Band 30, Heft 1

Background: Infertility and sexual dysfunction result from many different pediatric conditions and treatments and can profoundly impact quality of life. The American Academy of Pediatrics (AAP) has recommended consulting “fertility specialists” for counseling, but it remains unclear who these specialists are. Our objective was to assess whether pediatric subspecialists who manage hypogonadism and/or genitourinary conditions feel adequately trained to provide fertility and sexual function counseling. Methods: An online survey was distributed to members of Pediatric Endocrine Society (PES), Society for Pediatric Urology (SPU), and North American Society for Pediatric and Adolescent Gynecology (NASPAG). Providers’ comfort in counseling various age groups about fertility and sexual function was assessed via a five-point Likert scale. Providers reported whether they felt adequately trained in these areas. Results: Two hundred and eighty-four surveys were completed by endocrinologists, 124 surveys by urologists, and 41 surveys by gynecologists. Respondents (44% male, 86% Caucasian) represented 39 states and Canada. Seventy-nine percent were at academic centers. Thirty-four percent of providers had been practicing for >20 years. Comfort level was variable and lowest in young males. Ninety-one percent of pediatric endocrinologists reported routinely seeing patients at risk for infertility, but only 36% felt adequately trained in fertility, and 25% felt adequately trained in sexual function. Conclusions: Infertility and sexual dysfunction are often overlooked in pediatric care. Our results suggest that pediatric endocrinologists, who frequently manage male and female hypogonadism, should also receive formal training in these areas. Optimizing counseling would help prevent missed opportunities for fertility preservation and alleviate distress among patients and families.

Background: The objective of the study was to describe the prevalence, clinical characteristics and aetiological diagnosis in children with disorders of sex development (DSDs) presenting to a tertiary referral centre. Methods: This is a retrospective review of all cases of DSD referred to the Paediatric Endocrine Unit in Inkosi Albert Luthuli Central Hospital (IALCH) from January 1995 to December 2014. Results: A total of 416 children (15.1%; CI: 13.8%–16.5%) were diagnosed with DSD. The aetiological diagnosis based on the current classification [Lawson Wilkins Paediatric Endocrine Society (LWPES) and European Society for Paediatric Endocrinology (ESPE)] was sex chromosome DSD in 9.5% (n=33), 46 XX DSD in 33% (n=114) and 46 XY DSD in 57.5% (n=199). The most common diagnoses in descending order were a disorder in androgen synthesis and action (not classified) in 53% (n=182), ovotesticular DSD in 22% (n=75) and congenital adrenal hyperplasia (CAH) in 10% (n=36). Overall the median age of presentation was 10 months (IQR: 1 month–4.5 years). There was a significant relationship (p<0.001) between the age of presentation and aetiological diagnosis. The majority (97%) of African patients had a diagnosis of 46 XX DSD. Prematurity was present in 47% (n=83) of children with 46 XY DSD (p<0.001). Conclusions: DSD is not an uncommon diagnosis in African patients in sub-Saharan Africa. The most common aetiological diagnosis is 46 XY DSD in androgen synthesis and action, followed by ovotesticular DSD. CAH is only the third most common disorder.

Background: Abnormalities of dihydrotestosterone conversion [5α-reductase deficiency: online Mendelian inheritance in man (OMIM) 607306] or actions of androgens [partial androgen insensitivity syndrome (PAIS): OMIM 312300] during the 8th–12th weeks of gestation cause varying degrees of undervirilized external genitalia in 46, XY disorders of sex development (DSD) with increased testosterone production. The objective of the study was to determine clinical and genetic characteristics of Thai patients with 46, XY DSD. Methods: A cross-sectional study was conducted in 46, XY DSD with increased testosterone production (n=43) evaluated by a human chorionic gonadotropin (hCG) stimulation test or clinical features consistent with 5α-reductase deficiency or PAIS. PCR sequencing of the entire coding regions of the SRD5A2 and AR genes was performed. Molecular modeling analysis of the androgen receptor-ligand-binding domain (AR-LBD) of a novel mutation was constructed. Results: Mutations were found in seven patients (16.3%): five (11.6%) and two (4.7%) patients had mutations in SRD5A2 and AR , respectively. Two novel mutations, SRD5A2 c.383A>G (p.Y128C) and AR c.2176C>T (p.R726C), were identified. Dimensional structural analysis of the novel mutated AR (p.R726C) revealed that it affected the co-activator binding [binding function-3 (BF-3)], not the testosterone binding site. Short phallus length was associated with 5α-reductase deficiency. Conclusions: Around 16.3% of our patients with 46, XY DSD had 5α-reductase deficiency or PAIS. Two novel mutations of SRD5A2 and AR were identified. The novel mutated AR (p.R726C) might affect the co-activator binding (BF-3), not the testosterone binding site.

Background: Cystic fibrosis-related diabetes (CFRD) is a late cystic fibrosis (CF)-associated comorbidity whose prevalence is increasing sharply lifelong. Guidelines for glucose metabolism (GM) monitoring rely on the oral glucose tolerance test (OGTT). However, this test is neither sensitive nor specific. The aim of this study was to compare sensitivity and specificity of different methods for GM monitoring in children and adolescents with CF. Methods: Continuous glucose monitoring system (CGMS), used as the reference method, was compared with the OGTT, intravenous glucose tolerance test (IGTT), homeostasis model assessment index of insulin resistance (HOMA-IR), homeostasis model assessment index of β-cell function (HOMA-%B) and glycated haemoglobin A 1C . Patients were classified into three groups according to CGMS: normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes mellitus (DM). Results: Twenty-nine patients (median age: 13.1 years) were recruited. According to CGMS, 11 had DM, 12 IGT and six NGT, whereas OGTT identified three patients with DM and five with IGT. While 13 of 27 had insulin deficiency according to IGTT, there was 19 of 28 according to HOMA-%B. According to HOMA-IR, 12 of 28 had insulin resistance. HOMA-%B was the most sensitive method for CFRD screening [sensitivity 91% (95% CI), specificity 47% (95% CI) and negative predictive value 89% (95% CI)]. Conclusions: OGTT showed the weak capacity to diagnose DM in CF and should no longer be considered as the reference method for CFRD screening in patients with CF. In our study, HOMA-%B showed promising metrics for CFRD screening. Finally, CGMS revealed that pathological glucose excursions were frequent even early in life.

Background: Aegle marmelos (commonly known as Bael, golden apple) was formerly described to have anti-hyperglycemic activity. The present study aimed to explore the possible effects, in depth, of A. marmelos extracts on carbohydrate absorption, glucose utilization, and α-amylase inhibition and insulin content in pancreases of type 2 diabetic rats. Methods: This research begins with fasting blood glucose and oral glucose tolerance test (OGTT) to evaluate the primary anti-hyperglycemic effect in chemically induced type 2 diabetic rats. Furthermore, the plasma insulin concentration and serum glucose level were studied, which include measuring the sucrose content in six different segments of the gastrointestinal (GI) tract of the rats following oral sucrose feeding. An in situ, perfused, intestinal model in rats and glucose-fiber binding assay were conducted to find the effects of A. marmelos extracts on glucose absorption. Extract effects on carbohydrate breakdown, intestinal disaccharidase enzyme activity, and α-amylase inhibition were assessed. Effect on GI motility was evaluated using BaSO 4 milk traverse test. Results: Treatment of extracts suppressed blood glucose elevation after oral sucrose (2.5 g/kg) administration and significantly (p<0.05) improved oral glucose tolerance in type 2 diabetic rats. Aegle marmelos extracts showed remarkable (p<0.05) changes in plasma insulin secretion at 30 min and 60 min, respectively. A noticeable reduction in glucose absorption was observed in the in situ perfused rat intestinal model at two different doses (250 and 500 mg/kg). The extract was also found to inhibit the action of both α-amylase and intestinal disaccharidase enzyme, and this study was affirmed again by the sucrose malabsorption test, where sucrose digestion was inhibited throughout the length of the GI tract. During this chronic study, body mass of rats became normal and their polydipsic and polyphagic conditions were ameliorated also. Conclusions: The findings demonstrate that anti-hyperglycemic activity of A. marmelos is mediated by the inhibition of carbohydrate digestion and absorption, and improvement of insulin action to uptake glucose in peripheral tissue. Additional study is required to correlate A. marmelos extracts’ specific mechanism of glucose-fiber binding capacity and glucose transporters.

Background: While some obese children are metabolically healthy (MHO), some have additional health problems, such as hypertension, dyslipidemia, insulin resistance, and hepatosteatosis, which increase mortality and morbidity related to cardiovascular diseases (CVD) during adulthood. These children are metabolically unhealthy obese (MUO) children. In this study we assessed the factors that affect metabolic health in obesity and the clinical and laboratory findings that distinguish between MHO and MUO children. Methods: In total, 1085 patients aged 6–18 years, with age- and sex-matched BMI exceeding the 95th percentile were included in the study (mean 11.1±2.9 years, 57.6% female, 59.7% pubertal). Patients without dyslipidemia, insulin resistance, hepatosteatosis, or hypertension were considered as MHO. Dyslipidemia was defined as total cholesterol level over 200 mg/dL, triglyceride over 150 mg/dL, LDL over 130 mg/dL, or HDL under 40 mg/dL. Insulin resistance was calculated using the homeostasis model of assesment for insulin resistance (HOMA-IR) index. Hepatosteatosis was evaluated with abdominal ultrasound. Duration of obesity, physical activity and nutritional habits, screen time, and parental obesity were questioned. Thyroid and liver function tests were performed. Results: Six hundred and forty-two cases (59.2%) were MUO. Older age, male sex, increased BMI-SDS, and sedentary lifestyle were associated with MUO. Excessive junk food consumption was associated with MUO particularly among the prepubertal obese patients. Conclusions: Our results revealed that the most important factors that affect metabolic health in obesity are age and BMI. Positive effects of an active lifestyle and healthy eating habits are prominent in the prepubertal period and these habits should be formed earlier in life.

Background: Adipokines have been implicated in obesity, insulin resistance and sleep regulation. However, the role of chemerin and progranulin, two recently described adipokines, in the context of sleep remains unclear. The aim of this study was to compare nocturnal serum chemerin and progranulin levels between overweight/obese and normal-weight adolescents and to assess variations by sex, across different sleep stages and in relation to glucose metabolism. Methods: The study sample included 34 overweight/obese and 32 normal-weight adolescents from secondary schools and the Leipzig Research Center for Civilization Diseases (LIFE) Child study cohort. We obtained longitudinal serum adipokine levels during in-laboratory polysomnography followed by an oral glucose tolerance test. Results: Overweight/obese adolescents had significantly higher mean nocturnal serum chemerin area under the curve (AUC) levels (348.2±133.3 vs. 241.7±67.7 vs. ng/mL×h, p<0.001) compared to normal-weight controls. In detail, higher chemerin AUC levels in obese/overweight subjects were exclusively due to increased levels in females. No overall difference for serum progranulin AUC was found between the groups. However, when assessing sex-specific levels, serum progranulin AUC levels were ~30% higher in overweight/obese males compared to overweight/obese females. Of note, nocturnal serum chemerin and progranulin AUC did not exhibit a correlation with markers of glucose metabolism or sleep stages. Conclusions: Collectively, we report a sexual dimorphism in nocturnal progranulin and chemerin levels, which may help explain underlying differences in energy balance and body composition between males and females in the context of obesity.

Background: Advanced glycation end products (AGEs) and the receptor for AGE (RAGE) play an important role in the development of diabetic vascular complications. This study aimed at investigating the relationship between the soluble form of RAGE (sRAGE), endogenous secretory RAGE (esRAGE), and pentosidine in childhood diabetes. Methods: The study included 18 children with type 1 diabetes mellitus (T1DM), 10 with type 2 DM (T2DM), and 22 age-matched, non-diabetic children (control). Results: Serum sRAGE levels in the T1DM (2557.7 pg/mL) were significantly higher than both T2DM (1956.4 pg/mL) and control (1658.5 pg/mL). The circulating levels of esRAGE in T1DM and T2DM children were similar, but significantly higher than those of control. Serum pentosidine levels in the T1DM group were positively correlated with serum sRAGE and esRAGE levels, but not with anthropometric or biochemical measurements. The duration of diabetes and esRAGE levels were independent predictors of the circulating sRAGE levels. Conclusions: Unlike adults, children with diabetes exhibit high circulating esRAGE levels, and both sRAGE and esRAGE levels are correlated with pentosidine levels. These results suggest that circulating sRAGE and esRAGE in children may be surrogate markers for progressive glucose toxicity in pediatric patients with childhood-onset diabetes.

Background: As exchange counting poses difficulty for children with type 1 diabetes (T1D) attending diabetes camps, they often guesstimate food amount without performing an exchange calculation. The aim of the study was to compare the accuracy of estimation with exchange counting using the mobile food exchange calculator (MFEC). Methods: During a summer camp, 25 children with T1D on pumps estimated the number of carbohydrate (CE) and fat/protein exchanges (FPE) appropriate for main meals. Afterwards, the number of exchanges was counted with MFEC and electronic scales. Results: There was a difference between CE (p<0.0001) and FPE (p<0.0001) estimations and counting using MFEC. The youth miscalculated the true values of ≥1 CE and ≥1 FPE by 31% and 23%, respectively. They more often underestimated than overestimated CE and FPE (p<0.0001). The estimation error increased with younger age. Conclusions: Carbohydrate counting caused significant error in the exchange number. The use of MFEC facilitates correct exchange calculation. Patients should weigh food and calculate exchanges themselves using mobile applications.

Background: This study assessed whether non-fasting lipid markers could be substituted for fasting markers in screening for dyslipidemia, whether direct measurement of non-fasting low-density lipoprotein cholesterol [LDL-C (D)] could be substituted for the calculation of fasting LDL-C [LDL-C (F)], and the utility of measuring non-high-density lipoprotein cholesterol (non-HDL-C). Methods: In 33 children, the lipid profile was measured in the non-fasting and fasting states within 24 h. Correlations were examined between non-fasting LDL-C (D) or non-HDL-C levels and fasting LDL-C (F) levels. Results: Non-fasting triglyceride (TG), total cholesterol (TC), HDL-C, LDL-C (D), and non-HDL-C levels were all significantly higher than the fasting levels, but the mean difference was within 10% (except for TG). Non-fasting LDL-C (D) and non-HDL-C levels were strongly correlated with the fasting LDL-C (F) levels. Conclusions: In conclusion, except for TG, non-fasting lipid parameters are useful when screening children for dyslipidemia. Direct measurement of non-fasting LDL-C and calculation of non-fasting non-HDL-C could replace the calculation of fasting LDL-C because of convenience.

Background: The objective of this study was to compare the analysis of 17-hydroxyprogesterone (17-OHP) by radio-immunoassay (RIA) in serum with analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) on dried blood spot samples (DBSS) for monitoring therapy in children with congenital adrenal hyperplasia (CAH), and to investigate differences in 17-OHP values during the day. Methods: Fourteen children (8 females), median age 4.2 (0.3–16.0) years, were studied. Serum samples and DBSS were drawn before hydrocortisone dosing. Results: 17-OHP by LC-MS/MS in DBSS were highly correlated to 17-OHP by RIA in serum, r=0.956, p<0.01. A total of 26 three-time-point series were investigated. Using only the afternoon 17-OHP values to determine the hydrocortisone doses would have led to overdosing seven times and underdosing six times. Conclusions: Good agreement was demonstrated between 17-OHP determination by RIA in serum and LC-MS/MS on DBSS. Multiple 17-OHP measurements per day are required to ensure sufficient hydrocortisone dose adjustment.

Background: The objective of this study was to examine the clinical and molecular features, genotype-phenotype correlation and the efficacy of different diagnostic criteria for predicting a positive molecular test in Chinese Beckwith-Wiedemann syndrome (BWS) patients. Methods: A retrospective tertiary-wide study was performed in Hong Kong with 27 molecularly confirmed BWS patients between January 2010 and September 2015. Results: It was observed that 48.1% of the BWS cases were caused by loss of methylation at differentially methylated region 2 (DMR2-LoM) of the 11p15.5 region, 11.1% by gain of methylation at differentially methylated region 1 (DMR1-GoM) of the 11p15.5 region, 33.3% by paternal uniparental disomy 11 [upd (11)pat] and 7.5% by CDKN1C mutation. Two out of 27 (7.4%) had embryonal tumors. Both belonged to the DMR1-GoM subtype with one Wilm’s tumor diagnosed at 3 months of age and the other, hepatoblastoma, diagnosed at 6 months of age. However, no genotype-phenotype correlation can be concluded by this cohort study. Finally, for different clinical diagnostic criteria, the Debaun and Tucker criteria and the Ibrahim et al. weighing score system have the best performance for predicting a positive molecular test in our Chinese BWS cohort. Conclusions: It is the largest study of molecularly confirmed BWS in the Chinese. Their clinical and epigenetic features are comparable with other ethnic populations.

Background: Monogenic diabetes is a rare disease caused by single gene mutations. Maturity onset diabetes of the young (MODY) is one of the major forms of monogenic diabetes recognised in the paediatric population. To date, 13 genes have been related to MODY development. The aim of the study was to analyse the sequence of the BCL2-associated agonist of cell death ( BAD ) gene in patients with clinical suspicion of GCK -MODY, but who were negative for glucokinase ( GCK ) gene mutations. Methods: A group of 122 diabetic patients were recruited from the “Polish Registry for Paediatric and Adolescent Diabetes – nationwide genetic screening for monogenic diabetes” project. The molecular testing was performed by Sanger sequencing. Results: A total of 10 sequence variants of the BAD gene were identified in 122 analysed diabetic patients. Conclusions: Among the analysed patients suspected of MODY, one possible pathogenic variant was identified in one patient; however, further confirmation is required for a certain identification.

The association of anosmia and congenital hypogonadotropic hypogonadism (CHH) is well described; however, congenital arhinia is a malformation associated with CHH that occurs much more rarely. There have been three reports of male patients with hypogonadism and congenital arhinia in the literature to date. We present the first case of arhinia associated with CHH in a female patient. A 14 years and 8 months female with congenital arhinia presented with delayed puberty. Physical examination and laboratory evaluation were consistent with hypogonadotropic hypogonadism. She had no other hormone deficiencies and brain magnetic resonance imaging demonstrated a normal pituitary gland. Abdominal ultrasound showed a prepubertal uterus and ovaries. She was subsequently started on sex steroid treatment to induce secondary sexual characteristics. This case demonstrates that abnormalities of nasal development may provide an early diagnostic clue to hypogonadotropic hypogonadism, particularly in female patients who would not manifest classic signs of CHH in infancy (micropenis and cryptorchidism). Early diagnosis of CHH and timely initiation of sex steroid therapy is important to prevent comorbidities related to pubertal delay.

Treatment to induce puberty in boys is indicated in those who do not undergo spontaneous development at a normal age. Stimulating development of the secondary sex characteristics is possible using gradually increasing doses of testosterone esters (TEs) via intramuscular (IM) administration, which is the most widely used method of testosterone (T) supplementation. When TEs are administered as monthly injection, serum T levels exhibit large fluctuations with supraphysiologic levels seen immediately after the injection followed by a decrease into the low range. Transdermal T (TT) has also been used for replacement therapy in adult males with hypogonadism and this provides steadier serum T levels. We report three adolescent boys with delayed puberty who were treated with TT gel for pubertal induction/continuation. This route was chosen as an alternative therapy due to their hepatic dysfunction, as is known that TT avoids the hepatic first-pass metabolism.

Background: Heterozygous loss-of-function mutations in the natriuretic peptide receptor B gene ( NPR2 ) are responsible for short stature in patients without a distinct phenotype. Some of these patients have been treated with recombinant human growth hormone (rhGH) therapy with a variable response. Case presentation: The proband was a healthy boy who presented at the age of 5.1 years with familial short stature (height SDS of −3.1). He had a prominent forehead, a depressed nasal bridge, centripetal fat distribution and a high-pitched voice resembling that of children with GH deficiency. His hormonal evaluation showed low insulin-like growth factor-1 (IGF-1) but a normal GH peak at a stimulation test. During the first year of rhGH treatment, his growth velocity increased from 3.4 to 10.4 cm/year (height SDS change of +1.1). At the last visit, he was 8.8 years old and still on treatment, his growth velocity was 6.4 cm/year and height SDS was −1.8. Results: We identified through exome sequencing a novel heterozygous loss-of-function NPR2 mutation (c.2905G>C; p.Val969Leu). Cells cotransfected with the p.Val969Leu mutant showed a significant decrease in cyclic guanosine monophosphate (cGMP) production compared to the wild type (WT), suggesting a dominant negative effect. Conclusions: This case reveals a novel heterozygous loss-of-function NPR2 mutation responsible for familial short stature and the good response of rhGH therapy in this patient.

Acromicric dysplasia (AD) and geleophysic dysplasia (GD) are rare skeletal dysplasias characterized by short stature, acromelia, joint contracture, hepatomegaly, hoarseness and respiratory distress. Compared with GD, AD presents with milder clinical and radiological features. Radiological findings of AD and GD consist of shortened tubular bones of the hands and feet, and deformed capital femoral epiphyses. The genetic cause of AD and some cases of GD was shown to be mutations in the transforming growth factor (TGF) β-binding protein-like domain 5 of the fibrillin 1 gene ( FBN1 ), which is also mutated in Marfan syndrome. In the present study, we report and compare the highly varied clinical and radiological features of three Japanese AD/GD children. Our patients, harboring FBN1 mutations p.Tyr1699Cys, p.Ser1750Arg, and p.Gly1762Ser, shared common clinical symptoms such as severe short stature, acromelia and hepatomegaly. Short tubular bones of hands and deformities of femur heads are common radiological features of our patients.