Inactivating NHLH2 variants cause idiopathic hypogonadotropic hypogonadism and obesity in humans.

Metabolism has a role in determining the time of pubertal development and fertility. Nonetheless, molecular/cellular pathways linking metabolism/body weight to puberty/reproduction are unknown. The KNDy (Kisspeptin/Neurokinin B/Dynorphin) neurons in the arcuate nucleus of the hypothalamus constitute the GnRH (gonadotropin-releasing hormone) pulse generator. We previously created a mouse model with a whole-body targeted deletion of nescient helix-loop-helix 2 (Nhlh2; N2KO), a class II member of the basic helix-loop-helix family of transcription factors. As this mouse model features pubertal failure and late-onset obesity, we wanted to study whether NHLH2 represents a candidate molecule to link metabolism and puberty in the hypothalamus. Exome sequencing of a large Idiopathic Hypogonadotropic Hypogonadism cohort revealed obese patients with rare sequence variants in NHLH2, which were characterized by in-silico protein analysis, chromatin immunoprecipitation, and luciferase reporter assays. In vitro heterologous expression studies demonstrated that the variant p.R79C impairs Nhlh2 binding to the Mc4r promoter. Furthermore, p.R79C and other variants show impaired transactivation of the human KISS1 promoter. These are the first inactivating human variants that support NHLH2's critical role in human puberty and body weight control. Failure to carry out this function results in the absence of pubertal development and late-onset obesity in humans.

The Role of Umbilical Cord Blood Concentration of IGF-I, IGF-II, Leptin, Adiponectin, Ghrelin, Resistin, and Visfatin in Fetal Growth.

OBJECTIVE: Herein, we measured the concentration of insulinlike growth factor I (IGF-I), IGF-II, leptin, adiponectin, ghrelin, resistin, and visfatin in the umbilical cord blood of newborns categorized as "small for gestational age" (SGA), "appropriate for gestational age" (AGA), and "large for gestational age" (LGA). Our aim was to elucidate the link between the levels of these proteins and fetal growth. STUDY DESIGN: A total of 96 term infants were included and categorized into three weight categories. Their venous cord blood samples were collected to measure the levels of IGF-I, IGF-II, leptin, adiponectin, ghrelin, resistin, and visfatin. RESULTS: IGF-I, visfatin, and leptin levels showed significant differences among the groups. Pairwise comparisons showed that adiponectin (p = 0.023), resistin (p = 0.025), and ghrelin (p = 0.005) levels were significantly lower in the SGA group than in the LGA group. Correlation analyses showed a strong association of IGF-1, IGF-II, and leptin levels with birth weight (r = 0.644, p < 0.001; r = 0.441, p < 0.001; and r = 0.404, p < 0.001, respectively). CONCLUSION: SGA newborns showed a significantly higher visfatin concentration and lower ghrelin, leptin, resistin, and adiponectin levels than the AGA and LGA newborns did.

SLC4A4 compound heterozygous mutations in exon-intron boundary regions presenting with severe proximal renal tubular acidosis and extrarenal symptoms coexisting with Turner's syndrome: a case report.

BACKGROUND: Congenital NBCe1A deficiency with the SLC4A4 mutation causes severe proximal renal tubular acidosis, which often comprises extrarenal symptoms, such as intellectual disability and developmental delay, glaucoma, cataract and band keratopathy. To date, almost all mutations have been found to be homozygous mutations located in exons. CASE PRESENTATION: We performed direct nucleotide sequencing analysis of exons and exon-intron boundary regions of the SLC4A4 in a patient presenting with severe renal proximal tubule acidosis, glaucoma and intellectual disability and her parents without these signs. The examination revealed compound heterozygous mutations in exon-intron boundary regions, c.1076 + 3A > C and c.1772 - 2A > T, neither of which have been reported previously. While the former mutation was found in the mother, the latter was found in the father. The transcript of the SLC4A4 gene was almost undetectable, and the patient was also diagnosed with Turner's syndrome. CONCLUSIONS: We identified two novel SLC4A4 mutations, c.1076 + 3A > C and c.1772 - 2A > T. When presented in a compound heterozygous state, these mutations caused a phenotype of severe renal proximal tubular acidosis along with glaucoma and mental retardation. This is the first report of congenital proximal renal tubular acidosis carrying compound heterozygous SLC4A4 mutations in exon-intron boundary regions. We suggest that an mRNA surveillance mechanism, nonsense-mediated RNA decay, following aberrant splicing was the reason that the SLC4A4 transcript was almost undetectable in the proband.

Effectiveness of Two Different Methods for Pain Reduction During Insulin Injection in Children With Type 1 Diabetes: Buzzy and ShotBlocker.

BACKGROUND: Repeated injections may prevent children from performing insulin administration (skip dosing) and may cause anxiety. AIMS: To compare the effect of ShotBlocker and the combination of vibration and cold application (Buzzy) in reducing pain during insulin administration in children. METHODS: This research was designed as a randomized controlled experimental study. The study sample consisted of 60 children aged between 6 and 12 years who were diagnosed as having type 1 diabetes and received insulin from the Child Endocrinology Department of the medical faculty in Eskisehir Osmangazi University between May 2015 and June 2017. The children were randomized into the Buzzy (n = 20), ShotBlocker (n = 20), and control (n = 20) groups. Three instruments were used to obtain the research data: Interview and Observation Form, Children's Anxiety and Pain Scale (CAPS), and Faces Pain Scale-Revised (FPS-R). RESULTS: The mean age of the children was 9.43 ± 2.18 years (range 6-12 years). There were no significant differences among preprocedural anxiety levels of the study groups in terms of self-, parent-, and observer-reported levels (p = .935, p = .374, and p = .680, respectively). Children in the control group had higher levels of pain than children in the Buzzy and ShotBlocker groups (p = .008, p = .007, and p > .001, respectively). There was a significant difference between the groups with procedural anxiety levels reported by the family and observer (p = .006 and p = .002, respectively), favoring the intervention groups. LINKING EVIDENCE TO ACTION: Nurses should be aware of pain during insulin injection and use methods for pain relief accordingly. ShotBlocker is recommended as a helpful option in cases where a pain control method is required.

Anthropometric findings from birth to adulthood and their relation with karyotpye distribution in Turkish girls with Turner syndrome.

To evaluate the anthropometric features of girls with Turner syndrome (TS) at birth and presentation and the effect of karyotype on these parameters. Data were collected from 842 patients with TS from 35 different centers, who were followed-up between 1984 and 2014 and whose diagnosis age ranged from birth to 18 years. Of the 842 patients, 122 girls who received growth hormone, estrogen or oxandrolone were excluded, and 720 girls were included in the study. In this cohort, the frequency of small for gestational age (SGA) birth was 33%. The frequency of SGA birth was 4.2% (2/48) in preterm and 36% (174/483) in term neonates (P < 0.001). The mean birth length was 1.3 cm shorter and mean birth weight was 0.36 kg lower than that of the normal population. The mean age at diagnosis was 10.1 ± 4.4 years. Mean height, weight and body mass index standard deviation scores at presentation were -3.1 ± 1.7, -1.4 ± 1.5, and 0.4 ± 1.7, respectively. Patients with isochromosome Xq were significantly heavier than those with other karyotype groups (P = 0.007). Age at presentation was negatively correlated and mid-parental height was positively correlated with height at presentation. Mid-parental height and age at presentation were the only parameters that were associated with height of children with TS. The frequency of SGA birth was found higher in preterm than term neonates but the mechanism could not be clarified. We found no effect of karyotype on height of girls with TS, whereas weight was greater in 46,X,i(Xq) and 45,X/46,X,i(Xq) karyotype groups.

Comparison of Makorin Ring Finger Protein 3 Levels Between Obese and Normal Weight Patients with Central Precocious Puberty

Objective: Genetic studies of familial central precocious puberty (CPP) have suggested that makorin ring finger protein 3 (MKRN3) is the primary inhibitor of gonadotropin-releasing hormone secretion. Obesity in girls can cause early puberty by affecting the hypothalamic-pituitary-gonadal axis. This study evaluated serum MKRN3 levels of patients with CPP and its relationship with body mass index (BMI). Methods: The study included 92 CPP and 86 prepubertal healthy controls (HC) aged 6-10 years. The CPP and HC groups were divided into obese and non-obese subgroups to evaluate whether BMI affects MKRN3. Patients' presenting complaints, chronological age, height age, bone age, Tanner stage, standard deviation scores for weight, height, and BMI, levels of follicle-stimulating hormone, luteinizing hormone, estradiol, and MKRN3, and pelvic ultrasonography findings were recorded. Results: Serum MKRN3 levels were lower in the CPP group and lowest in the CPP-obese subgroup. There were significant differences in MKRN3 levels between the CPP-obese and CPP-normal weight (p=0.02), CPP-obese and HC-obese (p<0.001), and CPP-obese and HCnormal weight (p=0.03) groups. MKRN3 and BMI were negatively correlated in all cases (r=-0.326, p<0.001). Conclusion: The negative correlation between BMI and MKRN3, and lower MKRN3 levels in CPP-obese patients, suggests that adipose tissue has a role in the onset of puberty. More comprehensive studies are needed to determine the relationship between MKRN3 and adipose tissue.

Early-onset Chronic Keratitis as the First Presenting Component of Autoimmune Polyendocrinopathy Syndrome Type 1 (APS-1): A Case Report and Review of the Literature.

Autoimmune polyendocrine syndrome type 1 (APS-1), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare monogenic autosomal recessive autoimmune disease. It is caused by mutations in the autoimmune regulator (AIRE) gene. APS-1 is diagnosed clinically by the presence of two of the three major components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenocortical insufficiency. A 3.3-year-old girl was presented with a carpopedal spasm to the pediatric emergency clinic. She had a history of recurrent keratitis, and chronic candidiasis as urinary tract infections and oral thrashes. Hypoparathyroidism (HPT) was diagnosed based on low serum concentrations of calcium and parathyroid hormone and elevated serum concentrations of phosphate, and treatment with calcium and calcitriol supplementation was started. Genetic testing revealed homozygosity for nonsense c.769C>T (p.R257X) mutation in exon 6 in the AIRE gene which was reported previously. At the age of 5.6 years, she was presented with an adrenal crisis, and treatment with hydrocortisone and fludrocortisone was started. The reported case highlights that unexplained chronic keratitis in children may be the first and most severe component of this syndrome. The classic triad of APS-1 may also appear in the first decade of life.

Screening of Mutations in Maturity-onset Diabetes of the Young-related Genes and RFX6 in Children with Autoantibody-negative Type 1 Diabetes Mellitus.

Objective: Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes. To date, mutations have been identified in 14 different genes of patients with a clinical diagnosis of MODY. This study screened mutations in 14 MODY-related genes and the regulator factor X6 (RFX6) gene in children. Materials and Methods: The presence of clinical features of MODY and negative results for three autoantibody markers of T1DM in children and adolescents were used as inclusion criteria for genetic testing. The screening panel for next-generation sequencing included 14 MODY-related genes (GCK, HNF4A, HNF1A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1) and the RFX6 gene. Results: Twenty-four different variants in MODY-related genes were identified in 49 children diagnosed with autoantibody-negative type 1 diabetes mellitus (T1DM). A 12 variants were classified as P/LP while 12 were interpreted as variant of unknown significance (VUS). Nine of the pathogenic or likely pathogenic variants were found in GCK, two in HNF1B, and one in ABCC8. Three variants were novel, and one was a de novo variant. All of the variants, except one, showed heterozygotic inheritance. Conclusion: This study screened mutations in the 14 MODY-related genes and the regulatory factor X6 (RFX6) gene in Turkish children diagnosed with autoantibody-negative type 1 diabetes mellitus (T1DM). The frequencies of the MODY subtypes differed from previous reports. Although GCK-MODY was the most frequent mutation in Turkish children, similar to previous studies, the second most prevalent MODY subtype was HNF1B-MODY. This study also established three additional novel mutations in different MODY genes.

The earlier described mutation (c.307c > T [p.R103X]) in the SRD5A2 gene causing a 46,XY female phenotype.

Deletions and mutations in the 5-alpha-reductase type 2 (SRD5A2) gene have been identified in 46,XY disorders of sexual differentiation (DSD). The clinical spectrum is heterogeneous, varying from a normal female external genital appearance to clitoromegaly and isolated micropenis or microphallus associated with hypospadias of various degrees. We describe a 46,XY DSD patient with a homozygous c.307C>T (p.R103X) mutation in the SRD5A2 gene. The case presented with a normal female external genital phenotype.

Increased coagulation in childhood obesity.

OBJECTIVE: This study aims to explore the relation between childhood obesity and procoagulant and anticoagulant systems. METHOD: Fifty-one obese children and 32 normal-weighted children with similar age and gender distribution and between ages of 5 and 16 years were recruited to the study. Antropometric measures of all subjects, existence of any accompanying disease, and medication histories had been recorded. Full blood count, procoagulant, and anticoagulant coagulation tests were run for all subjects. RESULTS: When hematologic variables of obese children were compared with those of healthy controls, it was found that average erythrocyte hemoglobin concentration, erythrocyte distribution width, and platelet count of obese children are significantly higher than healthy control group. It was also found that fibrinogen, thrombin time, factor (F) VIII, FIX, FX, and von Willebrand factor levels of obese children are higher than healthy control group. By contrast, antithrombin levels of obese children are found to be lower. CONCLUSION: In our study, we found that there is a procoagulant increase in the coagulation system activity of obese children compared to non-obese healthy children, whereas there is a significant decrease in anticoagulant system. These changes occurred in obese patients, especially higher levels of plasma procoagulant factors such as fibrinogen, FVIII, FIX, and von Willebrand factor, lead us to think that there is an activity in these patients at endothelial level. Further studies are needed on endothelial activity of obese children.

PLXNB1 mutations in the etiology of idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) comprises a group of rare genetic disorders characterized by pubertal failure caused by gonadotropin-releasing hormone (GnRH) deficiency. Genetic factors involved in semaphorin/plexin signaling have been identified in patients with IHH. PlexinB1, a member of the plexin family receptors, serves as the receptor for semaphorin 4D (Sema4D). In mice, perturbations in Sema4D/PlexinB1 signaling leads to improper GnRH development, highlighting the importance of investigating PlexinB1 mutations in IHH families. In total, 336 IHH patients (normosmic IHH, n = 293 and Kallmann syndrome, n = 43) from 290 independent families were included in the present study. Six PLXNB1 rare sequence variants (p.N361S, p.V608A, p.R636C, p.V672A, p.R1031H, and p.C1318R) are described in eight normosmic IHH patients from seven independent families. These variants were examined using bioinformatic modeling and compared to mutants reported in PLXNA1. Based on these analyses, the variant p.R1031H was assayed for alterations in cell morphology, PlexinB1 expression, and migration using a GnRH cell line and Boyden chambers. Experiments showed reduced membrane expression and impaired migration in cells expressing this variant compared to the wild-type. Our results provide clinical, genetic, molecular/cellular, and modeling evidence to implicate variants in PLXNB1 in the etiology of IHH.

Novel mutations in the USH1C gene in Usher syndrome patients.

PURPOSE: Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by severe-profound sensorineural hearing loss, retinitis pigmentosa, and vestibular areflexia. To date, five USH1 genes have been identified. One of these genes is Usher syndrome 1C (USH1C), which encodes a protein, harmonin, containing PDZ domains. The aim of the present work was the mutation screening of the USH1C gene in a cohort of 33 Usher syndrome patients, to identify the genetic cause of the disease and to determine the relative involvement of this gene in USH1 pathogenesis in the Spanish population. METHODS: Thirty-three patients were screened for mutations in the USH1C gene by direct sequencing. Some had already been screened for mutations in the other known USH1 genes (myosin VIIA [MYO7A], cadherin-related 23 [CDH23], protocadherin-related 15 [PCDH15], and Usher syndrome 1G [USH1G]), but no mutation was found. RESULTS: Two novel mutations were found in the USH1C gene: a non-sense mutation (p.C224X) and a frame-shift mutation (p.D124TfsX7). These mutations were found in a homozygous state in two unrelated USH1 patients. CONCLUSIONS: In the present study, we detected two novel pathogenic mutations in the USH1C gene. Our results suggest that mutations in USH1C are responsible for 1.5% of USH1 disease in patients of Spanish origin (considering the total cohort of 65 Spanish USH1 patients since 2005), indicating that USH1C is a rare form of USH in this population.

Childhood obesity-related cardiovascular risk factors and carotid intima-media thickness.

The purpose of this study was to investigate the relationship between childhood obesity and carotid intima-media thickness (IMT). This is a cross-sectional study in obese children and non-obese control subjects. This study included 75 obese children and 40 non-obese control children. Systolic and diastolic blood pressure (SBP, DBP) values and waist and hip circumferences were measured. Fasting blood glucose and insulin concentrations, total cholesterol, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were assayed. The carotid IMT was measured by high resolution B-mode ultrasonography. Waist/hip ratios, SBP and DBP were significantly increased in the obese group compared to the non-obese children (all p < 0.001). The total cholesterol, LDL-C, HDL-C, and TG in the obese children were significantly different from values in the control subjects (all p < 0.001). Compared to the controls, the obese children demonstrated significant differences in a number of clinical risk factors including body weight, body mass index (BMI), BMI-standard deviation score (SDS), SBP/DBP, waist circumference, hip circumference, and waist/hip ratio (all p < 0.001). Compared to the controls, the obese children showed increased mean carotid IMT values [0.52 mm (95% confidence interval [CI], 0.40-0.64 mm) vs. 0.35 mm (95% CI, 0.24-0.38 mm), p < 0.001]. Univariate correlation analysis revealed that the carotid IMT was closely related to the BMI-SDS, SBP/DBP, waist and hip circumferences, serum TG, cholesterol, LDL-C, HDL-C, fasting serum insulin level, and insulin resistance indices including the homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose-to-insulin ratio (FGIR), and quantitative insulin-sensitivity check index (QUICKI). Multiple regression analysis showed that the BMI-SDS, TG and QUICKI were independent predictive risk factors for increased carotid IMT. Measurements of BMI-SDS, blood pressure, waist and hip circumferences, serum TG levels, the QUICKI insulin resistance index, and carotid IMT by ultrasonography are suitable in pediatric patients in a clinical setting and may be used for screening of obese children.

Neonatal Screening for Congenital Adrenal Hyperplasia in Turkey: Outcomes of Extended Pilot Study in 241,083 Infants

Objective: Turkish Directorate of Public Health introduced the first pilot screening program for congenital adrenal hyperplasia (CAH) in four Turkish cities in 2017, and in 2018 extended the program, with a slight change in screening strategy, to fourteen cities. To evaluate the performance of the extended study and update previously reported outcomes. Methods: Retrospective, descriptive study. Neonates of ≥32 gestational weeks and ≥1500 gr birth weight from fourteen cities, born between May-December 2018, were included. Screening protocol included one sample, two-tier testing as applied in the previous pilot study. In the first step, 17α-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay in dried blood spots (DBS) obtained at 3-5 days of life. Cases with positive initial screening underwent second tier testing by steroid profiling in DBS using liquid chromatographyt-andem mass spectrometry to measure 17-OHP, 21-deoxycortisol (21-S), cortisol (F), 11-deoxycortisol and androstenedione. The babies with a steroid ratio (21-S+17-OHP)/F of ≥0.7 (increased from ≥0.5 in the earlier pilot study) were referred to pediatric endocrinology clinics for diagnostic assessment. Results: In the evaluated period, 241,083 newborns were screened. 12,321 (5.11%) required second-tier testing and 880 (0.36%) were referred for clinical assessment, twenty of whom were diagnosed with CAH (10 females, 10 males). Sixteen were diagnosed as classical 21-hydroxylase deficiency (21-OHD) CAH (12 with salt-wasting and four with simple virilising CAH), and four cases were identified with 11ß-OHD CAH. No case of salt-wasting CAH was missed by neonatal screening (sensitivity was 100%). The incidence of classical 21-OHD and 11ß-OHD in the screened population was 1:15,067 and 1:60,270, respectively. Conclusion: Turkish neonatal CAH screening effectively led to earlier diagnosis of 21-OHD and 11ß-OHD, using steroid profiling as a second-tier test. This will result in improved care of these patients in the future.

A novel mutation of the GLUT2 gene in a Turkish patient with Fanconi-Bickel syndrome.

Fanconi-Bickel syndrome is a rare inherited disorder of carbohydrate metabolism. The disease is characterized by the association of a massive hepatomegaly due to glycogen accumulation, severe hypophosphatemic rickets and marked growth retardation due to proximal renal tubular dysfunction. Fanconi-Bickel syndrome is a single gene disease and is caused by defects in the facilitative glucose transporter 2 (GLUT2) gene (SLC2A2) on chromosome 3q26.1-26.3, which encodes for the glucose transporter protein 2 expressed in hepatocytes, pancreatic beta-cells, enterocytes, and renal tubular cells. Several mutations in a gene encoding a glucose transporter have been reported in patients with Fanconi-Bickel syndrome. Here we report a Turkish child who had a novel mutation that has not been described before and we discuss the knowledge regarding genetic mutations in this rare disease.

Pituitary hyperplasia mimicking pituitary macroadenoma in two adolescent patients with long-standing primary hypothyroidism: case reports and review of literature.

We report two cases with primary autoimmune hypothyroidism and an ectopic thyroid gland causing pituitary enlargement mimicking pituitary macroadenoma. One of the cases presented with complaints of headache and short stature and the other case with a complaint of menorrhagia. In both cases, the pituitary mass and symptoms resolved with levothyroxine replacement. Normal menses resumed. However, pituitary dynamic tests revealed persistent growth hormone and gonadotropin deficiency in one case and growth hormone deficiency in the other. To our knowledge, this is the first report in an adolescent of hypogonadotropic hypogonadism, growth hormone deficiency, and menorrhagia associated with pituitary hyperplasia secondary to primary hypothyroidism. The recognition of the association between reversible pituitary hyperplasia and primary hypothyroidism might eliminate unnecessary surgery.

Prolonged hungry bone syndrome in a 10-year-old child with parathyroid adenoma.

We report a case of primary hyperparathyroidism associated with prolonged hungry syndrome (HBS) after parathyroid adenomectomy in a 10-year-old girl. Bone mineral density (BMD) revealed severe loss of cancellous BMD. Overt bone disease, high alkaline phosphatase, decreased cancellous BMD and a large adenoma can be used as preoperative predictive risk factors of HBS in children.

Clinical, Histochemical, and Molecular Study of Three Turkish Siblings Diagnosed with H Syndrome, and Literature Review.

BACKGROUND: The term "H syndrome" was coined to denote the major clinical findings, which include hyperpigmentation, hypertrichosis, hearing loss, hepatosplenomegaly, hyperglycaemia, hypogonadism, hallux flexion contractures, and short height. OBJECTIVE: To report the clinical, endocrinological, histochemical, and genetic findings of three siblings. METHODS: Skin and liver biopsies were taken to investigate the histochemical characteristics of hyperpigmented hypertrichotic skin lesions and massive hepatomegaly. The levels of basal serum thyroid hormones, oestradiol, total testosterone, follicle-stimulating hormone, luteinising hormone, and stimulated growth hormone (GH) were measured to investigate the endocrine aspects of the syndrome. Mutation analysis was carried out in all six exons and exon-intron boundaries of SLC29A3 by direct sequencing. RESULTS: Physical examination of the patients revealed common charac-teristic findings of H syndrome. Additional clinical findings were sectorial iris atrophy in the younger sister. Laboratory evaluation revealed microcytic anaemia, markedly increased erythrocyte sedimentation rate and C-reactive protein levels, and humoral immune deficiency in the younger siblings, who presented with recurrent fever and sinopulmonary infection. Two different GH stimulation tests revealed GH deficiency in the younger sister with short stature. Liver and skin biopsies revealed polyclonal lymphohistiocytic and plasma cell infiltration. Sequencing of SLC29A3 in the three siblings revealed a novel homozygous mutation in exon 6, which caused the transition of arginine to tryptophan. CONCLUSION: This study not only extended the clinical and mutation spectrum of SLC29A3 in H syndrome, but also showed that short children should be assessed according to the guidelines for short stature in children.

Quality-of-life Evaluation of Healthy Siblings of Children with Chronic Illness

Background: Chronic disease of children can cause changes in the health-related quality of life (HrQoL) of the family members. Aims: To evaluate the HrQoL of healthy siblings of children with chronic disease. Study Design: Cross-sectional study. Methods: The study included healthy sibling of children with chronic disease (cerebral palsy, epilepsy, diabetes, celiac disease, hematologic/oncologic disease, or asthma) and healthy sibling of healthy children to evaluate the quality of life. We used the Pediatric Quality of Life Inventory questionnaire; the physical health and psychosocial health scores were calculated using the responses of the sibling and parent. The primary endpoint was the comparison of HrQoL scores of healthy siblings of children with chronic disease and that of healthy siblings of healthy children. Results: This study included a respective healthy sibling of 191 children with chronic disease and healthy sibling of 100 healthy children. The physical health, psychosocial health, and total health scores of healthy siblings of children with chronic disease were significantly lower than that of healthy siblings of healthy children (p<0.001). Among the healthy siblings of children with chronic disease, the lowest psychosocial health score was found in the siblings of children with cerebral palsy, hematologic/oncologic disease, and asthma (p<0.001). The global impact on the quality of life for healthy siblings of children with chronic disease was significantly higher in the self-report of the children than that of the parents (30.4% versus 15.1%, p<0.05). Conclusion: Most healthy siblings of children with chronic disease are physically and psychosocially affected and there is low parental awareness of this condition. This can increase the risk of emotional neglect and abuse of these children. Therefore, special support programs are needed for the families of children with chronic diseases.

Neonatal Screening for Congenital Adrenal Hyperplasia in Turkey: A Pilot Study with 38,935 Infants

Objective: Congenital adrenal hyperplasia (CAH) is the most common form of primary adrenal insufficiency in children. Neonatal screening for CAH is effective in detecting the salt-wasting (SW) form and in reducing mortality. In this study, our aim was to estimate the incidence of CAH in Turkey and to assess the characteristics and efficacy of the adopted newborn CAH screening strategy. Methods: A pilot newborn CAH screening study was carried out under the authority of the Turkish Directorate of Public Health. Newborn babies of ≥32 gestational weeks and ≥1500 gr birth weight from four cities, born between March 27-September 15, 2017 were included in the study. Screening protocol included one sample two-tier testing. In the first step, 17α-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay in dried blood spots (DBS) obtained at 3-5 days of life. The cases with positive initial screening were tested by steroid profiling in DBS using a liquid chromatography-tandem mass spectrometry method to measure 17-OHP, 21-deoxycortisol (21-S), cortisol (F), 11-deoxycortisol and androstenedione as a second-tier test. The babies with a steroid ratio (21-S+17-OHP)/F of ≥0.5 were referred to pediatric endocrinology clinics for diagnostic assessment. Results: 38,935 infants were tested, 2265 (5.82%) required second-tier testing and 212 (0.54%) were referred for clinical assessment, six of whom were diagnosed with CAH (four males, two females). Four cases were identified as SW 21-hydroxylase deficiency (21-OHD) (two males, two females). One male baby had simple virilizing 21-OHD and one male baby had 11-OHD CAH. The incidence of classical 21-OHD in the screened population was 1:7,787. Conclusion: The incidence of CAH due to classical 21-OHD is higher in Turkey compared to previous reports. We, therefore, suggest that CAH be added to the newborn screening panel in Turkey. The use of steroid profiling as a second-tier test was found to improve the efficacy of the screening and reduce the number of false-positives.