Genotype-phenotype correlation, gonadal malignancy risk, gender preference, and testosterone/dihydrotestosterone ratio in steroid 5-alpha-reductase type 2 deficiency: a multicenter study from Turkey.

BACKGROUND: Studies regarding genetic and clinical characteristics, gender preference, and gonadal malignancy rates for steroid 5-alpha-reductase type 2 deficiency (5α-RD2) are limited and they were conducted on small number of patients. OBJECTIVE: To present genotype-phenotype correlation, gonadal malignancy risk, gender preference, and diagnostic sensitivity of serum testosterone/dihydrotestosterone (T/DHT) ratio in patients with 5α-RD2. MATERIALS AND METHODS: Patients with variations in the SRD5A2 gene were included in the study. Demographic characteristics, phenotype, gender assignment, hormonal tests, molecular genetic data, and presence of gonadal malignancy were evaluated. RESULTS: A total of 85 patients were included in the study. Abnormality of the external genitalia was the most dominant phenotype (92.9%). Gender assignment was male in 58.8% and female in 29.4% of the patients, while it was uncertain for 11.8%. Fourteen patients underwent bilateral gonadectomy, and no gonadal malignancy was detected. The most frequent pathogenic variants were p.Ala65Pro (30.6%), p.Leu55Gln (16.5%), and p.Gly196Ser (15.3%). The p.Ala65Pro and p.Leu55Gln showed more undervirilization than the p.Gly196Ser. The diagnostic sensitivity of stimulated T/DHT ratio was higher than baseline serum T/DHT ratio, even in pubertal patients. The cut-off values yielding the best sensitivity for stimulated T/DHT ratio were ≥ 8.5 for minipuberty, ≥ 10 for prepuberty, and ≥ 17 for puberty. CONCLUSION: There is no significant genotype-phenotype correlation in 5α-RD2. Gonadal malignancy risk seems to be low. If genetic analysis is not available at the time of diagnosis, stimulated T/DHT ratio can be useful, especially if different cut-off values are utilized in accordance with the pubertal status.

A novel mutation in steroidogenic factor (SF1/NR5A1) gene in a patient with 46 XY DSD without adrenal insufficiency.

Steroidogenic factor-1 (SF-1), also known as nuclear receptor subfamily 5 group A member 1 (NR5A1), is a member of orphan receptor subfamily and located on chromosome 9 (9q33). In 46, XY individuals with mutation of SF-1 gene, adrenal failure, testis dysgenesis, androgen synthesis defects, hypospadias and anorchia with microphallus, infertility can occur from severe to mild. We report a case of a 20-day-old male who is admitted to our clinic due to ambiguous genitalia. In this report, we describe a novel heterozygous c.814A > C (p. T272P) NR5A1 mutation in a patient with 46, XY DSD without adrenal insufficiency. We describe a novel missense mutation c.814A > C (p. T272P) in NR5A1 gene which had not previously been reported. Also this report highlights that the potential diagnostic utility of next-generation sequencing is an effective strategy versus Sanger sequencing to identify genetic mosaicism in clinical practice.

Association Between Vitamin D Receptor Polymorphism and Familial Mediterranean Fever Disease in Turkish Children.

Familial Mediterranean fever (FMF) is an autosomal recessive, inherited autoinflammatory disease characterized by recurrent, self-limited attacks of fever, and inflammation of serosal surfaces. The aim of our study was to determine a possible relationship between Vitamin D receptor (VDR) gene polymorphisms and the risk of children with FMF. We investigated VDR FokI (rs10735810), TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232) polymorphisms in 50 children with FMF and 150 age-matched healthy control subjects. This study was performed by polymerase chain reaction-based restriction fragment length polymorphism. There was no significant difference between patients and controls for VDR FokI, TaqI, BsmI, and ApaI genotypes and alleles (p > 0.05). Results need to be supported by further investigations that define haplotype patterns for VDR gene polymorphisms in a larger group and different ethnic groups of FMF patients.

Serum nesfatin-1 and leptin levels in non-obese girls with premature thelarche.

AIM: We aimed to investigate serum nesfatin-1 level in girls with premature thelarche (PT) and its relationship with anthropometric parameters and leptin, which are involved in the initiation of pubertal process. SUBJECTS-METHODS: Non-obese girls who presented with the complaint of early (2-8 years) and isolated breast development were included in the study. The control group consisted of age-matched healthy prepubertal girls. Auxological measurements were performed in all subjects. Gonadotropin-releasing hormone (GnRH) stimulation test and bone age assessment were conducted in subjects with early breast development. Girls with a bone age/chronologic age ratio <1.2 and a peak luteinizing hormone (LH) response to GnRH stimulation <5 mIU/L were included in the PT group. RESULTS: The study included 22 non-obese girls with PT and 24 healthy prepubertal controls. Body mass index (BMI), BMI-standard deviation score (SDS) and height SDS were similar between the groups (p > 0.05). Serum leptin and nesfatin-1 levels were found significantly higher in the PT group compared to controls (p < 0.05). No correlation was detected between nesfatin-1 and basal LH, basal follicle stimulating hormone (FSH), stimulated peak LH, peak FSH, leptin levels and anthropometric parameters in the PT group (p > 0.05). CONCLUSION: Results of the present study showed that serum nesfatin-1 and leptin levels are significantly higher in girls with PT than in prepubertal controls. This finding suggests that similar to leptin, nesfatin-1 may also have a central or peripheral role in the initiation of pubertal process and may be related to PT pathogenesis.

Evaluation of the effects of insulin resistance on ECG parameters in obese children.

OBJECTIVE: Obese people are at increased risk of arrhythmia and sudden death, even in the absence of heart dysfunction. Increased insulin resistance, neurohumoral and autonomic changes in obesity can cause atrial and ventricular repolarization abnormalities. This study aimed to investigate the effect on ventricular repolarization parameters and to show the increased risk of ventricular arrhythmia in obese children. PATIENTS AND METHODS: The data of 50 obese children aged 2-18 who applied to the Pediatric Endocrinology Outpatient Clinic were evaluated prospectively. In 12-lead ECGs, heart rate, Pmax, Pmin, P-wave dispersion (Pwdisp), QTmax, QTmin, QT dispersion (QTd), QTcmax, QTcmin, QTc interval dispersion (QTcd), Tpeak-Tend interval (Tp-e), Tp-e/QT, Tp-e/QTc were calculated electronically. RESULTS: Tp-e time (0.041 ± 0.004/0.049 ± 0.015/p=0.018) and Tp parameters were measured in obese children with and without insulin resistance. Tp-e/QT ratio was also found to be high (p=0.035). There is a negative correlation between BMI SDS values and QTcmax and QTcmin values in patients with insulin resistance (p=0.015). CONCLUSIONS: In our study, the Tp-e interval and Tp-e/QT ratios, which had been revealed in literature to be more sensitive in demonstrating ventricular arrhythmias, were found to be higher in obese individuals with insulin resistance than in those without insulin resistance. Obese individuals with or without insulin resistance should be carefully evaluated in terms of atrial and ventricular depolarization and repolarization parameters with 12-lead ECG during their outpatient controls, and annual 24-hour Holter control should be performed to detect arrhythmias.

Low omentin-1 levels are related with clinical and metabolic parameters in obese children.

This is the first clinical study evaluating the relation of serum omentin 1 levels with anthropometric and metabolic parameters in obese children with a particular interest to identify the possible role of omentin 1 in childhood obesity and related metabolic disturbances.The study included obese children with a body mass index (BMI)>95th percentile and healthy children with a BMI<85th percentile. The healthy and obese subjects had similar age and gender distribution. Glucose, insulin, lipid profile, and omentin 1 levels were measured to evaluate the metabolic parameters.49 obese children who applied to our department with complaint of weight gain and 30 healthy age and sex matched subjects were enrolled. In obese children BMI, body mass index-standard deviation score (BMI-SDS), systolic blood pressure (SBP), diastolic blood pressure (DBP), mid-arm circumference (MAC), triceps skin fold (TSF), waist circumference (WC), homeostasis model assessment-insulin resistance (HOMA-IR), serum insulin, and triglyceride levels were higher whereas omentin-1 levels were lower than control subjects (p<0.05). In the obese group, omentin 1 level was negatively correlated with BMI, insulin, HOMA-IR, and WC, while no significant correlation was observed with other parameters (p>0.05). Additionally, although statistically insignificant, patients with IR (n=31) had lower omentin-1 levels compared to obese children without IR (n=18).Our data indicates that serum omentin 1 levels are i) lower in obese children and ii) negatively correlated with BMI, WC, HOMA-IR and insulin levels suggesting that omentin 1 might be a biomarker for metabolic dysfunction also in childhood and adolescence. Lower omentin 1 levels tended to be associated with insulin resistance however this association failed to reach statistical significance. Further studies in larger populations are needed to better-define the relation of omentin 1 and insulin resistance in obese children.

A novel GATA6 mutation leading to congenital heart defects and permanent neonatal diabetes: a case report.

Permanent neonatal diabetes mellitus is a rare condition mostly due to heterozygous mutations in the KCNJ11, ABCC8 and INS genes. Neonatal diabetes due to pancreatic agenesis is extremely rare. Mutations in PDX1, PTF1A, HNF1B, EIF2AK3, RFX6 and GATA6 genes have been shown to result in pancreatic agenesis or hypoplasia. This report describes a 40-day-old male infant diagnosed with permanent neonatal diabetes associated with atrial septal defect, pulmonary stenosis, patent ductus arteriosus and a novel de novo heterozygous missense mutation (p.N466S) in the GATA6 gene with no evidence of exocrine pancreas insufficiency. In addition to permanent neonatal diabetes, the patient had transient idiopathic neonatal cholestasis and hypoglycaemic episodes unrelated to insulin treatment, features that are rarely described in children with permanent neonatal diabetes.