Delayed Puberty and Management of Treatment.

Delayed puberty is defined as the lack of development of secondary sex characteristics in childhood. Based on a review of the literature, delayed puberty can be divided into three main categories: (i) hypergonadotropic hypogonadism (congenital and acquired), (ii) permanent hypogonadotropic hypogonadism (congenital and acquired), and (iii) transient hypogonadotropic hypogonadism [constitutional delay of growth and puberty (CDGP) and functional hypogonadotropic hypogonadism (FHH)]. CDGP is the most common cause of hypogonadism in both males and females, accounting for 60% and 30% respectively. Testosterone is the primary treatment for male hypogonadism, while estrogen and progesterone are used for female hypogonadism. However, in recent years, physiological induction therapy protocols such as human chorionic gonadotropin (hCG) monotherapy, hCG + Follicle-stimulating hormone combined therapy, and gonadotropin releasing hormone infusion have been recommended for the treatment of hypogonadotropic hypogonadism to increase long-term fertility success. There is no clear consensus on treatment protocols for physiological induction treatment and its effect on fertility. This review will discuss the clinical approach to hypogonadism, as well as traditional and physiological induction protocols.

Salivary Sex Steroid Levels in Infants and Their Relation with Infantile Colic.

Background: Hypothalamic-pituitary-gonadal axis is active during minipuberty, timing of which coincides with infantile colic. To the best of our knowledge, the relationship between these entities has not been investigated yet. Methods: Saliva samples were collected from 15- to 60-day-old term infants (n=139) between 9 am and 5 pm. Group 1 included infants with infantile colic (n=68, 54.4% female). Remaining healthy infants constituted Group 2 (n=71, 47.9% female). The salivary levels of estradiol (Esal) in females and testosterone (Tsal) in males were studied in duplicate by using the ELISA method. Results: The median (25th-75th centile) age and birth week for all infants were 33 (29-43) days and 39 (38.1-40) weeks, respectively. Levels of Tsal in males [Group 1, 73.35 (59.94-117.82) pg/mL vs Group 2, 77.66 (56.49-110.08) pg/mL, p=0.956] and Esal in females [Group 1, 3.91 (2.76-5.31) pg/mL vs Group 2, 4.03 (1.63-12.1) pg/mL, p=0.683] were similar among the groups. However, only in subjects with infantile colic (Group 1), Esal and body mass index (BMI) standard deviation scores of females were slightly correlated (Group 1, rs= 0.393, p=0.016 vs. Group 2, rs= 0.308, p=0.076) and there was a significant correlation between the sampling time and Tsal in males (Group 1, rs= 0.469, p=0.009 vs. Group 2, rs= -0.005, p=0.976). Conclusions: Random salivary sex steroid levels were similar among groups. However, only in subjects with infantile colic, salivary estradiol levels in females were positively correlated with BMI and salivary testosterone levels were higher later in the day among males. Thus, sex steroid production might be altered during minipuberty in subjects with infantile colic.

Aromatase Inhibitors May Increase the Risk of Cardiometabolic Complications in Adolescent Boys.

INTRODUCTION: Aromatase inhibitors (AIs) are increasingly used in children and adolescents to augment adult height. The aim of this study was to investigate the effects AIs have on cardiac morphology, functions and their relation to several metabolic parameters in adolescent boys. METHODS: Three groups matched for sex (boys, n = 67), age (median age 13.5 years), weight, height, body mass index, and puberty stages were enrolled: (i) Group 1: 23 patients using AIs (only AI (n = 6) or in combination with growth hormone (GH) (n = 17)) for at least 6 months; (ii) Group 2: 22 patients using only GH, and (iii) Group 3: 22 healthy boys. Two-dimensional, M-mode conventional Doppler and tissue Doppler examinations of the left ventricle (LV) were performed. Bioelectrical bioimpedance analyses was conducted and follicle-stimulating hormone, luteinizing hormone, total testosterone, lipid, and hemogram parameters were obtained. RESULTS: Patients in Group 1 had significantly higher serum total testosterone (p < 0.001) and hemoglobin (p < 0.001) levels, fat free mass (p = 0.005), LV mass (LVM) (p = 0.002), as well as increased LV posterior wall diameter (LVPWD) (p = 0.002), interventricular septum diameter (IVSD) (p = 0.019), and myocardial systolic wave velocity (Sm) (p = 0.020) compared to the two other control groups. No significant differences were observed in terms of diastolic and systolic functions and lipid profiles (p > 0.05). There were positive correlations between total testosterone, hemoglobin levels, LVM, LVPWD and IVSD (p < 0.05). CONCLUSION: Increased LVM, LVPWD, IVSD and Sm of patients receiving AI therapy in comparison to the control groups, and the significant correlations of these parameters with total testosterone and hemoglobin levels were determined as potential side effects of AIs. These findings emphasize the need of routine cardiac follow-up in patients using AIs.

Anaemia-based screening for resistance to thyroid hormone alpha in children.

BACKGROUND: The hypothyroid phenotype associated with resistance to thyroid hormone alpha (RTH-α) is associated with a diverse clinical picture. On the other hand, thyroid-stimulating hormone (TSH) levels are normal. Free triiodothyronine (fT3) and free thyroxine (fT4) levels can also be normal; however, normo- or macrocytic anaemia is usually present in reported cases. Diagnosis is challenging and there is limited data regarding screening methods. OBJECTIVE: The study aimed to assess the efficiency of a screening strategy for RTH-α. SUBJECTS AND METHODS: Out of a total of 6540 children evaluated at the outpatient clinics of paediatric neurology over 2 years and who underwent complete blood count and thyroid function tests, 432 were found to have anaemia. Within this group, we identified 42 children without an underlying specific neurological aetiology who exhibited normo- or macrocytic anaemia, normal TSH levels, fT3 levels in the upper half of the normal range or high, and fT4 levels in the lower half of the normal range or low. We excluded one patient who had already been diagnosed with RTH-α and nine patients could not be reached. Subsequently, clinical evaluation, biochemical assessment, and THRA sequencing analysis were conducted on 32 children. The findings were compared with those of the known RTH-α patients in our unit. RESULTS: The median age of the patients was 5.7 (5.1-7.4) years, and 22 of them were males (69%). The main reasons for assessment in paediatric neurology clinics were autism spectrum disorder (n = 12, 38%), epilepsy (n = 11, 34%), and delay in developmental stages (n = 8, 25%). Constipation was present in five of the cases (16%), while the closure of the anterior fontanelle and tooth eruption were delayed in two cases (6%) and one case (3%), respectively. The median length/height and weight standard deviation (SD) scores were 0.3 [(-0.8)-(1.1)] and -0.1 [(-0.8)-(0.3)], respectively. The median fT3, fT4, and TSH levels were 4.6 (4.2-5.0) pg/mL, 0.9 (0.8-1.0) ng/dL, and 2.2 (1.8-3.1) uIU/mL, respectively. Thirteen of the patients (41%) had high fT3 levels, while none of them had low fT4 levels. The normo- or macrocytic anaemia rate was 47% (normocytic/macrocytic, n = 8/7) at the time of reassessment. Serum creatine kinase (CK) was elevated in five patients (16%; one had anaemia). None of the subjects had a pathological variant in THRA. Known RTH-α patients had significantly lower median height SD score, higher rates of delayed tooth eruption and closure of the anterior fontanelle, lower haemoglobin levels, and higher mean corpuscular volume (MCV) and CK levels as compared to those found without RTH-α. CONCLUSIONS: This approach found one known patient with RTH-α but did not reveal any new cases. Notably, normo- or macrocytic anaemia did not persist in nearly half of the screened patients. A screening strategy that takes clinical findings and prominent laboratory features suggestive of RTH-α into account could lower unnecessary genetic analysis of THRA in patients presenting with neurological problems.

Atypical Presentation and Course of ACTH-independent Cushing's Syndrome in Two Families.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare genetic disease mainly associated with Carney complex (CNC), which is caused by germline mutations of the regulatory subunit type 1A (RIα) of the cAMP-dependent protein kinase (PRKAR1A) gene. We report three cases suffering from CNC with unique features in diagnosis and follow-up. All cases had obesity and a cushingoid appearance and exhibited laboratory characteristics of hypercortisolism. However biochemical and radiological examinations initially suggested Cushing's disease in one case . All of the cases were treated surgically; two of them underwent bilateral adrenalectomy at once, one of them had unilateral adrenalectomy at first but required contralateral adrenalectomy after nine months. Contrary to what is usually known regarding PPNAD, the adrenal glands of two cases (case 2 and 3) had a macronodular morphology. Genetic analyses revealed pathogenic variants in PRKAR1A (case 1: c.440+5 G>A, not reported in the literature; cases 2 and 3: c.349G>T, p.V117F). One case developed Hodgkin lymphoma five year after adrenalectomy, this association was not previously reported with CNC. The findings of these families provide important information for a better understanding of the genetic pathogenesis, diagnosis, and clinical management of CNC. Hodgkin lymphoma may be a component of CNC.

Clinical Characteristics of Children with Combined Pituitary Hormone Deficiency and the Effects of Growth Hormone Treatment.

AIM: We aimed to describe the clinical characteristics of patients with congenital combined pituitary hormone deficiency (CPHD) and evaluate the first-year growth responses of individuals with CPHD and isolated growth hormone deficiency (IGHD) in order to establish the influence of other hormone deficiencies on growth response. PATIENTS AND METHODS: This retrospective study was conducted in four tertiary care centers in Turkey. The records of patients diagnosed with CPHD (n=39) and severe IGHD (n=50) were collected. Cases with acquired lesions or chronic diseases were not included in the study. Data are presented as median (interquartile range). RESULTS: Among 39 patients (13 females; 33%) with a diagnosis of CPHD, the majority of patients (64%) presented initially with combined deficits at baseline examination, whereas isolated deficiencies (36%) were less prevalent. Among all patients with GH deficiency, TSH, ACTH, FSH/LH, and ADH deficiencies were present in 94%, 74%, 44%, and 9% of patients, respectively. Patients with CPHD were diagnosed at a younger age (4.9 (8.4) vs. 11.6 (4.1), p<0.001, respectively) and had lower peak GH concentrations (0.4 (1.8) vs. 3.7 (2.9), p<0.001, respectively) than patients with IGHD. Patients with IGHD and CPHD had similar first-year growth responses (Δheight SD score of 0.55 (0.63) vs. 0.76 (0.71), respectively, p=0.45). CONCLUSIONS: We established the nature and timing of numerous hormonal deficits emerging over time. We also identified that the existence of CPHD did not hinder growth response.

Which method is more effective in predicting adult height in pubertal girls treated with gonadotropin-releasing hormone agonist?

PURPOSE: The aim of the present study was to determine the efficiency of three different predictive models [Bayley-Pinneau (BP), Roche-Wainer-Thissen (RWT), and Tanner-Whitehouse 2 (TW2)] by comparing their predictions with near-adult height data of girls receiving gonadotropin-releasing hormone agonist (GnRHa) therapy. METHODS: Clinical findings were retrospectively analyzed. Bone ages obtained before treatment were evaluated from left hand and wrist radiographs by three researchers. Predicted adult height (PAH) was calculated using the BP, RWT, and TW2 methods for each patient at the beginning of therapy. RESULTS: The median age at diagnosis of the 48 patients included in the study was 8.8 (8.9-9.3) years. There was no significant difference between the mean bone ages evaluated separately with the Greulich-Pyle atlas and the TW3-RUS method (p=0.34). Among the PAH methods, only PAH measured by the BP method was very close to and no different from near adult height (NAH) [159.8±6.3 vs. 158.8±9.3 cm. p=0.3; (-0.5±1.1) vs. (-0.7±1.6) standard deviation score, p=0.1]. Accordingly, the BP method was found to be the most accurate prediction tool in girls with puberty treated with GnRHa. CONCLUSION: The BP method is more effective at predicting adult height than the RWT and TW2 methods in female patients who will receive GnRHa treatment.

Adverse Events Associated with COVID-19 Vaccination in Adolescents with Endocrinological Disorders: A Cross-Sectional Study

Objective: The aim was to evaluate the adverse events seen after Coronavirus disease-2019 (COVID-19) vaccination in pediatric patients with diagnosed endocrinological problems and to compare them with healthy controls. Methods: In this cross-sectional study, patients aged 12-18 years who attended a single department between January and May 2022 and were followed up for at least six months due to endocrine diseases, and healthy subjects in the same age group, all of whom had received a COVID-19 vaccine [BNT162b2 mRNA or inactivated vaccine] were included. Adverse events experienced after the vaccination were evaluated by questionnaire. Results: A total of 160 subjects (85 patients, 75 healthy controls) with a median (25-75p) age of 15.5 (14.1-16.9) years were included. The frequency of adverse events was higher in those vaccinated with the mRNA vaccine compared to the inactivated one after the first dose (p=0.015). The incidence of adverse events observed after the first and second doses of both COVID-19 vaccines was similar in the patient and control groups (p=0.879 and p=0.495, respectively), with local reactions being the most common. The frequency of adverse events was similar among the patients who did or did not receive any endocrinological treatment (p>0.05). The incidence and severity of systemic reactions were similar to those in healthy subjects for both vaccine doses, regardless of the underlying diagnosis, autoimmunity state, or treatment regimen used in patients with endocrine diseases. Conclusion: The incidence and severity of adverse events associated with COVID-19 vaccinations in adolescents with endocrinological disorders were similar to healthy subjects, in the early post-vaccination period.

Growth Hormone Dosing Estimations Based on Body Weight Versus Body Surface Area

Objective: Both body weight (BW)- and body surface area (BSA)-based dosing regimens have been recommended for growth hormone (rhGH) replacement. The aim was to compare the two regimens to determine if either resulted in inadequate treatment depending on anthropometric factors. Methods: The retrospective study included children diagnosed with idiopathic isolated growth hormone deficiency. BW-based dosing in mcg/kg/day was converted to BSA in mg/m2/day to determine the equivalent amounts of the given rhGH. Those with a BW-to-BSA ratio of more than 1 were allocated to the "relatively over-dosed group", while the remaining patients with a ratio of less than 1 were assigned to the "relatively under-dosed" group. Patients with a height gain greater than 0.5 standard deviation score (SDS) at the end of one year were classified as the height gain at goal (HAG), whereas those with a height gain of less than 0.5 SDS were assigned as the height gain not at goal (NHAG). Results: The study included 60 patients (18 girls, 30%). Thirty-six (60%) patients were classified as HAG. The ratio of dosing based on BW-to-BSA was positively correlated both with the ages and body mass index (BMI) levels of the patients, leveling off at the age of 11 at a BMI of 18 kg/m2. The relative dose estimations (over- and under-dosed groups) differed significantly between the patients classified as HAG or NHAG. Fifty-six percent of NHAG compared to 44% of HAG patients received relatively higher doses, while 79% of HAG compared to 21% of NHAG received relatively lower doses (p=0.006). When the patients were subdivided according to their pubertal status, higher doses were administrated mostly to the pubertal patients in both the NHAG and HAG groups. In the pre-pubertal age group, 73% of NHAG compared to 27% of HAG received relatively higher doses, while 25% of NHAG compared to 75% of HAG received relatively lower doses (p=0.01). Conclusion: Dosing based on BW may be preferable in both prepubertal and pubertal children who do not show adequate growth responses. In prepubertal children, relatively lower doses calculated based on BW rather than BSA provide similar efficacy at lower costs.

Hemoglobin A1C can differentiate subjects with GCK mutations among patients suspected to have MODY.

OBJECTIVES: The aim of this study is to determine the clinical and molecular characteristics enabling differential diagnosis in a group of Turkish children clinically diagnosed with MODY and identify the cut-off value of HbA1c, which can distinguish patients with GCK variants from young-onset type 1 and type 2 diabetes. METHODS: The study included 49 patients from 48 unrelated families who were admitted between 2018 and 2020 with a clinical diagnosis of MODY. Clinical and laboratory characteristics of the patients at the time of the diagnosis were obtained from hospital records. Variant analysis of ten MODY genes was performed using targeted next-generation sequencing (NGS) panel and the variants were classified according to American Collage of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. RESULTS: A total of 14 (28%) pathogenic/likely pathogenic variants were detected among 49 patients. 11 variants in GCK and 3 variants in HNF1A genes were found. We identified four novel variants in GCK gene. Using ROC analysis, we found that best cut-off value of HbA1c at the time of diagnosis for predicting the subjects with a GCK variant among patients suspected to have MODY was 6.95% (sensitivity 90%, specificity 86%, AUC 0.89 [95% CI: 0.783-1]). Most of the cases without GCK variant (33/38 [86%]) had an HbA1c value above this cutoff value. We found that among participants suspected of having MODY, family history, HbA1c at the time of diagnosis, and not using insulin therapy were the most differentiating variables of patients with GCK variants. CONCLUSIONS: Family history, HbA1c at the time of diagnosis, and not receiving insulin therapy were found to be the most distinguishing variables of patients with GCK variants among subjects suspected to have MODY.

Clinical course of primary empty sella in children: a singlecenter experience.

BACKGROUND: Various studies, mainly conducted in adults, have examined the hormonal axis in primary empty sella (PES), and reported various forms of pituitary deficiencies. We report our experience with PES in pediatric patients in terms of pituitary function, associated impairments, and responses to treatment. METHODS: We reviewed 10,560 cranial and 325 pituitary magnetic resonance imagings (MRIs) performed at our university hospital between January 2010 and December 2020 and identified patients with PES. Patients with additional abnormal MRI findings, a history of cranial surgery or radiotherapy, autoimmunity, long-term use of chemotherapeutic or immunosuppressive agents or incomplete diagnostic evaluation were excluded. Clinical, radiological and laboratory evaluations were recorded. RESULTS: The study included 17 patients [9 girls, 8 boys; median age 12.4 years (7.25, 4.3 - 17)]. The median size of the pituitary was 2 mm (0.7, 1.2 - 3). Based on age-dependent pituitary height measurements, fifteen (88%) patients had pituitary gland hypoplasia. Five patients presented with short stature, two had both pubertal delay and short stature, and one had pubertal delay. Nine patients presented with neurological symptoms such as headaches, tinnitus, tics, and dizziness. Five short patients had growth hormone deficiency. None of the patients had hyper- or hypoprolactinemia, adrenal insufficiency, hypothyroidism, or diabetes insipidus. There was statistically no significant association between the size of the pituitary gland and the severity of hypopituitarism (p = 0.42). CONCLUSIONS: The high incidence of pituitary dysfunctions ascertain that this entity should not be considered a normal variant but, should instead be carefully evaluated with appropriate basal and dynamic hormonal testing.

Efficacy of aromatase inhibitor therapy in a case with large cell calcifying Sertoli cell tumour-associated prepubertal gynaecomastia.

OBJECTIVES: Large cell calcifying Sertoli cell tumours (LCCSCTs) are one of the infrequent causes of prepubertal gynaecomastia. Most of these tumours are in the content of Peutz-Jeghers syndrome (PJS) or other familial syndromes (Carney complex). CASE PRESENTATION: Here, we report a long-term follow-up of an 8.5-year-old prepubertal boy with a diagnosis of PJS, who presented with bilateral gynaecomastia, advanced bone age and accelerated growth velocity, and were found to have bilateral multifocal testicular microcalcifications. As the findings were compatible with LCCSCT, anastrozole was initiated. Gynaecomastia completely regressed and growth velocity and pubertal development were appropriate for age during follow-up. Testicular lesions slightly increased in size. After four years of medication, anastrozole was discontinued but was restarted due to the recurrence of gynaecomastia after six months. CONCLUSIONS: Testicular tumour should be investigated in a patient with PJS who presents with prepubertal gynaecomastia. When findings are consistent with LCCSCT, aromatase inhibitors may be preferred in the treatment.

Biochemical indicators of euthyroid sick syndrome in critically ill children.

OBJECTIVES: This study aimed to determine the prevalence and predictors of euthyroid sick syndrome (ESS) in pediatric intensive care, and to establish a link between thyroid function tests and mortality. METHODS: Between January 2015 and March 2020, children admitted to our pediatric intensive care unit (PICU) and tested for free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) levels were included. Patients with decreased fT3, with normal or decreased fT4, and normal or decreased TSH levels were assigned to the ESS group. The association between biochemical indicators and ESS, as well as the relationship between fT3 and mortality, were examined. RESULTS: A total of 141 (36%) of 386 children included to study were classified in the ESS group. The ESS group had a higher rate of 28-day mortality (12 [8.5%] vs. 9 [3.7%]). Blood urea nitrogen (BUN), albumin, platelet, lactate, and pediatric index of mortality 3 [PIM3 (%)] were significantly associated with ESS (odds ratios in order: 1.024, 0.422, 0.729, 1.208, 1.013). Multivariate regression analysis showed that BUN, albumin, platelet, and lactate were independently associated with ESS progression. The area under curve (AUC [95%CI]) for fT3 was 0.644 (0.555-0.789) to detect mortality. Children with a fT3 level lower than 2.31 pg/mL had significantly higher 28-day mortality (log rank test, p=0.001). CONCLUSIONS: Our study identified BUN, albumin, lactate, and platelet count as independent risk factors for ESS progression in children. Furthermore, our findings indicated a correlation between fT3 and mortality, which makes fT3 an ideal candidate to be included in mortality indices.

Has the Frequency of Precocious Puberty and Rapidly Progressive Early Puberty Increased in Girls During the COVID-19 Pandemic?

Objective: Early puberty is development of secondary sex characteristics earlier than the expected normal age range. We subjectively observed an increased frequency of early puberty during the Coronavirus disease-2019 (COVID-19) lockdown and aimed to show the clinical, demographic characteristics of the cases and the change in its incidence. Methods: Female patients with central precocious puberty (CPP, n=28) and rapidly progressive early puberty (RPEP, n=61), presenting to our clinic before (January 2019-March 2020) and during the COVID-19 pandemic (April 2020-June 2021) were included. Results: Among 28 CPP cases, six (21%) presented before the pandemic lockdown, whereas 22 (79%) were diagnosed during the COVID-19 pandemic lockdown. While RPEP was seen in 16 (26%) patients before the pandemic, 45 (74%) patients were diagnosed during the lockdown period. Presentation with menarche was seen in 15 RPEP patients; two (13%) were in the prepandemic period and 13 (87%) were in the lockdown period. Chronological age, bone age, bone age to chronological age ratio, height, weight, and body mass index standard deviation scores of patients with RPEP and CPP were similar between the prepandemic and pandemic period. Conclusion: In this cohort, the frequency of CPP and RPP cases were significantly (p<0.001) increased during the COVID-19 pandemic, possibly due to environmental changes.

Atypical comorbidities in a child considered to have type 1 diabetes led to the diagnosis of SLC29A3 spectrum disorder.

INTRODUCTION: SLC29A3 spectrum disorder is an autosomal, recessively inherited, autoinflammatory, multisystem disorder characterized by distinctive cutaneous features, including hyperpigmentation or hypertrichosis, hepatosplenomegaly, hearing loss, cardiac anomalies, hypogonadism, short stature, and insulin-dependent diabetes. CASE PRESENTATION: Herein, we report a 6-year-old boy who presented with features resembling type 1 diabetes mellitus, but his clinical course was complicated by IgA nephropathy, pure red cell aplasia, and recurrent febrile episodes. The patient was tested for the presence of pathogenic variants in 53 genes related to monogenic diabetes and found to be compound heterozygous for two SLC29A3 pathogenic variants (p. Arg386Gln and p. Leu298fs). CONCLUSION: This case demonstrated that SLC29A3 spectrum disorder should be included in the differential diagnosis of diabetes with atypical comorbidities, even when the distinctive dermatological hallmarks of SLC29A3 spectrum disorder are entirely absent.

Initial neutrophil/lymphocyte and lymphocyte/monocyte ratios can predict future insulin need in newly diagnosed type 1 diabetes mellitus.

OBJECTIVES: The exact mechanism of partial clinical remission in type 1 diabetes mellitus (T1DM) has not been elucidated yet. The severity of the inflammation at the time of diagnosis may affect the occurrence or duration of this phase. We aimed to investigate the relationship between hematological inflammatory parameters at the time of diagnosis in T1DM and (i) daily insulin requirement during the follow-up and (ii) the presence of partial clinical remission period, which was determined according to insulin dose-adjusted HbA1c levels. METHODS: A single-center retrospective study was conducted, including children who were diagnosed with T1DM, were positive for at least one autoantibody, and were followed up for one year in our clinic between 2010 and 2020. RESULTS: Sixty-eight patients (55.9% female, 64.7% prepubertal) were included in the study, whose mean age was 8.4 ± 4.2 years. A total of 38 patients (55.9%) had partial clinical remission. None of the initial hematological indices were associated with the occurrence of partial remission. Initial neutrophil/lymphocyte ratio (NLR) and derived-NLR (d-NLR) levels were significantly lower (p=0.011 and 0.033, respectively) and lymphocyte/monocyte ratio (LMR) levels were significantly higher (p=0.005) in patients who showed an insulin requirement of <0.5 IU/kg/day at the 3rd month after diagnosis. CONCLUSIONS: Initial hematological parameters were not found as a predictor of partial clinical remission period in T1DM in children. However, a lower NLR and d-NLR, or a higher LMR at the time of diagnosis can be used as an indicator of a low daily insulin need at the 3rd month of T1DM.

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.

Low Complement C1q/TNF-related Protein-13 Levels are Associated with Childhood Obesity But not Binge Eating Disorder

Objective: C1q/tumor necrosis factor-related proteins (CTRPs) are recently described members of the adipokine family. CTRP-13, a new member of this family, has been shown to increase insulin sensitivity and had an anorexigenic effect on food intake in experimental studies. The aim was to investigate serum CTRP-13 levels in children with obesity, and its relationship with other adipokines, metabolic parameters, or binge eating disorder (BED). Methods: A cross-sectional study was conducted with 105 pubertal children attending a single center. Clinical (metabolic syndrome, BED) and biochemical (glucose, insulin, lipids, leptin, adiponectin, CTRP-13 levels) parameters were assessed. Results: Sixty children with obesity [24 males (40%); median age 14.7 (13.0-16.4) years] and 45 healthy controls [15 males (33.3%); median age 15.2 (14.1-16.5) years] were included. Serum adiponectin and CTRP-13 levels were significantly lower in children with obesity than controls (7.1 vs 20.1 µg/mL, p<0.001; 64.7 vs 103.8 ng/mL, p<0.001, respectively). CTRP-13 levels correlated negatively with body mass index (Spearman rho=-0.230, p=0.018) and positively with high-density lipoprotein-cholesterol levels (Spearman rho=0.218, p=0.026). There was no significant difference in serum CTRP-13 concentrations in terms of the presence of metabolic syndrome or BED. Conclusion: Childhood obesity seems to be causing dysregulation in adipokine production and function, including the down-regulation of CTRP-13. The positive correlation between CTRP-13 and HDL-C levels suggested a possible effect of this adipokine on lipid metabolism. Thus CTRP-13 may be a novel biomarker for dyslipidemia in childhood obesity.

Clinical, genetic characteristics and treatment outcomes of children and adolescents with osteogenesis imperfecta: a two-center experience.

BACKGROUND: Osteogenesis imperfecta (OI), is a heritable, heterogeneous connective tissue disorder, characterized by fragile bones. There are conflicting results about genotype-phenotype correlations and efficiency of bisphosphonate treatment in this disorder. AIM: We aimed to evaluate the clinical, genetic characteristics, and long-term follow-up results of children and adolescents with OI. MATERIALS AND METHODS: A two-center retrospective study was conducted using demographic, clinical, and genetic data obtained from the medical records of the patients. RESULTS: Twenty-nine patients (62% male, median age; 3.6 years) with OI diagnosis from 26 families were included in the study. Thirteen different variants (nine were novel) were described in 16 patients in COL1A1, COL1A2, and P3H1 genes. Our siblings with homozygous P3H1 variants had a severe phenotype with intrauterine and neonatal fractures. Twenty-two patients were treated with bisphosphonates (17 of them with pamidronate, five with alendronate) with a median duration of 3.0 (1.6-4.8) years. Eleven patients (50%) suffered from fractures after the treatment. Haploinsufficiency variants in COL1A1 caused a milder skeletal phenotype with less fracture count and better treatment outcomes than structural variants. When compared with the anthropometric measurements at the initial diagnosis time, height Z-scores were lower on the last clinical follow-up (p = 0.009). CONCLUSIONS: We could not find an obvious genotype-phenotype correlation in Turkish OI patients with COL1A1 or COL1A2 variants. Treatment with pamidronate was effective in reducing fracture counts, without any long-term adverse effects.

A 4-hour Profile of 17-hydroxyprogesterone in Salt-wasting Congenital Adrenal Hyperplasia: Is the Serial Monitoring Strategy Worth the Effort?

Objective: Since there is no gold standard laboratory variable for adjustment of treatment in congenital adrenal hyperplasia (CAH), the aim was to assess the use of a 4-hour profile of serum 17-hydroxyprogesterone (17-OHP) to determine the most appropriate sample time and level of 17-OHP in predicting the metabolic control and evaluate the role of sex hormone-binding globulin (SHBG) in hyperandrogenemia. Methods: This study included children with salt-wasting CAH. Measurements for 17-OHP and cortisol were made from samples obtained before and 1, 2, and 4 hours after the morning dose of hydrocortisone. Patients were designated to have poor metabolic control when androstenedione levels according to age and sex-specific reference intervals were high and annual height standard deviation score (SDS) changes were ≥0.5. Results: The study cohort was 16 children (9 girls) with a median age of 7-years old. Premedication 17-OHP levels were strongly correlated with 17-OHP levels 1, 2, and 4 hours after the morning dose (rs=0.929, p<0.01; rs=0.943, p<0.01; rs=0.835, p<0.01, respectively). 17-OHP profiles (0, 1, 2, 4 hours) of poor (n=6) and good (n=10) metabolically controlled cases were similar. Among the patients with poor metabolic control, two cases had 17-OHP levels <2 ng/mL at all times. The remaining patients with poor metabolic control had median 17-OHP levels above 104 ng/mL, 82 ng/mL, 14 ng/mL, and 4 ng/mL, for baseline and 1, 2, and 4 hours, respectively. Differences between the poor and well-controlled group were androstenedione levels with respect to upper limit of normal [1.8 (1.5) and 0.5 (1.5) ng/mL, respectively p=0.03], annual change in height SDS [0.7 (0.2) and -0.03 (0.8) SDS, respectively, p=0.001], and daily hydrocortisone doses [7 (6) and 16 (8) mg/m2/day, respectively, p=0.02]. Androstenedione and SHBG levels were negatively correlated in the pubertal children (rs=-0.7, p=0.04). Conclusion: We conclude that: (i) a 4-hour 17-OHP profile is not useful in predicting hyperandrogenemia; (ii) suppressed levels of 17-OHP do not always indicate overtreatment; (iii) reference intervals of 17-OHP for different time periods might be of importance; (iv) low hydrocortisone doses should be avoided; and (v) SHBG could be used in pubertal children as an indicator of hyperandrogenemia.