The relationship between infancy growth rate and the onset of puberty in both genders.

BackgroundIn 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.MethodsA 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.ResultsGirls 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).ConclusionEarly growth acceleration might be important for the timing of puberty in both genders.

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.

Adherence to growth hormone therapy: results of a multicenter study.

OBJECTIVE: To evaluate the adherence to growth hormone (GH) therapy and identify the influencing factors and outcomes in children. METHODS: A total of 217 GH-naïve patients in 6 pediatric endocrinology clinics were enrolled in the study. Structured questionnaires were filled out and patients were evaluated at the initiation and 3rd, 6th, and 12th months of therapy. Patients were categorized into 4 adherence segments based on percentage of doses omitted at each evaluation period, classified as excellent if 0%, good if 5%, fair if 5 to 10%, and poor if > 10%. RESULTS: There was a decrement in adherence to GH therapy during the study period (P = .006). Patients who showed excellent and good adherence to therapy had better growth velocity and growth velocity standard deviation scores (SDSs) (P = .014 and P = .015, respectively). A negative correlation between growth velocity SDS and number of missed injections was also observed (r = -.412; P = .007). A positive correlation between delta insulin-like growth factor-1 (IGF-1) SDS and growth velocity was demonstrated (r = .239; P = .042). IGF-1 levels were significantly higher in patients who showed excellent and good adherence to therapy (P = .01). Adherence was better in boys than in girls (P = .035), but adherence rates were not associated with age, cause of GH treatment, socioeconomic status, person who administered the injections, type of injection device, or GH product. CONCLUSION: Poor adherence to GH therapy was common in our group of patients and was one of the factors underlying suboptimal growth during therapy. Before considering other problems that can affect growth, clinicians should confirm good adherence to therapy.

Netherton syndrome associated with growth hormone deficiency.

Netherton syndrome (NS) is a rare autosomal recessive disorder characterized by ichthyosiform scaling, hair abnormalities, and variable atopic features. Mutations in the serine protease inhibitor Kazal type 5 (SPINK5) gene leading to lymphoepithelial Kazal-type-related inhibitor (LEKTI) deficiency cause NS. Growth retardation is a classic feature of NS, but growth hormone (GH) deficiency with subsequent response to GH therapy is not documented in the literature. It is proposed that a lack of inhibition of proteases due to a deficiency of LEKTI in the pituitary gland leads to the overprocessing of human GH in NS. Herein we report three patients with NS who had growth retardation associated with GH deficiency and responded well to GH therapy.

Evaluation of endocrine function in children admitted to pediatric intensive care unit.

BACKGROUND: Although studied widely in adulthood, little is known about endocrinological disorders during critical illnesses in childhood. The aims of this study were to define the endocrinological changes in patients admitted to pediatric intensive care unit (PICU) and to identify their effects on prognosis. METHODS: Forty patients with a mean age of 5.1 years admitted to PICU were enrolled in the study. Blood samples were taken at admission and at 24 and 48 h to measure cortisol, adrenocorticotropic hormone (ACTH), prolactin, growth hormone (GH), GH binding protein (GHBP), insulin-like growth factor-binding protein-3 (IGFBP-3) and interleukin-6 (IL-6). The severity of the patient's condition was assessed using pediatric risk of mortality (PRISM) and pediatric logistic organ dysfunction (PELOD) scores. RESULTS: PRISM and PELOD scores were significantly higher in non-survivors. Cortisol, ACTH, prolactin, GH, GHBP, IGFBP-3 and IL-6 were not significantly different between the survivors and non-survivors. There was a negative correlation between baseline IGFBP-3 and PRISM scores. A positive correlation was seen between cortisol level at 24 h and PRISM score. On multivariate linear regression analysis, PRISM score was best explained by ACTH and cortisol at 24 h. A positive weak correlation was detected between IL-6 at 24 h and PELOD scores. CONCLUSIONS: Although there was no difference between survivors and non-survivors regarding the studied endocrine parameters, there were associations between cortisol, ACTH, IL-6 and IGFBP-3 and risk assessment scores, and, given that these scores correlated with mortality, these parameters might be useful as prognostic factors.

Adolescents with obesity treated with exenatide maintain endogenous GLP-1, reduce DPP-4, and improve glycemic control.

Background: GLP-1 receptor agonists (GLP-1RA) are increasingly used to treat adolescent obesity. However, the effect on endogenous GLP-1 secretory patterns following treatment in adolescents is unknown. The GLP-1RA exenatide was shown to significantly lower BMI and 2-hour glucose in adolescents with obesity, in the placebo-controlled, randomized controlled trial Combat-JUDO. The aim of this study was to evaluate effects of weekly injections of 2 mg exenatide extended release on secretory patterns of endogenous hormones during OGTT. Subjects and Measurements: This study was a pre-planned sub-study of the Combat-JUDO trial, set at the Pediatric clinic at Uppsala University Hospital, Sweden and Paracelsus Medical University, Austria. 44 adolescents with obesity were included and randomized 1:1 to treatment:placebo. 19 patients in the treatment group and 18 in the placebo group completed the trial. Before and after treatment, GLP-1, glucose, insulin, glucagon and glicentin levels were measured during OGTT; DPP-4 and proinsulin were measured at fasting. A per-protocol approach was used in the analyses. Results: Exenatide treatment did not affect GLP-1 levels during OGTT. Treatment significantly lowered DPP-4, proinsulin and the proinsulin-to-insulin ratio at fasting, increased glicentin levels but did not affect insulin, C-peptide or glucagon levels during OGTT. Conclusion: Weekly s.c. injections with 2 mg of exenatide maintains endogenous total GLP-1 levels and lowers circulating DPP-4 levels. This adds an argument in favor of using exenatide in the treatment of pediatric obesity. Clinical trial registration: clinicaltrials.gov, identifier NCT02794402.

Thyroid hormones in children on antiepileptic therapy.

The aim of this study was to evaluate the thyroid function alterations in a group of epileptic children taking antiepileptic drugs (AEDs). Patients demographic data and the free throxine (fT4) and thyroid-stimulating hormone (TSH) levels at the beginning of the treatment and at the third, sixth and ninth months of AED treatment were recorded retrospectively. A total of 106 children, 59 males and 47 females, were enrolled in the study. Mean patient age was 3.7 years, ranging between 3 months and 14 years. In total, 54% of patients were on valproic acid (VPA), 16% phenobarbital (PB), 14% were on carbamazepine (CBZ), 6% were on oxcarbazepine (OXC), 5% were on levetiracetam, and 5% were on topiramate therapy. There were no significant differences in average fT4 values between the drug groups. But the mean fT4 levels of the patients on VPA therapy showed a clear decrease within the observation period. No significant difference in average TSH values between the groups was detected in the beginning and in the third and sixth month. However, in the ninth month, a significant increase in TSH values was found in the VPA group (p = 0.007). In the patients taking VPA, average TSH values rose progressively while staying within normal limits. During follow-up, thyroid dysfunction were found in 21 patients (19.6%). A statistically significant relationship was found between severe electroencephalography (EEG) findings and thyroid dysfunction (p = 0.041). It was concluded that epileptic children with severe EEG findings and using VPA could have thyroid dysfunction. These patients should be followed up closely by thyroid function tests during treatment.

Impact of Smoking, Obesity and Maternal Diabetes on SHBG Levels in Newborns.

BACKGROUND: Low levels of SHBG have become a marker for insulin resistance and diabetes. Babies born to mothers who are obese, have diabetes, or smoke during pregnancy are at greater risk of developing obesity and diabetes later in life. AIMS: To examine the impact of maternal obesity, diabetes and smoking on SHBG levels in newborns. STUDY DESIGN: This cross-sectional study is part of an ongoing multicenter, longitudinal study. SUBJECTS: 98 healthy newborns and their parents, including 16 mothers with diabetes and 31 mothers with a smoking history. OUTCOME MEASURES: Cord blood and second day venipuncture samples were collected for measurement of SHBG and insulin. RESULTS: Babies born to mothers with diabetes had lower SHBG levels in cord blood [14.0 (8.9-20.4) vs. 19.6 (14.9-25.1) nmol/L; p=0.011] and on day 2 [18.8 (12.6-21.2) vs. 22.9 (17.1-29.1) nmol/L; p=0.015] than controls. Maternal diabetes remained negatively associated with SHBG levels in cord blood (p=0.02) and on day 2 (p=0.04) when adjusted for mothers' age, smoking status, pre-pregnancy weight and weight gain during pregnancy. SHBG levels in cord blood and day 2 samples were similar in babies born to mothers who were overweight-obese but not diabetic vs. normal weight, or were smokers when compared to non-smokers. CONCLUSIONS: SHBG levels are lower in newborns born to mothers with diabetes than without diabetes, and may be a marker for babies' life-long risk for abnormal metabolic health. On the other hand, the adverse effects of tobacco smoke on the fetus do not appear to directly influence SHBG levels.

High levels of FSH before puberty are associated with increased risk of metabolic syndrome during pubertal transition.

BACKGROUND: During perimenopause, the rise in serum follicle-stimulating hormone (FSH) is associated with increased adiposity, insulin resistance (IR), and metabolic syndrome (MetS). However, data for the pubertal period, which is characterized by increasing FSH levels and changing body composition, are limited. OBJECTIVES: To investigate the relationships between FSH and anthropometric changes, IR markers, and development of MetS in the peripubertal period. METHODS: Uppsala Longitudinal Study of Childhood Obesity (ULSCO) is an ongoing study that aims to understand the factors contributing to childhood obesity and the development of obesity-related diseases. We analysed the subset of participants who were prepubertal at the first visit (n = 95, 77 with obesity). Mean follow-up time was 3.0 ± 1.4 years. RESULTS: Higher serum FSH levels at the first visit were associated with an increased likelihood of elevation in body mass index (BMI SDS) (p = 0.025, OR = 16.10) and having MetS (p = 0.044, OR = 4.67) at the follow-up. We observed nonlinear relationships between varying serum FSH levels and markers of adiposity and IR, especially in girls. At the first visit, when girls were prepubertal, FSH was negatively associated with BMI (ß = -0.491, p = 0.005) and positively associated with sex hormone-binding globulin (SHBG) (ß = 0.625, p = 0.002). With the progression of puberty, negative associations between BMI and SHBG disappeared while FSH became positively associated with HOMA-IR (ß = 0.678, p = 0.025) and fasting insulin (ß = 0.668, p = 0.027). CONCLUSIONS: Higher serum FSH levels in prepubertal children were associated with an increased risk of MetS development during pubertal transition. Along with nonlinear associations between varying serum FSH levels and IR markers, our results might imply a relationship between FSH and IR of puberty.

Frequency of Ambiguous Genitalia in 14,177 Newborns in Turkey.

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.

Evaluation and Treatment Results of Ovarian Cysts in Childhood and Adolescence: A Multicenter, Retrospective Study of 100 Patients.

STUDY OBJECTIVE: To investigate the characteristics of children with ovarian cysts and evaluate treatment strategies. DESIGN: Retrospective study. SETTING: Eight pediatric endocrinology clinics, Turkey. PARTICIPANTS: A total of 100 children and adolescents with ovarian cysts. INTERVENTIONS: Patient data collected via retrospective chart review. Patients were stratified according to age into 4 groups (newborns, 1-12 months, 1-8 years, and 8-18 years). MAIN OUTCOME MEASURES: Special emphasis was given to torsion and tumor cases, concomitant diseases, treatment modalities, and problems during follow-up. RESULTS: Most newborns and infants were asymptomatic with the cysts being discovered incidentally; in girls ages 1-8, symptoms were common, including breast budding (47.1%, 16 of 34) and vaginal bleeding (29.4%, 10 of 34). Girls older than 8 years mostly presented with abdominal pain (31.6%, 12 of 38) and menstrual irregularity (21.1%, 8 of 38). Most of our patients were diagnosed with a simple ovarian cyst, but 9 patients were found to have ovarian tumors. Ovarian torsion was detected in 7 patients; 5 with large and 2 with small cysts (<20 mm). Two patients had central precocious puberty (CPP) at presentation and 5 patients developed CPP during follow-up. The surgical intervention rate was high (38%, 38 of 100), but was associated with earlier treatment year, and this association remained significant after adjusting for confounders (P = .035). CONCLUSION: Most girls have simple cysts, which have a favorable prognosis without intervention; however, there might be coexisting pathologies or complications such as tumors, torsion, and CPP; hence these patients should be evaluated accordingly and treated with a multidisciplinary approach.

Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort.

CONTEXT: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. OBJECTIVE: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. DESIGN: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. SETTING: The study was conducted in 19 tertiary pediatric endocrinology clinics. PATIENTS: Ninety-five children (48 females, aged 0-18 y, eight familial) with PAI of unknown etiology participated in the study. RESULTS: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged. CONCLUSION: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.

Molecular analysis of PROP1, POU1F1, LHX3, and HESX1 in Turkish patients with combined pituitary hormone deficiency: a multicenter study.

To investigate the specific mutations in PROP1, POU1F1, LHX3, and HESX1 genes in patients with combined pituitary hormone deficiency (CPHD) in Turkey. Seventy-six patients with CPHD were included in this study. Based on clinical, hormonal, and neuro-radiological data, relevant transcription factor genes were evaluated by Sanger sequencing and multiplex ligation-dependent probe amplification. Total frequency of mutations was 30.9 % in patients with CPHD. Frequency was significantly higher in familial patients (p = 0.001). Three different types of mutations in PROP1 gene (complete gene deletion, c.301-302delAG, a novel mutation; IVS1+2T>G) were found in 12 unrelated patients (21.8 %). Mutations in PROP1 gene were markedly higher in familial than in sporadic cases (58.8 vs. 5.3 %, p < 0.001). Homozygous complete gene deletion was the most common mutation in PROP1 gene (8/12) and was identified in six familial patients. Four different homozygous mutations [p.Q4X, novel mutations; exons 1-2 deletion, p.V153F, p.I244S] were detected in POU1F1 gene. Central precocious puberty was firstly observed in a sporadic-male patient with homozygous POU1F1 (p.I244S) mutation. A homozygous mutation in HESX1 gene (p.R160H) was detected in one patient. This study is the first to investigate specific mutations in CPHD patients in Turkey. Complete deletion in PROP1 gene was the most common mutation encountered in patients with CPHD. We believe that the results of this study will contribute to the establishment of genetic screening strategies in Turkey, as well as to the studies on phenotype-genotype correlations and early diagnosis of CPHD patients.

Permanent neonatal diabetes mellitus: same mutation, different glycemic control with sulfonylurea therapy on long-term follow-up.

Permanent neonatal diabetes mellitus (PNDM) is a rare condition presenting before six months of age. Mutations in the genes encoding the ATP-sensitive potassium (KATP) channel are the most common causes. Sulfonylurea (SU) therapy leads to dramatic improvement in diabetes control and quality of life in most patients who carry these mutations. Here, we report the long-term follow-up results of two siblings with PNDM who were treated with insulin until ABCC8 gene mutation was identified, and were successfully transferred to oral SU therapy. After 3.5 years of follow-up on SU, one patient had a very good response, while the other one had a poor response. Bad compliance to diet was thought to be the most probable reason for poor glycemic control in this patient. In conclusion, molecular genetic diagnosis in all patients with PNDM is recommended. Compliance to treatment should be an important aspect of the follow-up of these patients.

Clinical and laboratory characteristics of children referred for early puberty: preponderance in 7-8 years of age.

OBJECTIVE: The aim of this study was to evaluate the girls referred to the pediatric outpatient clinic with a presumptive diagnosis of early puberty due to early onset of breast development or pubarche. METHODS: Within the study period, we evaluated 289 subjects referred for concerns about early onset of puberty. History, anthropometric data, bone age (BA), hormones including luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and dehydroepiandrosterone sulfate, as well as pelvic ultrasonography (USG)-derived ovarian and uterine volumes were analyzed. RESULTS: Of the 289 girls referred for early onset of pubertal development, 64 (22.1%) had false alarms for puberty. Of the remaining 225 girls, 41 (18.2%) were diagnosed as premature pubarche, 56 (24.9%) as premature thelarche (PT), and 128 (56.9%) as precocious puberty (PP). Girls with early-onset puberty had more advanced BA, greater uterine and ovarian volumes, and also higher LH values than subjects with PP and PT. Nearly half of these girls were 7-8 years of age. Body mass index (BMI) standard deviation score was significantly higher in the PP cases. CONCLUSIONS: There is a need for primary care physicians to be more knowledgeable on puberty and on puberty problems. There seems to be a preponderance of PP in 7-8-year-old children . Increased BMI may have a role in the trend towards earlier onset of puberty.