Epidemiology of type 1 diabetes mellitus in children and adolescents: A 50-year, single-center experience.

BACKGROUND: Global variations in epidemiology of type 1 diabetes mellitus (T1DM) exist. This study is designed to examine demographic and clinical features of T1DM over the past 3 decades as well as evolving trends in epidemiology over last 50 years. METHODS: Clinical characteristics of 925 patients with T1DM over last 30 years (1990-2019) were evaluated and compared to previously published data of 477 patients diagnosed between 1969 and 1990 from one of the major referral centers for diabetes in Turkey. RESULTS: Mean age at diagnosis decreased from 9.5 ± 4.0 to 7.1 ± 3.6 years within the past 50 years (p < .001). Age at diagnosis peaked at 12-14 years between 1969 and 1990, then fell to 10-11.9 years between 1990 and 1999, and to 4-5.9 years between 2000-2009 and 2010-2019 (p = .005). Although the percentage of patients diagnosed <6 years of age is gradually increasing, the percentage between the ages of 6 and 11.9 years is decreasing, and the percentage diagnosed ≥12 years remained stable. A total of 47.5% of patients had ketoacidosis, 38.2% had ketosis, and 14.3% had only hyperglycemia. 23% of patients had severe diabetic ketoacidosis (DKA), whereas 42% had moderate. Over last 3 decades, there has been no change in frequency of ketoacidosis at presentation, but there has been significant decline in severity (p = .865, and p < .001, respectively). Although the frequency of patients with mild DKA increased over time, frequency of patients with moderate DKA decreased; however, no significant difference was observed among patients with severe ketoacidosis. DKA was more frequent and severe in patients <6 years of age (p = .005, and p < .001, respectively). CONCLUSION: Age at diagnosis shifted to younger ages in T1DM in the past 50 years. Half of patients had ketoacidosis at diagnosis and frequency of presentation with DKA did not decrease, but severity decreased slightly. Increase in prevalence of T1DM in the younger age group and the fact that half of patients present with DKA indicate that awareness should be increased in terms of early diagnosis and treatment.

DOCK8 deficiency with hypereosinophilia and the syndrome of inappropriate antidiuretic hormone secretion during herpes infection.

BACKGROUND: Hyperimmunoglobulin E syndrome (HIES) due to dedicator of cytokinesis8 (DOCK8) deficiency may present in infancy and childhood with different clinical features involving recurrent infections, allergic dysregulation, and autoimmunity. CASE: In this report, we describe a patient who first presented with severe hypereosinophilia and went on to develop the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the context of a severe herpes infection. Investigation revealed the presence of underlying DOCK8 deficiency presenting with atypical clinical features. CONCLUSIONS: Distinct inflammatory features associated with infections may be seen in the course of primary immunodeficiency diseases, and early functional and molecular genetic tests will aid the proper management.

Cystic fibrosis related bone disease in children: Can it be predicted?

BACKGROUND&AIMS: Cystic fibrosis (CF) -related bone disease (CFBD) is an important complication of CF, and low BMD in childhood is a precursor of CFBD. Here, we aimed to investigate bone turnover biomarkers, including osteocalcin (OC), receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in relation to low BMD in children with CF (cwCF). We also evaluated factors which could affect bone turnover with particular emphasis on fat-free mass (FFM), forced expiratory volume in 1 s (FEV1), hand grip strength (HGS), and functional capacity and physical activity. METHODS: Sixteen cwCF aged 8-18 years with moderate low BMD (group1) and 64 cwCF with normal BMD (group2) were enrolled. Serum RANKL, OC, and OPG were determined by immunoenzymatic assays. Multiple parameters including pancreatic status, lung functions, body mass index (BMI), FFM measured by bioelectric impedance analysis (BIA), 6-minute walk test, vitamin D, nutritional intake, HGS, functional capacity and physical activity, serum and urine biomarkers were compared between the two groups. RESULTS: We found similar serum levels of RANKL (p = 0.501), OC (p = 0.445), OPG (p = 0.380), and RANKL/OPG ratio (p = 0.449) between group1 and group2 in cwCF. BMI z-score (p < 0.001), FFMI z-score (p < 0.001), FEV1 z-score (p = 0.007), and right-HGS (%pred) (p = 0.009) significantly differed between the two groups. Multivariate linear regression revealed that the only factors that predicted BMD were FFMI z-score and HGS %pred. CONCLUSION: Serum OC, OPG, RANKL and RANKL/OPG ratio did not predict BMD in cwCF. FFMI z-score and HGS %pred measured by non-invasive and practical methods were the best predictors of BMD.

Challenges During the Coronavirus Disease 2019 Pandemic: Diabetes Control and Psychosocial Issues in Children with Type 1 Diabetes Mellitus and Their Mothers.

OBJECTIVE: Governments have enforced restrictions to prevent the spread of coronavirus dis- ease 2019, which has affected lifestyle and psychosocial well-being. The aim of this study is to examine the psychosocial dimensions of children with type 1 diabetes mellitus and lifestyle changes in the face of the pandemic. MATERIALS AND METHODS: Sixty school-aged children with type 1 diabetes mellitus were included to evaluate socioeconomic status, lifestyle changes, and psychological state after a 3-month school closure, using a questionnaire as well as scales in children and mothers [Depression-Anx iety-Stress Scale (short-form), Revised Child Anxiety-Depression Scale (parent-version), The Perceived Stress Scale in Children] via a Google® Form. The effect of pre-pandemic glycemic control on lifestyle and factors affecting HbA1c change were also investigated. RESULTS: The percentage of mothers having scale scores above the cutoff in terms of stress, anxiety, and depression were 18.3%, 23.3%, and 33.3%, respectively. Mother's and children's anxiety, depression, and stress scores were positively correlated. Employed mothers had higher depression scores. Paternal unemployment increased the anxiety of the mothers. Seventy-eight percent (n = 46) of the mothers thought that diabetes in their children increased the risk of coro- navirus disease 2019 infection, and children of these mothers had higher depression, anxiety, and stress scores(P = .01, P < .01, P < .01). The majority of participants were adversely affected by coronavirus disease 2019 in terms of daily routines and dietary compliance. Patients with poor-controlled type 1 diabetes mellitus deteriorated more in terms of diet compliance (P = .01). CONCLUSION: Coronavirus disease 2019 affects the psychosocial dimensions in the family of chil- dren with type 1 diabetes mellitus. The psychosocial impact is reflected within the family and may affect diabetic control. Thus, it should be handled within the context of family. The provi- sion of proper information and guidance to parents may be crucial to alleviate the psychosocial burden on the family during the pandemic.

Alterations in insulin-like growth factor system in spinal muscular atrophy.

INTRODUCTION/AIMS: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by survival motor neuron (SMN) protein deficiency. Insulin-like growth factor-I (IGF-I) is a myotrophic and neurotrophic factor that has been reported to be dysregulated in in vivo SMA model systems. However, detailed analyses of the IGF-I system in SMA patients are missing. In this study, we analyzed the components of the IGF-I system in serum and archived skeletal muscle biopsies of SMA patients. METHODS: Serum IGF-I, IGF binding protein (IGFBP)-3, and IGFBP-5 levels were analyzed in 11 SMA patients and 13 healthy children by immunoradiometric and enzyme-linked immunosorbent assays. The expression of IGF-I, IGF-I receptor, and IGFBP-5 proteins was investigated by immunofluorescence analysis in the archived skeletal muscle biopsies of nine SMA patients, six patients with non-SMA-related neuromuscular disease and atrophic fibers in muscle biopsy, and four controls. RESULTS: A significant decrease in IGF-I levels (mean ± SD: -1.39 ± 1.46 vs. 0.017 ± 0.83, p = .02) and increase in IGFBP-5 levels (mean ± SD: 2358.5 ± 1617.4 ng/mL vs. 1003.4 ± 274.3 ng/mL, p = .03) were detected in serum samples of SMA patients compared to healthy controls. Increased expression of IGF-I, IGF-I receptor, and IGFBP-5 was detected in skeletal muscle biopsies of SMA patients and non-SMA neuromuscular diseases, indicating atrophy-specific alterations in the pathway. DISCUSSION: Our findings suggested that the components of the IGF-I system are altered in SMA patients at both the systemic and tissue-specific levels.

Hyperinsulinism May Be Underreported in Hypoglycemic Patients with Phosphomannomutase 2 Deficiency

Objective: Phosphomannomutase 2 deficiency (PMM2-CDG) is a disorder of protein N-glycosylation with a wide clinical spectrum. Hypoglycemia is rarely reported in PMM2-CDG. In this study, we evaluated cause, treatment options and outcomes in cases with hypoglycemia in the course of PMM2-CDG. Methods: Clinical records of patients followed with PMM2-CDG within the last two decades were reviewed. Medical data of patients with hypoglycemia were evaluated in more detail. Demographic and clinical findings, organ involvement and laboratory investigations at time of hypoglycemia were recorded. Time of first attack of hypoglycemia, cause, treatment modalities, duration of hypoglycemia (permanent/transient), and duration of treatment, as well as outcome were also recorded. Other published cases with PMM2-CDG and hypoglycemia are also reviewed in order to elucidate characteristics as well as pathophysiology of hypoglycemia. Results: Nine patients with PMM2-CDG were reviewed, and hypoglycemia was present in three cases. All three had hyperinsulinism as the cause of hypoglycemia. In the first two cases reported here, serum insulin level concurrent with hypoglycemic episodes was elevated, and glucose response was exaggerated during glucagon test, favoring hyperinsulinism. However, in the third case, the serum insulin level at time of hypoglycemia was not so high but hypoglycemia responded well to diazoxide. Hyperinsulinism was permanent in two of these three cases. No genotype-phenotype correlation was observed with respect to hyperinsulinism. Conclusion: The main cause of hypoglycemia in PMM2-CDG appears to be hyperinsulinism. Although insulin levels at the time of hypoglycemia may not be very high, hypoglycemia in patients with PMM2 responds well to diazoxide.

Feminizing Adrenocortical Tumors as a Rare Etiology of Isosexual/Contrasexual Pseudopuberty

Objective: Estrogen-secreting adrenocortical tumors (ACTs) are quite rare with feminizing adrenocortical tumors (FATs) accounting for 0.37-2% of all ACTs. The aim was to evaluate clinical and hormonal characteristics of FATS as well as treatment options and follow-up in the pediatric age group. Methods: Medical records of children with ACTs presenting to a single center in the last two decades were reviewed. Literature review within Pubmed revealed 34 pediatric patients (22 boys) with FAT among 192 articles. Results: Among the 25 children presenting with ACTs in the last two decades, two new pediatric cases of FAT were identified, one benign and the other malignant, in two genders with different clinical presentations. Literature review showed that FATs are extremely rare tumors that are most commonly seen in men and boys presenting with gynecomastia. FATs are more common in children ≤8 years of age, with a median age at diagnosis of six years. While boys present with contrasexual pseudopuberty signs, girls present with isosexual pseudopuberty. A high estrogen level strongly supports diagnosis, while elevations in other adrenal hormones may be seen. FATs are usually malignant in adults and prognosis is generally very poor. However, in children approximately half are benign although assessment of malignant potential depends on clinical behavior of the tumor. FATs are very unpredictable so even after surgery long-term follow-up is required. FATs presenting in childhood may have a better prognosis than adult presentation tumors as most FATs in children are followed without recurrence of tumor. Conclusion: FATs are more common in children ≤8 years of age, with a median age at diagnosis of six years. FATs in childhood may have a better prognosis than in adult males.

Sleep disordered breathing in patients with Prader willi syndrome: Impact of underlying genetic mechanism.

INTRODUCTION: Sleep-disordered breathing (SDB) is common in children with PWS. In the current study, we aimed to evaluate the severity of SDB in patients with PWS using polysomnography (PSG), and assess the effect of the underlying genetic mechanism on PSG parameters. METHODS: Children with PWS, referred to our sleep laboratory between March 2016 and January 2020 were enrolled. PSG parameters, demographic data, body mass index (BMI), and symptoms related to SDB were recorded. The effect of non-invasive ventilation strategies and the outcome of therapy on PSG parameters were evaluated. RESULTS: In our study, 64.5% of the patients had severe sleep apnea syndrome (total apnea hypopnea index (AHI) ≥10 events/hour). 22.6% had significantly high (>5 events/hour) central sleep apnea. Patients with a deletion had significantly lower initial and mean SaO2, longer sleep time SaO2 under 90%, oxygen desaturation % and total AHI when compared to those with uniparental disomy. PSG parameters were similar between patients who did or didn't receive growth hormone treatment. CONCLUSION: The majority of the PWS patients had severe sleep apnea syndrome characterized mainly by hypopneas which were accompanied by central apneas. There was a more severe impact on oxygen parameters and total AHI in patients with deletions.

Sertoli-Leydig cell tumor, thyroid follicular carcinoma and rhabdomyosarcoma of the uterine cervix in a prepubertal girl with pathogenic germline variant in DICER1 gene.

BACKGROUND: DICER1 syndrome is a hereditary cancer predisposition syndrome which is related DICER1 gene and may present a variety of manifestations. CASE: A prepubertal girl with ovarian Sertoli-Leydig cell tumor, thyroid follicular carcinoma, embryonal rhabdomyosarcoma of the cervix and lung cyst is presented. Genetic analysis demonstrated mutation (c.3377delC, c.71delC) in 14q32.13 loci and confirmed the diagnosis of DICER1 syndrome. CONCLUSION: The case is presented to emphasize the importance of early diagnosis of alterations in DICER1 gene and close follow-up for the development of DICER1 syndrome related pathologies, and necessity for genetic evaluation of the family.

Alpha-Melanocyte-Stimulating Hormone is Elevated in Hypothalamic Obesity Associated with Childhood Craniopharyngioma.

OBJECTIVE: The purpose of this study was to investigate the peripheral concentrations of leptin and neuropeptides taking part in the melanocortin pathway in hypothalamic obesity (HO) associated with craniopharyngioma (CP) and to find a peripheral marker for diagnosis. METHODS: Thirty-one patients (52% girls; median age 16 years) with CP were enrolled in the study group. They were grouped as CP with obesity (CPobesity , n = 17) and CP without obesity (CPnonobesity , n = 14). Two control groups without CP consisted of 27 children with obesity (OC) (55% girls; median age 13.8 years) and 25 children without obesity (normal control [NC]) (72% girls; median age 14.5 years). Obesity was defined as BMI percentile ≥ 95%. Fasting serum concentrations of leptin, brain-derived neurotrophic factor (BDNF), and alpha-melanocyte-stimulating hormone (α-MSH) were measured in the groups. RESULTS: Leptin and BDNF concentrations were correlated with BMI SD score (SDS) in controls (OC + NC) and CP. However, there was no correlation between α-MSH and BMI-SDS in CP or control groups. After adjusting for age, sex, and BMI-SDS, α-MSH was found to be significantly higher in CPobesity than in other groups, whereas leptin and BDNF were comparable among the four groups. CONCLUSIONS: Serum BDNF, just like leptin, increased with BMI, regardless of hypothalamic damage. On the contrary, α-MSH concentration was significantly high in HO, designating a potential biomarker for HO in CP.

Basal Serum Thyroxine Level should Guide Initial Thyroxine Replacement Dose in Neonates with Congenital Hypothyroidism

Objective: Initial high-dose sodium levothyroxine (Na-LT4) (10-15 µg/kg/day) replacement for primary congenital hypothyroidism (CH) is recommended in guidelines. However, high-dose Na-LT4 risks iatrogenic hyperthyroidism. The aim of this study was to investigate the normalizing effect of varying initial doses of Na-LT4 on serum thyroid hormone levels. Methods: Fifty-two patients were analyzed retrospectively. The patients were classified into mild (27/51.9%), moderate (11/21.1%) and severe (14/26.9%) CH, based on initial free thyroxine (fT4) levels. Time taken to achieve target hormone levels was compared within groups. Results: Initial mean Na-LT4 doses for mild, moderate and severe disease were 6.9±3.3, 9.4±2.2 and 10.2±2 µg/kg/day. Serum fT4 levels reached the upper half of normal range (>1.32 ng/dL) in a median of 16, 13 and 16 days in patients with mild, moderate and severe CH with the mean time from initial treatment to first control visit of 14.8±6 days (range 1-36). There was no significant difference in terms of time to achieve target fT4 hormone levels according to disease severity (p=0.478). Seven (25.9%), eight (72.7%) and eight (57.1%) patients experienced hyperthyroxinemia (serum fT4 >1.94 ng/dL) in the mild, moderate, and severe CH groups at the first visit, respectively (p=0.016). Conclusion: Not all patients diagnosed with CH require high-dose Na-LT4. Initial dose of Na-LT4 may be selected on the basis of pre-treatment thyroid hormone levels. Some patients with moderate and severe CH, experienced iatrogenic hyperthyroxinemia even though the dose was close to the lower limit of the recommended range in guidelines. We suggest that lower initial doses may be appropriate with closer follow-up within the first week.

Treatment response to long term antiresorptive therapy in osteogenesis imperfecta type VI: does genotype matter?

OBJECTIVES: Osteogenesis imperfecta type VI (OI VI) follows a progressive and severe course, yet unlike other forms of severe OI it has a later onset of fractures, and extra-skeletal findings are not part of the clinical picture. Another difference is that there is an increase in unmineralized osteoid tissue in OI VI, which hinders the effect of bisphosphonates-the current standard of treatment for OI. Therefore, the response to standard treatments in OI VI is not satisfactory. Herein, we report long-term follow-up of two cases with novel SERPINF1 mutations, who show great variation in their treatment response to bisphosphonates. CASE PRESENTATION: The first case was given pamidronate at the age of 15 months when he could sit independently, followed a fluctuating course under treatment, fracture rate did not decrease, however he was able to mobilize with walker at the age of 10 years. On the other hand, the second case developed severe deformities and became wheelchair-bound under pamidronate, thus the treatment was switched to denosumab. Unfortunately, there was no improvement under denosumab after 15 months too, and since bone pain increased, denosumab treatment was stopped. He was put on zoledronic acid instead. CONCLUSION: SERPINF1 transcript amount may be an important factor to explain the variation in response to pamidronate therapy. In OI VI patients, the factors affecting the clinical course should be identified and new or combined treatment options should be established.

Gender-related differences in etiology of organic central precocious puberty.

BACKGROUND: Central precocious puberty (CPP) is idiopathic in 90% of girls and 60% of boys, while some cases are caused by lesions of central nervous system (CNS), a condition often referred to as organic CPP. We aimed to analyze the etiology of organic CPP in a large cohort of girls and boys and determine gender-related differences. METHODS: Medical files of 256 girls and 120 boys diagnosed and treated for CPP in a single center in the last two decades were reviewed. Patients were classified into four groups with respect to previous history and MRI findings: (1) previously established CNS pathology at the time of diagnosis, (2) novel CNS pathology previously asymptomatic, (3) incidentalomas considered to be unrelated to CPP, and (4) completely normal MRI. Group 1 and 2 were considered as organic CPP whereas group 3 and 4 were considered as idiopathic CPP. RESULTS: Prevalence of CNS pathology was significantly higher in boys than girls (21.7% vs 6.2%). Previous CNS pathologies such as developmental anomaly of CNS, parenchymal injury, necrotic lesions and hydrocephalus were present in 3.5% of girls and 8.3% of boys. Prevalence of novel CNS pathology as determined by imaging among neurologically asymptomatic patients was 2.8% in girls and 14.5% in boys. The most common novel CNS pathologies in boys were hamartomas (5%) and suprasellar arachnoid cysts (3.3%); which were significantly lower in girls (0.8 and 0.8% respectively). Onset of organic CPP was before six years in girls, and seven years in boys. CONCLUSIONS: Organic CPP was 3.5 times more common in boys compared to girls. It is possible to detect an underlying CNS pathology in one out of every five boys with CPP. Frequency and distribution of organic etiology also differ between girls and boys, hypothalamic hamartomas and suprasellar arachnoid cysts being more common in boys than girls. The likelihood of novel intracranial pathology associated with CPP is quite low in girls with an onset after six years of age and in boys with an onset after seven years of age.

Obstructive sleep apnea in children with hypothalamic obesity: Evaluation of possible related factors.

INTRODUCTION: Hypothalamic obesity (HO) is a type of obesity that is caused by hypothalamic damage. HO can be complicated by obstructive sleep apnea syndrome (OSAS) due to anatomical narrowing of the upper airway and hypothalamic damage-induced dysfunction of the sleep control mechanisms. We aimed to explore the presence and severity of OSAS in children with HO and hypothesized that OSAS is more severe and frequent in HO than exogenous obesity (EO). METHODS: This cross-sectional study was conducted among children aged 6.6-17.9 years. Subjects with HO (n = 14) and controls with EO (n = 19) were consecutively recruited through an endocrinology clinic. All patients underwent full-night polysomnography. The primary outcomes were obstructive apnea-hypopnea index (OAHI) and the severity of OSAS. We analyzed the polysomnography findings, biochemical parameters, Brodsky and modified Mallampati scores, and blood pressure compared with the controls. We explored the different obesity types and these variables in association with OAHI using multiple linear regression (MLR). RESULTS: Age and body mass index z scores (BMI-z) were similar between the EO and HO groups. The OAHI of HO (5.8) was higher than that of EO (2.2). In MLR, the predicted OAHI was formulated as an equation using regression coefficients of obesity type (HO), age, and BMI-z (R2 = .41). In the logistic regression analysis, the odds ratio of moderate/severe OSA was 5.6 for HO. CONCLUSIONS: Children with HO have a higher risk of moderate/severe OSAS than children with EO. Polysomnography should be considered in all patients with HO.

Effect of long-term glucocorticoid therapy on bone mineral density of the patients with congenital adrenal hyperplasia.

BACKGROUND AND OBJECTIVES: Congenital adrenal hyperplasia (CAH) is characterized by androgen excess which should be treated with life-long glucocorticoid therapy, thus can affect bone mineralization. We aimed to evaluate the bone mineral density (BMD) and determine the factors affecting bone mineralization in patients with CAH. METHOD: This prospective case-control study was conducted in children, adolescents and young adults with classical 21-hydroxylase CAH, and age-, sex-, and pubertal stage matched healthy controls. Lumbar1-4 BMD was determined by dual-energy X-ray absorptiometry. BMD z-score was calculated using national standards with respect to height age and was referred as `low BMD` if z-score < -1 SD. Univariate analyses were performed between low BMD and normal BMD groups, and multivariate logistic regression analysis was performed to assess the independent predictors of low BMD. Correlations of Body Mass Index (BMI)-z-score, average serum 17-hydroxyprogesterone level, duration of treatment, average and cumulative glucocorticoid doses with BMD z-score were evaluated with Spearman analyses. RESULTS: Each group included 37 cases. BMD z-score of patients with CAH [0.47 (-0.04 - 1.56)] was higher than control group [-0.43 (-0.82 -0.05)]; p= < 0.001. Number of patients with low BMD was similar in both groups; [CAH: 6(16.2%), control: 5(13.5%); p= 0.744]. BMI- z-score was higher in patients with CAH when compared to control group; p= < 0.001. BMI z-score was lower in low BMD group as comparison to normal BMD group; p= 0.041. Each 1.0 decrease in BMI z-score, risk of having low BMD was found to increase by 1.79 (%95 CI: 1.03- 3.12, p= 0.040). BMI-z-score, average serum 17-hydroxyprogesterone level, duration of treatment, average and cumulative glucocorticoid doses were not found to be correlated with BMD z-score. CONCLUSION: Long-term glucocorticoid therapy did not have negative effect on BMD of patients with CAH. Higher BMI z-score in patients with CAH may have a positive effect on preserving bone health. Precautions should be taken for increased risk of obesity.

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.

Treatment with Depot Leuprolide Acetate in Girls with Idiopathic Precocious Puberty: What Parameter should be Used in Deciding on the Initial Dose?

Objective: Doses of gonadotropin releasing hormone (GnRH) analogues used to treat idiopathic central precocious puberty (iCPP) vary among clinicians. Study aims were to evaluate the efficacy of a monthly 3.75 mg dose of leuprolide acetate (LA) to suppress the hypothalamo-pituitary-gonadal (HPG) axis in girls with iCPP and to determine factors that may have an impact on the supressing dose. Methods: Study subjects were 220 girls receiving LA for iCPP. LA was started at a dose of 3.75 mg/28 days. Suppression was assessed using the GnRH test at the third month. To assess clinical suppression signs and symptoms of puberty were also evaluated. The dose of LA was increased to 7.5 mg/28 days in those who had a peak luteinising hormone (LH) ≥2 IU/L and in whom adequate clinical suppression of puberty was absent. Receiver operating characteristic curves were used to determine thresholds for clinical and hormonal factors affecting the suppressing dose of LA. Logistic regression analyses were used to investigate thresholds which might differentiate between those requiring high dose for suppression and those in whom lower dose LA was adequate. Results: Peak stimulated LH <2 IU/L was achieved in 88.6% with a dose of LA of 3.75 mg (0.11±0.03 mg/kg). Significant variables for differentiating the two doses were body weight (Wt) of 36.2 kg and/or body mass index (BMI)-standard deviation scores (SDS) of 1.64 (p<0.001). Multiple logistic regressions showed that Wt and BMI-SDS values above thresholds indicated requirement of LA at a dose of 7.5 mg/28 days (p<0.001). Conclusion: Monthly injections of 3.75 mg LA is an effective treatment in the majority of girls with iCPP. However, a higher initial dose may be preferred in patients with a Wt ≥36 kg or BMI-SDS ≥1.6 for effective suppression of the HPG axis.

Further expanding the mutational spectrum and investigation of genotype-phenotype correlation in 3M syndrome.

3M syndrome is characterized by severe pre- and postnatal growth retardation, typical facial features, and normal intelligence. Homozygous or compound heterozygous mutations in either CUL7, OBSL1, or CCDC8 have been identified in the etiology so far. Clinical and molecular features of 24 patients (23 patients and a fetus) from 19 unrelated families with a clinical diagnosis of 3M syndrome were evaluated and genotype-phenotype correlations were investigated with the use of DNA sequencing, chromosomal microarray, and whole exome sequencing accordingly. A genetic etiology could be established in 20 patients (n = 20/24, 83%). Eleven distinct CUL7 or OBSL1 mutations, among which eight was novel, were identified in 18 patients (n = 18/24, 75%). Ten patients had CUL7 (n = 10/18, 56%) while eight had OBSL1 (n = 8/18, 44%) mutations. Birth weight and height standard deviation scores at admission were significantly (p < 0.05) lower in patients with CUL7 mutation compared to that of patients with OBSL1 mutation. Two patients with a similar phenotype had a de novo 20p13p deletion involving BMP2. No genetic etiology could be established in four patients (n = 4/28, 17%). This study yet represents the largest cohort of 3M syndrome patients from a single center in Turkey. Microdeletions involving BMP2 may cause a phenotype similar to 3M syndrome with some distinctive features. Larger cohort of patients are required to establish genotype-phenotype correlations in 3M syndrome.

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.