Atypical STAT5B deficiency, severe short stature and mild immunodeficiency associated with a novel homozygous STAT5B Variant.

STAT5B deficiency, a rare autosomal recessive disorder characterized by severe growth hormone insensitivity (GHI) and immunodeficiency, can manifest as fatal pulmonary complications. We describe atypical STAT5B deficiency associated with a novel homozygous frame-shift STAT5B variant [c.1453delG, p.(Asp485Thrfs*29)] identified in a young 17.6 yr old female subject who had severe postnatal growth impairment, biochemistries typical of GHI, an immune profile notable for hypergammaglobulinaemia and elevated B lymphocytes, and lack of pulmonary disease. Marked elevation of serum prolactin and pathologically diagnosed eczema were evident. In reconstitution studies, the STAT5B p.(Asp485Thrfs*29) was expressed although expression was reduced compared to wild-type STAT5B and a previously identified STAT5B p.(Gln368Profs*9) variant. Both truncated STAT5B peptides could not be activated by GH, nor mobilize to the nucleus. We conclude that an intact, functional, STAT5B is essential for normal GH-mediated growth, while expressed loss-of-function STAT5B variants may alleviate severe immune and pulmonary issues normally associated with STAT5B deficiency.

Early and late diagnoses of 17ß-Hydroxysteroid dehydrogenase type-3 deficiency in two unrelated patients.

17ß-hydroxysteroid dehydrogenase type 3 deficiency is a rare cause of 46 XY disorders of sexual development. Mutations in the HSD17B3 gene result in reduced activity of the 17ß-HSD3 enzyme, decreasing the conversion of androstenedione to testosterone. In this report, two cases, admitted with different clinical findings in the neonatal and adolescent periods and were decided to be raised in different genders are presented. The first case who had complete female external genitalia presented on the third postnatal day with the complaint of swelling in the groin. He was decided to be raised as a male and was treated successfully with parenteral testosterone in order to increase phallus size before surgical correction of the external genitalia. The second case was an adolescent girl who presented due to pubertal virilisation and primary amenorrhoea and chose female gender. Molecular genetic analyses of the HSD17B3 gene revealed two different previously reported homozygous variants. We emphasise that patients with 17ß-hydroxysteroid dehydrogenase type 3 deficiency can present with heterogeneous clinical findings in different age groups. Early diagnosis is important to prevent future gender confusion and related problems.

Macular Variability in Children and Adolescents with Metabolic Syndrome: A Cross-sectional Study Examining the Associations with Anthropometric Measurements, Metabolic Parameters and Inflammatory Markers

Objective: Macular damage may be observed in obesity and metabolic syndrome (MetS), a condition which leads to chronic subclinical inflammation and affects most organ systems. To investigate the association between macular variability and anthropometric measurements, metabolic parameters, and inflammatory markers in children and adolescents with MetS. Methods: Two hundred and twenty eyes of 62 obese and 48 healthy children and adolescents were examined. Bilateral macular retinal thickness (MRT) and macular retinal volume (MRV) were measured in all subjects using optical coherence tomography. Associations between mean MRT and mean MRV and age, auxological measurements including body mass index standard deviation scores (BMI-SDS) and waist circumference-SDS (WC-SDS), metabolic parameters and inflammatory parameters including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio and systemic immune-inflammatory index (SIII) were investigated. Results: No statistically significant difference was observed between the groups in terms of age or sex distribution (p>0.05). Mean MRT (r=-0.326, p=0.007) and MRV (r=-0.303, p=0.007) values in the obese group with MetS decreased as homeostasis model assessment-insulin resistance (HOMA-IR) values increased. SIII values were higher in obese groups, but particularly in obese subject with MetS, compared to the control group (p=0.021). The decrease in mean MRT (r=-0.544, p=0.046) and MRV (r=-0.651, p=0.031) in the obese subjects with MetS was negatively correlated with NLR. Mean MRT and MRV decreased in all obese subjects as SIII increased (p<0.05). Conclusion: This is the first study to show that mean MRT and MRV values decrease as BMI-SDS, WC-SDS and HOMA-IR increase in obese children and adolescents with MetS. NLR and SIII may serve as markers of chronic inflammation in obese children with MetS associated with macular damage.

Evaluation of Turner Syndrome Knowledge among Physicians and Parents

Objective: Turner syndrome (TS) is one of the most common chromosomal abnormalities and an important cause of short stature and infertility due to ovarian failure in females. The aim was to evaluate the knowledge of TS among physicians and parents of children with TS and to enhance awareness about this subject. Methods: One hundred and forty physicians were included in the study. The study population comprised 37 pediatricians (26.4%), 15 gynecologists (10.7%), 88 family physicians (62.9%) and 30 parents who had daughters with a diagnosis of TS. Two separate questionnaires were administered to evaluate TS knowledge of physicians and parents. Results: According to the self-reports of physicians, 49% had insufficient knowledge of TS, while 15.7% indicated that they had no knowledge of TS. The mean percentage of correct answers was 50.71±16.17% for all physicians. When the entire group of physicians was considered, 67.1% of them did not know the approximate incidence of TS, while 14.3% of them incorrectly indicated that TS was a condition that was seen in boys. The mean percentage of correct answers among parents was 68±15%, and there was no difference between the mothers' and fathers' correct answer rates (p=0.063). The majority of parents was not aware of TS-associated diseases and increased malignancy risk in TS. Conclusion: Physician knowledge of TS was poor and that there is a need for continued education about TS at the medical faculty and post-graduate levels.

Targeted next generation sequencing in patients with maturity-onset diabetes of the young (MODY).

Background Maturity-onset diabetes of the young (MODY) is a common form of monogenic diabetes. Fourteen genes have been identified, each leading to cause a different type of MODY. The aims of this study were to reveal both known and novel variants in MODY genes in patients with MODY using targeted next generation sequencing (NGS) and to present the genotype-phenotype correlations. Methods Mutation analysis of MODY genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, INS and KCNJ11) was performed using targeted NGS in 106 patients with a clinical diagnosis of MODY. The variants were evaluated according to American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. Results A total of 18 (17%) variants were revealed among all patients. Seven variants in GCK, six in HNF4A, four in HNF1A and one in ABCC8 genes were found. Eight of them were previously published and 10 of them were assessed as novel pathogenic or likely pathogenic variants. Conclusions While the most frequent mutations are found in the HNF1A gene in the literature, most of the variants were found in the GCK gene in our patient group using the NGS method, which allows simultaneous analysis of multiple genes in a single panel.

The overlap of gastroesophageal reflux disease and functional constipation in children: the efficacy of constipation treatment.

OBJECTIVES: This study was designed to investigate the frequency of gastroesophageal reflux disease (GERD) in children with functional constipation (FC). It was structured to assess the improvement level in reflux symptoms by measuring the acid reflux in these patients after they had received FC treatment. METHODS: Ninety-four children who suffered from constipation were evaluated prospectively. Data forms were completed to assess the GERD symptoms in all the cases. Twenty-four-hour pH meter monitoring was performed in 55 of the patients with GERD symptoms. The cases with abnormal acid reflux were treated by conventional therapy for FC. These cases were re-evaluated for GERD symptoms and weekly defecation frequency, and 24-h pH meter monitoring was performed at the end of a 3-month period. RESULTS: An abnormal level of acid reflux was determined in 23 of the 55 cases. After the constipation treatment, a significant improvement was achieved in the acid reflux index and GERD symptoms, whereas the weekly defecation frequency increased. CONCLUSION: GERD is a frequent problem in children with FC. Treatment of the constipation can improve the reflux symptoms and abnormal acid reflux in these cases. Physicians should bear in mind the co-occurrence of these two prevalent problems for better disease management.

An Unusual Presentation of 46,XY Pure Gonadal Dysgenesis: Spontaneous Breast Development and Menstruation.

46,XY pure gonadal dysgenesis (Swyer syndrome) is characterized by normal female genitalia at birth. It usually first becomes apparent in adolescence with delayed puberty and amenorrhea. Rarely, patients can present with spontaneous breast development and/or menstruation. A fifteen-year-old girl presented to our clinic with the complaint of primary amenorrhea. On physical examination, her external genitals were completely female. Breast development and pubic hair were compatible with Tanner stage V. Hormonal evaluation revealed a hypergonadotropic state despite a normal estrogen level. Chromosome analysis revealed a 46,XY karyotype. Pelvic ultrasonography showed small gonads and a normal sized uterus for age. SRY gene expression was confirmed by multiplex polymerase chain reaction. Direct sequencing on genomic DNA did not reveal a mutation in the SRY, SF1 and WT1 genes. After the diagnosis of Swyer syndrome was made, the patient started to have spontaneous menstrual cycles and therefore failed to attend her follow-up visits. After nine months, the patient underwent diagnostic laparoscopy. Frozen examination of multiple biopsies from gonad tissues revealed gonadoblastoma. With this report, we emphasize the importance of performing karyotype analysis, which is diagnostic for Swyer syndrome, in all cases with primary or secondary amenorrhea even in the presence of normal breast development. We also suggest that normal pubertal development in patients with Swyer syndrome may be associated with the presence of a hormonally active tumor.

Importance of the liver ultrasound scores in pubertal obese children with nonalcoholic fatty liver disease.

AIM: The purpose of our study was to determine the relationship between liver ultrasound scores and insulin sensitivity in a population of obese children with nonalcoholic fatty liver disease (NAFLD) and the relationships between other metabolic features and ultrasound scores. METHODS: One hundred sixty-nine obese adolescents, 96 girls, and 73 boys (mean age: 12.7 ± 1.3 years, mean body mass index: 26.3 ± 4.6) were enrolled the study. The obese subjects were divided into 2 groups based on their pubertal status. Ultrasonography findings were scored in this study included hepatorenal echo contrast, liver brightness, deep attenuation, and vascular blurring. Scores ranged from 0 to 6 points, and NAFLD was defined if ultrasound score was ≥ 1. Insulin resistance was evaluated by homeostasis model assessment (HOMA-IR) from fasting samples. RESULTS: Prevalence of NAFLD in pubertal children (61.9%) had significantly higher than pre-pubertal children (40.8%) (P=.008). Transaminases ratio was significantly correlated in both prepubertal (r=0.231; P=.03) and pubertal (r=0.628, P=0.017) groups. HOMA-IR values were elevated in both groups; however, liver ultrasound score was positively correlated with HOMA-IR (r=0.735, P=.014) in pubertal children. CONCLUSION: NAFLD prevalence among obese children is quite high, especially pubertal adolescents than prepubertal children. We demonstrated an association between insulin resistance and NAFLD ultrasound scoring in pubertal obese children. We suggested that ultrasound examination of the liver be included in the routine check-up of the pubertal obese children with insulin resistance to allow the detection of NAFLD at an early stage.

Severe hypercalcemia associated with Williams syndrome successfully treated with pamidronate infusion therapy.

Infantile hypercalcemia becomes manifest in 15% of patients with Williams syndrome (WS) and generally is not clinically severe. However, some patients with WS can have severe hypercalcemia and do not respond well to traditional therapies. Recently, pamidronate has been used in the treatment of childhood hypercalcemia associated with many disorders, but there is little experience with the treatment of hypercalcemia with bisphosphonates in patients with WS. We present a 17-month-old female patient, who had been diagnosed as WS by genetic analysis, admitted to our clinic for the investigation of severe hypercalcemia (4.02 mmol/L). Because the patient did not respond very well to fluid administration, furosemide infusion, and dietary calcium restriction, pamidronate infusion was performed and calcium levels returned to normal within 2 days. This case report is presented to point out that pamidronate therapy seems to be a safe and efficient way of treating life-threatening hypercalcemia in WS.

Therapeutic effect of metformin and vitamin E versus prescriptive diet in obese adolescents with fatty liver.

OBJECTIVE: The aim of the study was to determine whether metformin or vitamin E treatment for six months is effective in reducing body weight, blood pressure, and also ameliorating insulin resistance, adiponectin, and tumor necrosis factor (TNF)-alpha in obese adolescents with non-alcoholic fatty liver disease (NAFLD). METHODS: Sixty-seven obese adolescents with liver steatosis (age range, 9 - 17 years) were included in the study. The metformin group received an 850-mg dose of metformin daily and the vitamin E group received 400 U vitamin E /daily, in capsule form for 6 months, plus an individually tailored diet, exercise, and behavioral therapy. RESULTS: After 6 months later, there was a significant decline in body mass index, and fasting insulin and homeostatic model assessment (HOMA) values in all three groups. Moreover, in comparingson of changes in HOMA among the groups, the metformin- treated group showed significantly improved metabolic control and insulin sensitivity (HOMA) at the end of the study. There were no significant differences for changes of adiponectin, TNF-alpha, in all three groups after 6 months study. CONCLUSION: These data suggest that metformin treatment is more effective than dietary advice and vitamin E treatment in reducing insulin resistance, and also in ameliorating metabolic parameters such as fasting insulin and lipid levels, in obese adolescents having NAFLD.