Melek Yıldız

A novel mutation of AMH in three siblings with persistent Mullerian duct syndrome

Abstract Background: Persistent Mullerian duct syndrome (PMDS) is a rare form of male 46,XY disorder of sex development characterized by the presence of Mullerian duct derivatives in otherwise phenotypically normal males. Aim: To report a novel mutation of the anti-Mullerian hormone (AMH) gene in two of three siblings with PMDS. Cases: A 2-year-old male presented with recurrent left-sided inguinal hernia and absence of right testis. Laparoscopic surgery disclosed Mullerian duct derivates and transverse testicular ectopia. AMH level was found to be low [1.6 ng/mL (normal range 7.4–373.1), 11.42 pmol/L (normal range 52.8–2663.9)]. His 15-year-old and 7-year-old elder brothers were invited, and bilateral undescended testes were noted upon examination. Female reproductive structures were identified during surgery but no transverse testicular ectopia. All cases had 46,XY karyotype. Genetic analyses could be done in two of them and a unique homozygous T to C base substitution was found at position 1591 in the AMH gene. Conclusion: This is the first report of the AMH gene mutation which is referred as p.Y531H (c.1591T>C), which resulted in different phenotypes of PMDS in three siblings.

Two different patterns of mini-puberty in two 46,XY newborns with 17β-hydroxysteroid dehydrogenase type 3 deficiency.

Abstract We report two newborns with female external genitalia and bilateral inguinal swelling who were diagnosed with 17β-hydroxysteroid dehydrogenase type 3 deficiency, a rare cause of 46,XY disorder of sexual development. The first case had normal clitoral size and vaginal and urethral openings, palpable gonads in the inguinal region, low testosterone, and low levels of basal and GNRH-stimulated gonadotropin. The second case had similar external genitalia, low testosterone but borderline basal and normal stimulated gonadotropin levels. Low testosterone/androstenedione ratios (0.22 and 0.24, respectively; normal, >0.8) after human chorionic gonadotropin stimulation indicated 17β-hydroxysteroid dehydrogenase type 3 deficiency. HSD17B3 sequencing revealed a homozygous novel mutation (c.464A>C, p.H155P) in exon 6 in the first case and homozygous c.239G>A (p.R80Q) in exon 3 in the second.

Genetic Diagnosis Using Whole Exome Analysis in Two Cases with Malignant Osteopetrosis of Infancy

Ad dress for Cor res pon den ce Korcan Demir MD, Dr. Behçet Uz Children’s Hospital, Clinic of Pediatric Endocrinology, İzmir, Turkey Phone: +90 232 412 60 77 E-mail: korcan.demir@deu.edu.tr, korcandemir@gmail.com ©Jo ur nal of Cli ni cal Re se arch in Pe di at ric En doc ri no logy, Pub lis hed by Ga le nos Pub lis hing. Genetic Diagnosis Using Whole Exome Analysis in Two Cases with Malignant Osteopetrosis of Infancy J Clin Res Pediatr Endocrinol 2015;7(4):356-357 DO I: 10.4274/jcrpe.2597

Clinical Heterogeneity and Phenotypic Expansion of NaPi-IIa-Associated Disease.

Context NaPi-IIa, encoded by SLC34A1, is a key phosphate transporter in the mammalian proximal tubule and plays a cardinal role in renal phosphate handling. NaPi-IIa impairment has been linked to various overlapping clinical syndromes, including hypophosphatemic nephrolithiasis with osteoporosis, renal Fanconi syndrome with chronic kidney disease, and, most recently, idiopathic infantile hypercalcemia and nephrocalcinosis. Objectives We studied the molecular basis of idiopathic infantile hypercalcemia with partial proximal tubulopathy in two apparently unrelated patients of Israeli and Turkish descent. Design Genetic analysis in two affected children and their close relatives was performed using whole-exome sequencing, followed by in vitro localization and trafficking analysis of mutant NaPi-IIa. Results Mutation and haplotype analyses in both patients revealed a previously described homozygous loss-of-function inserted duplication (p.I154_V160dup) in NaPi-IIa, which is inherited identical-by-descent from a common ancestor. The shared mutation was originally reported by our team in two adult siblings with renal Fanconi syndrome, hypophosphatemic bone disease, and progressive renal failure who are family members of one of the infants reported herein. In vitro localization assays and biochemical analysis of p.I154_V160dup and of additional NaPi-IIa mutants harboring a trafficking defect indicate aberrant retention at the endoplasmic reticulum in an immature and underglycosylated state, leading to premature proteasomal degradation. Conclusions Our findings expand the phenotypic spectrum of NaPi-IIa disruption, reinforce its link with proximal tubular impairment, enable longitudinal study of the natural history of the disease, and shed light on cellular pathways associated with loss of function and impaired trafficking of NaPi-IIa mutants.

Melanocortin-4 Receptor Gene Mutations in a Group of Turkish Obese Children and Adolescents

Objective: Melanocortin-4 receptor (MC4R) mutations are the most common known cause of monogenic obesity. Data regarding MC4R mutations in Turkish subjects are limited. To determine the prevalence of MC4R mutations in a group of Turkish morbid obese children and adolescents. Methods: MC4R was sequenced in 47 consecutive morbidly obese children and adolescents (28 girls and 19 boys, aged 1-18 years) who presented during a one-year period. Inclusion criterion was a body mass index (BMI) ≥120% of the 95th percentile or ≥35 kg/m2. Patients with chronic diseases, Cushing syndrome, hypothyroidism, or suspected syndromes that could cause obesity were excluded. Onset of obesity was before age 10 years in all subjects. Results: Mean age was 13.2±4.1 years, age at onset of obesity 5.1±2.1 years, height standard deviation (SD) score 1.21±0.93, BMI 40.0±8.8 kg/m2, and BMI SD score was 2.72±0.37. One novel (c.870delG) and two previously reported (c.496 G>A, c.346_347delAG) mutations were found in four (8.5%) obese children and adolescents. The novel mutation (c.870delG) was predicted to be a disease-causing frame-shift mutation using in silico analyses. Fasting glucose and lipid levels of the patients with MC4R mutation were normal, but insulin resistance was present in two of the subjects. Six more individuals with MC4R mutation (1 child, 5 adults) were detected following analyses of the family members of affected children. Conclusion: MC4R mutations are frequently found in morbid obese Turkish children and adolescents.

Association of Wolfram syndrome with Fallot tetralogy in a girl.

Wolfram syndrome (DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is a rare neurodegenerative disorder. Mutations of the WFS1 (wolframin) on chromosome 4 are responsible for the clinical manifestations in majority of patients with Wolfram syndrome. Wolfram syndrome is also accompanied by neurologic and psychiatric disorders, urodynamic abnormalities, restricted joint motility, cardiovascular and gastrointestinal autonomic neuropathy, hypergonadotrophic hypogonadism in males and diabetic microvascular disorders. There are very limited data in the literature regarding cardiac malformations associated in children with Wolfram syndrome. A 5-year-old girl with Wolfram syndrome and tetralogy of Fallot is presented herein.

Incidence of Type 1 Diabetes in Children Aged Below 18 Years During 2013-2015 in Northwest Turkey

Objective: To assess the incidence of type 1 diabetes mellitus (T1DM) in children under 18 years of age in the northwest region of Turkey during 2013-2015. Methods: All newly diagnosed T1DM cases were recorded prospectively during 2013-2015. Total, as well as gender and age group specific (0-4, 5-9, 10-14 and 15-17 age) mean incidences per 100,000 per year were calculated. Results: There were 1,773 patients diagnosed during 2013-2015 (588 cases in 2013, 592 cases in 2014, 593 cases in 2015). Of these, 862 (48.6%) were girls and 911 (51.4%) were boys. The mean age at diagnosis was 9.2±4.2 years and it was not significantly different between girls (9.0±4.1 years) and boys (9.4±4.4 years) (p=0.052). The crude mean incidence was 8.99/100.000 confidence interval (CI) (95% CI: 8.58-9.42). Although mean incidence was similar between boys [8.98/100.000 (CI: 8.40 to 9.58)] and girls [9.01/100.000 (CI: 8.42 to 9.63)], there was male predominance in all groups except for 5-9 year age group. The standardized mean incidence was 9.02/100.000 according to the World Health Organization standard population. The mean incidence for the 0-4, 5-9, 10-14 and 15-17 age groups was 6.13, 11.68, 11.7 and 5.04/100.000 respectively. The incidence of T1DM was similar over the course of three years (p=0.95). A significant increase in the proportion of cases diagnosed was observed in the autumn-winter seasons. Conclusion: The northwest region of Turkey experienced an intermediate incidence of T1DM over the period of the study.