clearer prognosis and personalized management to patients, more than 50% of the DSD cases still do not have an accurate genetic diagnosis. NR5A1 (previously known as SF-1), is a transcriptional regulator of genes required for normal development and functional maintenance of the gonads and the adrenal glands.

Novel frameshift mutation of the NR0B1(DAX1) in two tall adult brothers.

NR0B1 (nuclear receptor subfamily 0, group B, member 1) is a transcription factor encoded by DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) responsible for the development and maintenance of the steroidogenic tissues. In humans the DAX1 mutations cause congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism (HHG) in boys. Here we report two brothers who were assessed by endocrinologist at the age of 51 and 43 because of their serious osteoporosis.

Evaluation of DSD training schools organized by cost action BM1303 "DSDnet".

Background: The Differences of Sex Development network (DSDnet) aims to establish interactive relationships between clinicians, scientists, support groups and people with a difference of sex development (DSD) to improve the overall care for people affected by such condition. DSDnet has hosted three Training Schools (TSs) in Ghent, Bologna and Budapest between 2015 and 2017 with the primary purpose of providing multidisciplinary training to young professionals and encouraging ongoing activity in the field of DSD. The aim of our study was to evaluate the success and long-term effect effectiveness of these three TSs.

[Genetic factors in hypopituitarism. The role of transcription factors in pituitary hormone deficiency].

Developmental disorders affecting the hypothalamic-pituitary system can result in pituitary hormone deficiency showing a diverse clinical presentation. A significant majority of these disorders are closely linked to defects in transcription factor genes which play a major role in pituitary development. Those affecting the early phase of organogenesis typically lead to complex conditions affecting the pituitary as well as structures in the central nervous system.

[The prevalence of SHOX gene deletion in children with idiopathic short stature. A multicentric study].

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.

New Mutations Associated with Rasopathies in a Central European Population and Genotype-Phenotype Correlations.

We performed the genetic analysis of Rasopathy syndromes in patients from Central European by direct sequencing followed by next generation sequencing of genes associated with Rasopathies. All 51 patients harboured the typical features of Rasopathy syndromes. Thirty-five mutations were identified in the examined patients (22 in PTPN11, two in SOS1, one in RIT1, one in SHOC2, two in HRAS, three in BRAF, two in MAP2K1 and two in the NF1 gene).

The 83,557insA variant of the gene coding 11β-hydroxysteroid dehydrogenase type 1 enzyme associates with serum osteocalcin in patients with endogenous Cushing's syndrome.

Objective: The type 1 and type 2 isoenzymes of the 11β-hydroxysteroid dehydrogenase (HSD11B) play an important role in the prereceptor regulation of glucocorticoid bioavailability and action. The potential importance of gene variants coding HSD11B has not been previously evaluated in patients with endogenous hypercortisolism. The aim of the present study was to explore presumed associations between the 83,557insA variant of the HSD11B1 gene and circulating hormone concentrations, bone turnover and bone mineral density (BMD) in patients with endogenous Cushing's syndrome (CS).

Hyperthyroidism caused by a germline activating mutation of the thyrotropin receptor gene: difficulties in diagnosis and therapy.

Background: Germline activating mutations of the thyrotropin receptor (TSHR) gene have been considered as the only known cause of sporadic nonautoimmune hyperthyroidism in the pediatric population. Here we describe the long-term follow-up and evaluation of a patient with sporadic nonautoimmune primary hyperthyroidism who was found to have a de novo germline activating mutation of the TSHR gene.

Summary: The patient was an infant who presented at the age of 10 months in an unconscious state with exsiccation, wet skin, fever, and tachycardia.

Y-chromosome markers in Turner syndrome: Screening of 130 patients.

Background: The presence of Y-chromosome material in patients with Turner syndrome (TS) is a risk factor for the development of gonadoblastoma. Cytogenetic analysis detects Y-chromosome mosaicism in about 5% of Turner patients. However, if Y-chromosome sequences are present in only a few cells, they may be missed by routine analysis.

[Extracellular calcium sensing under normal and pathological conditions].

Ionic calcium has been known as an important intracellular second messenger for many decades. In addition, a whole series of experimental and clinical studies from the past fifteen years have provided evidence that extracellular ionic calcium itself is also a first messenger, since it is the ligand of a cell surface G-protein coupled receptor called calcium-sensing receptor. This review summarizes the current knowledge on the role of calcium-sensing receptor in the maintenance of calcium homeostasis, its functions in various tissues and some of the most important disorders characterized by defective calcium sensing.

Overrepresentation of BclI polymorphism of the glucocorticoid receptor gene in pregnant women with HELLP syndrome.

Background: Because the pathological background of preeclampsia and its severe variant, HELLP syndrome (hemolysis, elevated liver enzymes and low platelet counts) appears to involve a pathological maternal-fetal immune adaptation, we examined whether any association could exist between these disorders and polymorphisms of the glucocorticoid receptor (GR) gene.

Methods: The BclI, N363S, and ER22/23EK polymorphisms of the GR gene were determined in 300 healthy pregnant women, 150 pregnant women with severe preeclampsia including 17 pregnant women with HELLP syndrome.

Results: There were no significant differences in carrier and allelic frequencies of the N363S and ER22/23EK polymorphisms between healthy pregnant women and those with severe preeclampsia.

The protective effect of the ER22/23EK polymorphism against an excessive weight gain during pregnancy.

It has been shown that women who gained an excessive weight during pregnancy had an increase in long-term BMI compared with those without an excessive weight gain. Several studies have demonstrated that some polymorphisms of the glucocorticoid receptor (GR) gene may influence body composition and metabolic parameters. In the present study, we wanted to explore whether any association could exist between the BclI, N363S and ER22/23EK polymorphisms of the GR gene and the weight gain during pregnancy.

Association between birth weight in preterm neonates and the BclI polymorphism of the glucocorticoid receptor gene.

Endogenous and exogenous glucocorticoids influence fetal growth and development, and maternal administration of synthetic glucocorticoids may decrease the risk of perinatal morbidity including lung disease in preterm neonates. Because polymorphisms of the glucocorticoid receptor gene are known to influence the sensitivity to glucocorticoids, in the present study we examined whether any associations could exist among the BclI, N363S and ER22/23EK polymorphisms of the glucocorticoid receptor gene and gestational age, birth weight and/or perinatal morbidity of 125 preterm neonates born at 28-35 weeks' gestation with (n=57) or without maternal dexamethasone treatment (n=68). The prevalence of the three polymorphisms in the whole group of preterm infants was similar to that reported in healthy adult Hungarian population.

Laterality disturbance and hypopituitarism. A case report of co-existing situs inversus totalis and combined pituitary hormone deficiency.

The authors present the case history of a 52-yr-old male patient with a unique association of combined pituitary hormone deficiency (CPHD) and situs inversus totalis. Except for signs and symptoms of pituitary hormone deficiency, the patient had no dysmorphic features, and hearing impairment, primary mental or neurological defects were also absent. Pituitary magnetic resonance imaging (MRI) scan showed hypoplasia of the anterior lobe of the pituitary gland and an ectopic posterior pituitary lobe.

Polymorphisms of the glucocorticoid receptor gene in Graves ophthalmopathy.

Background/aims: Glucocorticoids have an important role in the regulation of the immune system, and alterations in glucocorticoid signaling may have an impact on the pathophysiology of autoimmune and inflammatory disorders. Because polymorphisms of the glucocorticoid receptor (GR) gene, including the N363S, ER22/23EK, A3669G and BclI variants were found to influence glucocorticoid signalling, we examined whether these polymorphisms could be associated with the development or clinical manifestations of Graves ophthalmopathy (GO).

Methods: The carrier and allelic frequencies of the N363S, ER22/23EK, A3669G, and BclI polymorphisms of the GR were determined in 95 Hungarian outpatients with GO and 160 healthy controls.