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Abstract Context Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. Objective To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. Design, Setting, and Participants We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. Results This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. Conclusions ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI. Exome sequencing was used to investigate genes and mutational mechanisms contributing to primary ovarian insufficiency, and to gain insights into disease biology and underlying pathophysiology.

The aim of this study was to analyze the relationship between premature adrenarche (PA) and metabolic syndrome (MeS) parameters at presentation and during puberty. This study comprised 47 girls with PA. Age- and puberty-matched 22 healthy girls without PA were the control group. Patients were evaluated at admission (first evaluation) and later in puberty (second evaluation). Anthropometric measurements, lipid levels, and hormonal parameters were studied and oral glucose tolerance test was performed. Indices for insulin resistance (IR) were calculated. The study group was divided in subgroups according to body mass index (BMI) and compared with the control group. The age of the PA group at first evaluation was 8.0 ± 1.1 years; mean height SDS and BMI SDS were 0.4 ± 1.2 and 0.6 ± 0.9, respectively. Age of PA group at the second evaluation was 12.9 ± 2.4 years. Frequency of obesity and overweight was 14.9 and 23.4%. Dyslipidemia ratio was 28.3%. PA group had significantly higher BMI than controls. Mean insulin concentration was higher and mean glucose and FGIR were lower in PA group and also dyslipidemia ratio was 5.3 times higher in PA than controls (p = 0.040). In PA group, overweight/obese subjects had still higher BMI at second evaluation and also higher fasting glucose, insulin, HOMA-IR. However, PA children with exaggerated DHEAS concentrations compared to those without had similar BMI SDS, insulin sensitivity, and secretion indices and lipid profile at second evaluation. BMI SDS at first evaluation was positively correlated with HOMA-IR at puberty; however, there is no correlation between DHEAS at first evaluation and HOMA-IR at puberty.Conclusion: BMI at adrenarche is more important than prepubertal adrogen concentrations such as DHEAS, while predicting the IR in puberty. Long-term follow-up of children supports the observation that PA per se may be related to IR; however, the risk increases with obesity.What is Known:• Premature adrenarche (PA) is receiving more attention as evidence emerges for a relation between early androgen excess and metabolic syndrome.• The onset of the adrenal androgen production before 8 years in girls defined as PA. Pubarche, axillary hair, apocrine body odor, acne are typical phenotypic features of PA.What is New:• Body mass index at adrenarche is an important risk factor for development of insulin resistance in pubertal ages.• Degree of dehydroepiandrosterone sulfate elevation was not shown as a risk factor for insulin resistance.

Abstract Background Given the rarity of 11β-hydroxylase deficiency (11βOHD), there is a paucity of data about the differences in clinical and biochemical characteristics of classic (C-11βOHD) and nonclassic 11βOHD (NC-11βOHD). Objective To characterize a multicenter pediatric cohort with 11βOHD. Method The clinical and biochemical characteristics were retrospectively retrieved. CYP11B1 gene sequencing was performed. Seventeen plasma steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. Results 102 patients (C-11βOHD, n = 92; NC-11βOHD, n = 10) from 76 families (46,XX; n = 53) had biallelic CYP11B1 mutations (novel 9 out of 30). Five 46,XX patients (10%) were raised as males. Nineteen patients (19%) had initially been misdiagnosed with 21-hydroxylase deficiency. Female adult height was 152 cm [−1.85 SD score (SDS)] and male 160.4 cm (−2.56 SDS).None of the NC-11βOHD girls had ambiguous genitalia (C-11βOHD 100%), and none of the NC-11βOHD patients were hypertensive (C-11βOHD 50%). Compared to NC-11βOHD, C-11βOHD patients were diagnosed earlier (1.33 vs 6.9 years; P < 0.0001), had higher bone age-to-chronological age (P = 0.04) and lower adult height (−2.46 vs −1.32 SDS; P = 0.05). The concentrations of 11-oxygenated androgens and 21-deoxycortisol were low in all patients. The baseline ACTH and stimulated cortisol were normal in NC-11βOHD. Baseline cortisol; cortisone; 11-deoxycortisol; 11-deoxycorticosterone and corticosterone concentrations; and 11-deoxycortisol/cortisol, 11-deoxycorticosterone/cortisol, and androstenedione/cortisol ratios were higher in C-11βOHD than NC-11βOHD patients (P < 0.05). The 11-deoxycortisol/cortisol ratio >2.2, <1.5, and <0.1 had 100% specificity to segregate C-11βOHD, NC-11βOHD, and control groups. Conclusion NC-11βOHD can escape from clinical attention due to relatively mild clinical presentation. However, steroid profiles enable the diagnosis, differential diagnosis, and subtyping of 11βOHD.

It is known that telomere length (TL) (evaluated with T/S ratio) is shortened in the presence of obesity. In this study, we aimed to investigate how obesity in adolescents and non-alcoholic liver disease (NAFLD) within the obese group affect TL and the clinical significance of the human telomerase reverse transcriptase (hTERT) gene MNS16A VNTR variant in terms of NAFLD. Adolescents with exogenous obesity and healthy controls (aged 10–19 years) who applied to our adolescent outpatient clinic between May-October 2023 were included in this study. We performed upper abdominal ultrasonography to investigate the presence of NAFLD in adolescents with obesity and divided into two groups: those without hepatosteatosis (obese NAFLD (-)) and those with hepatosteatosis (obese NAFLD (+)). We recorded body weight, height, waist circumference, and blood pressure measurements and measured the T/S ratio (telomere sequence copy number/gene single copy number) by the Quantitative Polymerase Chain Reaction method. The groups were compared using frequentist and Bayesian methods. Eighty-three obese adolescents [63 NAFLD(+) 20 NAFLD(-)] and 69 lean controls were included in the study. Pairwise comparisons revealed that T/S ratio was significantly lower in the obese NAFLD (-) group than the obese NAFLD (+) and the control group ( p  = 0.025, p  = 0.007, respectively). T/S ratio was lower in the LL allele group than in the other alleles ( p  = 0.022) and slightly higher in the obese group with metabolic syndrome compared to the obese group without metabolic syndrome ( p  = 0.072). hTERT-MNS16A-VNTR gene variant LL allele had a negative correlation with T/S ratio among the obese adolescent group. Patients with LL alleles had higher ALT, GGT, HOMA-IR, and ALT/AST. Diastolic blood pressure had a significant correlation with the T/S ratio. The T/S ratio was shorter in the obese adolescent group compared to healthy ones but was higher in the NAFLD (+) obese compared to the NAFLD (-) obese. ALT level and ALT/AST ratio were higher, T/S ratio was lower in the hTERT MNS16A VNTR variant LL allele group among obese adolescents. In addition, there was a significant correlation between the T/S ratio and diastolic blood pressure in obese adolescents.

Joubert syndrome (JS) and JS-related disorders are a group of developmental delay, multiple congenital anomalies and complex midbrain–hindbrain malformations. A few cases of JS with multiple pituitary hormone deficiency (MPHD) have been reported in literature. Here, we presented an unusual presentation of JS in a newborn with MPHD. This case is intended to draw attention to the rare association of JS and MDPH by increasing the awareness of this syndrome.

This study aimed to integrate the existing updated reference standards for the growth of Turkish infants and children and to compare these values with World Health Organization (WHO) reference data, data from some European countries, and also with previous local data. Weight, height, and head circumference measurements were obtained on 2,391 boys and 2,102 girls who were regular attenders of a well child clinic and on 1,100 boys and 1,020 girls attending schools in relatively well-off districts in İstanbul. Mean number of measurements per child was 8.2±3.6 in the age group 0-5 years and 5.5±3.3 in the age group 6-18 years. All children were from well-to-do families and all were healthy. All measurements with the exception of measurements at birth, which were based on reported values, were done by trained personnel. The LMS method was used in the analyses and in the construction of the percentile charts. There is an increase in weight for age and body mass index values for age starting in prepubertal ages, indicating an increasing trend for obesity. Compared to WHO reference data, weight and height values in Turkish children were slightly higher in infants and in children younger than 5 years, while they showed similarity to those reported for children from Norway and Belgium. Head circumference values, which were slightly higher than the WHO references in the first 5 years, were comparable to the data on Belgian and Norwegian children in the first 9 years of life. At older ages, Turkish children showed higher values for head circumference. The relatively larger head circumference values were interpreted to reflect a genetic characteristic.

Background Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5–10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs. Methods In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO. Discussion The present study will be the first to evaluate—in a randomised, double-blind, placebo-controlled way—the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention. Trial registration EudraCT 2021–003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .

Background In this study, we examined the hypothesis that weight gain and linear growth during the first years of life influence the onset of puberty both in girls and in boys. Methods A cohort of 157 healthy children, aged 6–9 years, was evaluated and their growth patterns were analyzed retrospectively. Repeated measures mixed model was used to examine the longitudinal anthropometric data. Results Girls with pubertal signs were heavier than their peers starting at 9 months of age ( P =0.02), and the difference became more evident over time ( P <0.001). Accelerated weight gain between 6 and 15 months of age was found to increase the odds of having a pubertal sign at the study visit (odds ratio (OR)=34.5) after adjusting for birth weight, gestational age and current age, height, weight, and BMI ( P =0.004). Anthropometric indices of boys with or without pubertal signs were not significantly different at the study visit, but boys with accelerated height gain between 9 and 15 months of age were more likely to have pubertal signs (OR=15.8) after adjusting for birth weight, gestational age and current age, height, weight, and BMI ( P =0.016). Conclusion Early growth acceleration might be important for the timing of puberty in both genders.

Central adrenal insufficiency (CAI) occurs due to a pituitary gland disorder (secondary AI) or hypothalamic dysfunction (tertiary AI). It is a potentially life-threatening condition that has many congenital and acquired causes. Adrenocorticotropic hormone deficiency may be isolated or more commonly it can be accompanied by other pituitary hormone deficiencies or midline defects. The signs and symptoms of CAI are associated with glucocorticoid deficiency. A three-step diagnostic approach including dynamic stimulation tests is recommended in the evaluation of patients with suspected CAI. Here, members of the ‘Adrenal Working Group’ of ‘The Turkish Society for Pediatric Endocrinology and Diabetes’ present an evidence-based review with good practice points and recommendations for etiology and diagnostic approach in children and adolescents with CAI.

Abstract Context Limited data are available on the exact incidence of disorders of sex development (DSD) with genital ambiguity at birth. Objective To determine frequency of ambiguous genitalia in newborns. Design Prospective multicenter study. Setting Three tertiary care hospitals. Patients or Other Participants All 14,177 babies born during the study period were included. Main Outcome Measures All newborns were examined at birth; data on weeks of gestation, birth weight, and length were collected. A structured questionnaire was used for data collection. Quigley and Prader scales were used for phenotypic grading. Clinical and genetic investigations were performed. Results Eighteen babies with ambiguous genitalia were found among 14,177 newborns (1.3/1000). Fifteen newborns had 46,XY DSD, one had 46,XX congenital adrenal hyperplasia, and one had 45,X/46,XY mixed gonadal dysgenesis. Karyotype analysis was not done in one baby who died in the neonatal period. The ratio of prematurity was higher in the DSD group (44% vs 11%; P < 0.001) and the ratio of small for gestational age was also higher in the DSD group (22% vs 5%; P = 0.007). Eight babies with DSD had mothers who had additional medical conditions, such as preeclampsia, depression, insulin resistance, and gestational diabetes mellitus. Conclusion The frequency of ambiguous genitalia was higher than in previous studies, but, as with any experiment, the finding should be met with caution because this study was conducted in tertiary care hospitals. In addition, lower birth weight in the DSD group supports the hypothesis that early placental dysfunction might be important in the etiology of male genital anomalies.