Volume 32, Issue 9

Background Fibroblast growth factor 21 (FGF21) is considered an important regulator of lipid and glucose metabolism. However, the role of FGF21 in macronutrient intake and metabolic disease, particularly in pediatric population, still needs further clarification. This study aimed to evaluate the association of rs11665896 in the FGF21 gene with metabolic status and macronutrient intake in a cohort of Mexican children with obesity. Methods Eighty-four lean children and 113 children with obesity, from 8 to 11 years of age, were recruited. FGF21 rs11665896 was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Somatometric evaluations, nutrient intake, glucose, lipids, insulin and FGF21 serum levels were measured in the obesity group. Results The T allele of rs11665896 in the FGF21 gene was associated with obesity (odds ratio [OR] = 1.99, 95% confidence interval [CI] = 1.14–3.46; p = 0.0151). Subjects with obesity carrying the TT genotype consumed less lipids and more carbohydrates compared to other genotypes. Circulating FGF21 levels correlated negatively with carbohydrate intake (r = −0.232, p = 0.022) and positively with body weight (r = 0.269, p = 0.007), waist (r = 0.242, p = 0.016) and hip girth (r = 0.204, p = 0.042). FGF21 levels were lower in carriers of at least one T allele. Conclusions Genetic variants in FGF21 could influence metabolic status, food preferences and qualitative changes in nutritional behavior in children.

Background The main objective of this study was to compare future glycemic control in children diagnosed with type 1 diabetes mellitus (T1DM) at toddler age and preschool/school age. In addition, we aimed to examine risk factors known to be associated with future glycated hemoglobin A 1c (HbA 1c) levels in children diagnosed with T1DM. Methods This is a retrospective cohort study of 85 patients diagnosed with T1DM at toddler age (group 1; 0–2.9 years; n = 36) or preschool/school age (group 2; 5–6.9 years; n = 49) who were followed up at the University Children’s Hospital in Zurich for at least 10 consecutive years or until the age of 15 years. Results The mean HbA 1c level in the first year after diagnosis had a highly predictive value about glycemic control in the following 6 years. In addition, a longer duration of T1DM was associated with higher HbA 1c values. HbA 1c values did not differ significantly within 11 years after diagnosis between children in the two age groups. Neither was a difference found when comparing the two groups in respect to their chronological age, although a trend was noted (p = 0.09). This trend is very likely due to a longer duration of diabetes in group 1. Conclusions HbA 1c level in the first year predicts glycemic control for the next 6 years and deterioration of HbA 1c values can be noted with longer duration of T1DM. Moreover, our study demonstrated similar future glycemic control in patients diagnosed with T1DM at toddler age and preschool/school age.

Objectives We aimed to evaluate children with type 1 diabetes (T1D) with early age at onset (EAO) for clinical, immune and metabolic features in order to identify age-related disease phenotypes. Methods Comparative study of two groups of T1D children: EAO (≤5 years) and later age at onset (LAO; >5 years), regarding the presence of other autoimmune (AI) diseases, diabetes ketoacidosis and immunologic profile at onset and metabolic data 1 year after diagnosis. Statistical analysis was performed with significance set for p < 0.05. Results The study included 137 children (EAO = 52, mean age 3.6 ± 1.5 [mean ± standard deviation (SD)] and LAO = 85, mean age 10.4 ± 2.9). EAO was more associated with concomitant AI diseases (p = 0.032). Despite no differences in disease onset, EAO presented with lower C-peptide levels (p = 0.01) and higher absolute lymphocyte number (p < 0.0001), with an inverse correlation between these two variables (p = 0.028). Additionally, the EAO group had a higher frequency of serum detection of three antibodies (Abs) (p = 0.0008), specifically insulin Abs (p = 0.0001). One year after diagnosis, EAO had higher total daily insulin (TDI) dose (p = 0.008), despite similar hemoglobin A 1c (HbA 1c ). Conclusions Our data show an association of EAO T1D with more AI diseases, higher number of Abs, lower initial insulin reservoir and higher insulin requirements 1 year after diagnosis. In this group, immune imbalance seems more evident and disease progression faster, probably reflecting distinct “immune environment” with different ages at disease onset. Further studies in the field of immunogenetics and immune tolerance are required, to improve patient stratification and find novel targets for therapeutic intervention.

Background Cerebral edema is a fatal complication that can occur in children with diabetic ketoacidosis (DKA). Its clinical signs are generally not explicit, and subclinical cerebral edema can occur. This study is one of the few longitudinal studies conducted to identify cerebral edema in patients with DKA by measuring the optic nerve sheath diameter (ONSD). The aim of this study was to investigate cerebral edema in children with DKA with serial measurement of ONSD, which is an early and reliable indicator of cerebral edema, and to monitor changes in ONSD during therapy. Methods The study was conducted by measuring ONSD ultrasonographically at baseline and during the course of therapy in patients with DKA. All participants were diagnosed and received therapy at our unit between May 2016 and June 2017. The study was registered with the Clinical Trials database, with a study number of NCT02937441. Measurements were obtained while the patients were in the supine position with their eyes closed, and axial transbulbar images of both eyes were obtained with a 6–15-MHz linear probe. Results The ONSD values of children with DKA changed during the treatment, reaching the highest values at 12–16 h of therapy, and the greatest ONSD was observed in children who had moderate and severe DKA. Conclusions During treatment of children with DKA, it is possible to predict cerebral edema by measuring ONSD, and this may contribute to clinical management, especially fluid treatment.

Background Childhood obesity is a serious health condition with increasing rates worldwide. The aim of this study was to investigate the association between inflammation, oxidative stress, vitamin D, copper and zinc in pre-obese and obese children compared to controls. Methods The study involved 202 children aged 7–15 years (63.9% boys), randomly chosen from 10 elementary schools in Podgorica, Montenegro. Participants were divided into three groups according to their nutritional status (International Obesity Task Force [IOTF] criteria): normal-weight (42.1%), pre-obese (40.6%) and obese (17.3%). Serum biochemical analyses were performed (C-reactive protein [CRP], retinol-binding protein [RBP], total antioxidant status [TAS], total vitamin D [VD], copper and zinc). Results Serum TAS and CRP concentrations were higher in pre-obese and obese children compared to controls (p < 0.001). Serum VD concentrations were lower in pre-obese and obese children compared to their normal-weight peers (p = 0.027 and p = 0.054, respectively). Copper, zinc and RBP concentrations did not differ significantly among the groups (p > 0.05). In pre-obese and obese children, a positive correlation was found between CRP and copper (r = 0.305, p = 0.011 and r = 0.440, p = 0.013, respectively), and TAS and RBP (r = 0.528, p < 0.001 and r = 0.434, p = 0.015, respectively). Standard regression analyses showed that CRP and TAS increase (p < 0.001) whereas VD decreases (p = 0.011) with the body mass index (BMI). Conclusions We show that pre-obesity and obesity in childhood are positively associated with oxidative stress and inflammation, and inversely associated with VD status. Copper and zinc concentrations were not associated with excess fat in children.

Background Type I pseudohypoaldosteronism (PHA1) is a rare condition characterised by profound salt wasting, hyperkalaemia and metabolic acidosis due to renal tubular resistance to aldosterone (PHA1a) or defective sodium epithelial channels (PHA1b or systemic PHA). Our aim was to review the clinical presentation related to the genotype in patients with PHA1. Methods A questionnaire-based cross-sectional survey was undertaken through the British Society of Paediatric Endocrinology and Diabetes (BSPED) examining the clinical presentation and management of patients with genetically confirmed PHA1. We also reviewed previously reported patients where genotypic and phenotypic information were reported. Results Genetic confirmation was made in 12 patients with PHA1; four had PHA1a, including one novel mutation in NR3C2 ; eight had PHA1b, including three with novel mutations in SCNN1A and one novel mutation in SCNN1B. It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile. Patients presenting with missense mutations of SCNN1A and SCNN1B had a less marked rise in serum aldosterone suggesting preservation in sodium epithelial channel function. Conclusions We advocate early genetic testing in patients with presumed PHA1, given the challenges in differentiating between patients with PHA1a and PHA1b. Clinical course differs between patients with NR3C2 and SCNN1A mutations with a poorer prognosis in those with multisystem PHA. There were no obvious genotype-phenotype correlations between mutations on the same gene in our cohort and others, although a lower serum aldosterone may suggest a missense mutation in SCNN1 in patients with PHA1b.

Background Prolactin-secreting pituitary adenomas in childhood and adolescence are rare. First-line therapy consists of dopamine agonists (DAs) like cabergoline. Experience in treating prolactinomas in paediatric and adolescent patients is limited. Methods This study was a retrospective analysis of clinical data, laboratory data, radiological findings and medical treatment of paediatric and adolescent patients with prolactinomas between 2009 and 2018. Results Our cohort of nine patients had a median age at diagnosis of 13 years (range 5–17). Main presenting symptoms were weight gain, disorders of the pituitary-gonadal axis and headache. Treatment with cabergoline resulted in a marked reduction in prolactin concentration in all nine patients. Tumour mass reduction was confirmed by magnetic resonance imaging (MRI) scan in seven patients. Noteworthy is that cabergoline therapy triggered frequent adverse effects in a total of eight patients – seven of whom suffered from mental disorders, five of whom had neurological symptoms and five of whom had gastrointestinal problems. The adverse effects occurred at a median dose of only 0.5 mg/week (range 0.25–2.0). Most symptoms were alleviated after the cabergoline dose was lowered. Therapy discontinuation was not necessary in any patient. Conclusions Cabergoline effectively lowers prolactin levels and may reduce tumour mass in paediatric and adolescent patients with prolactinomas. Potential adverse effects may include mental disorders and behavioural problems even at low cabergoline doses. Low starting doses and careful individual dose adjustments are required to enable therapy adherence.

Background Primary ovarian insufficiency (POI) can be seen in adolescents secondary to genetic or autoimmune conditions, or gonadotoxic therapies. Often times, its underlying cause is not identified. It is a rare condition in pediatrics, but a thorough evaluation is required for a timely diagnosis and optimizing outcomes. Objectives We aim to describe the clinical phenotype of idiopathic POI in an adolescent population seen in a referral center, and evaluate its diagnostic approach. Methods All patients evaluated between 2012 and 2018 were identified using the diagnostic codes for POI. Medical records were manually reviewed and clinical information was extracted. Cases were excluded from the final sample if they were found to have incomplete diagnostic information, Turner syndrome, eating disorders, gonadal surgeries and/or a history of oncological conditions or treatments. Results Forty-eight patients with POI were identified, and only seven met the established criteria. Anti-ovarian and anti-thyroid antibodies were evaluated in 100% and 86%, respectively, while only 29% were tested for anti-adrenal autoimmunity. The karyotype was obtained consistently, while the fragile X mental retardation 1 ( FMR1 ) gene expansion was only assessed in approximately a third of the patients. Finally, only 29% of patients received reproductive counseling or referral to a fertility specialist. Conclusions Diagnostic evaluation for POI appears to be challenging to pediatric providers. Anti-ovarian antibodies are frequently obtained despite the lack of their clinical significance in POI, while anti-adrenal antibodies, which are the preferred diagnostic test, are not commonly obtained. Reproductive orientation or referral is seldom provided to the adolescent population.

Background Insulin-like 3 hormone (INSL3) is involved in the process of testicular descent, and has been thoroughly studied in cryptorchidism. However, INSL3 allelic variations found in the human genome were heterozygous and only a few of them were found exclusively in patients with cryptorchidism. Under this perspective, we aimed to study the presence of INSL3 allelic variations in a cohort of patients with cryptorchidism and to estimate their potential consequences. Methods Blood samples were collected from 46 male patients with non-syndromic cryptorchidism and from 43 age-matched controls. DNA extraction and polymerase chain reaction (PCR) were performed for exons 1 and 2 of the INSL3 gene in all subjects. Sequencing analysis was carried out on the PCR products. All data were grouped according to testicular location. Results Seven variations of a single nucleotide (SNVs) were identified both in patients with cryptorchidism and in controls: rs2286663 (c.27G > A), rs1047233 (c.126A > G) and rs6523 (c.178A > G) at exon 1, rs74531687 (c.191-30C > T) at the intron, rs121912556 (c.305G > A) at exon 2 and rs17750642 (c.*101C > A) and rs1003887 (c.*263G > A) at the untranslated region (UTR). The allelic variants rs74531687 and rs121912556 were found for the first time in the Greek population. The novel homozygotic combination of the three allelic variants rs1047233-rs6523-rs1003887 seemed to present a stronger correlation with more severe forms of cryptorchidism. Conclusions The combination of specific INSL3 SNVs rather than the existence of each one of them alone may offer a new insight into the involvement of allelic variants in phenotypic variability and severity.

Background This study aimed to evaluate the imaging findings of patients who underwent an abdominal and pelvic magnetic resonance imaging (MRI) due to primary amenorrhea. Methods The pelvic and abdominal images of 34 female patients (mean age 15.61 years, range 14–19 years) were retrospectively analyzed by a single radiologist blinded to the clinical and laboratory data of the patients (other than primary amenorrhea) to evaluate the etiology of primary amenorrhea. The anatomy and anomalies of the internal genital organs and other accompanying abdominopelvic anomalies were investigated. Results Gonadal dysgenesis was present in 14 patients (41.17%) and Müllerian duct anomalies (MDAs) were present in 20 (58.83%) (Mayer-Rokitansky-Kuster-Hauser [MRKH] syndrome in 13 [65%], distal vaginal obstruction [DVO] findings in five [25%], and obstructed hemivagina and ipsilateral renal anomaly [OHVIRA] syndrome in two [10%]). Seven patients with MRKH (53.84%) were of type 1 and six (46.15%) were of type 2. A total of eight additional anomalies (vertebral and renal) were detected, six in MRKH and two in OHVIRA syndrome cases. Endometrioma and hematosalpinx were observed in one of the five patients with DVO (5%). Conclusions Primary amenorrhea is a common symptom that affects both the physical and psychosocial status of individuals. Determination of the underlying etiology is the first step in planning treatment. The evaluation of internal genital organ anomalies involved in the etiology is important for sexual function and fertility. MRI is a non-invasive imaging modality that should be preferred in these cases as it provides detailed data about the anatomy and anomalies of internal genital organs due to its high soft tissue contrast resolution.

Background The aim of this study was to investigate the effect of 12 weeks of aerobic training, 4 weeks of detraining and use gonadotropin-releasing hormone agonist (GnRHa) on serum C-reactive protein (CRP) and cortisol levels in girls with central precocious puberty (CPP). Methods Forty-five girls (aged 6–8 years) with precocious puberty were randomly divided into three groups (medication, training and medicine + training groups). Fifteen healthy girls (without precocious puberty) were also included as the control group. Serum CRP and cortisol levels were measured at baseline by the enzyme-linked immunosorbent assay (ELISA) technique. Then, the experimental groups performed an aerobic training program for 3 days/week 20–75 min per day at 45–75% maximum heart rate for 12 weeks. The medication groups also received GnRHa during the study, once a month (1 mL every 4 weeks) by intramuscular injection. Serum CRP and cortisol levels were measured again 48 h after the last training session and also after 4 weeks of detraining. Results Analysis of variance (ANOVA) with repeated measures showed a significant decrease in CRP (p = 0.02) and cortisol levels (p = 0.01) in the training group and the medicine + training group. Detraining led to return of CRP and cortisol levels to the pre-training levels (p = 0.001). No significant difference in serum CRP (p = 0.43) and cortisol levels (p = 0.06) was observed in the medication group. Further, no significant difference was observed between groups in CRP and cortisol. Conclusions Long-term regular moderate training decreases inflammation indices, and detraining eliminates the benefits of training in girls with precocious puberty.

Background/objective The olfactory bulb (OB) and pubertal development have a close relationship as they share a common ontogenetic origin. The aim of this study was to analyze the potential relationship between precocious puberty (PP) in girls as a sign of early pubertal timing and their OB volume as an indicator of its functional activity. Design In the study group (n = 125), OB volume, pituitary height (PH), body mass index (BMI) and body surface (S) variables were retrospectively investigated in 49 girls included in the PP group and 76 healthy girls constituting the control group. Volumetric and length measurements were performed on a magnetic resonance imaging (MRI) scan by using manual segmentation of slices. Results The mean OB volume (73.41 ± 17.21 mm 3 ) and PH (4.96 ± 1.01 mm) were significantly higher in the PP group (p = 0.001 and p = 0.001, respectively). The mean volume difference between the right and left bulbs (1.52 ± 1.87) was higher in the PP group (p = 0.03). The body surface (1.05 ± 0.16 m 2 ) was larger in the PP group (p = 0.09). There was a high correlation between the OB volume and PH (r 125  = 0.716). There was a moderate correlation between the body surface and OB volume (r 125  = 654), and a weak correlation between the former (S) and the PH (r 125  = 452). Conclusions This study showed that there is a strong correlation between increased OB volume and PH in cases with PP. It indicates that increased OB volume may be a strong clue that olfactory functions play a role in pubertal timing in humans, although it does not show definitive proof of a causal relationship.

Parenteral options for treating neonatal hypoglycemia (NH) include: intramuscular (i.m.) glucagon or intravenous (i.v.) glucose 10%. So far, the role of i.m. glucagon in treating NH has not been adequately assessed. We retrospectively studied 236 neonates with NH. One hundred and twenty-one infants received oral glucose-fortified-milk-based formula (OGFM) and their blood glucose level (BGL) was maintained thereafter. Two groups of infants required intervention: (a) OGFM + i.m. glucagon (n = 77, 32.6%) and (b) OGFM + i.v. glucose bolus (n = 38, 16.1%). BGL1, BGL2 and BGL3 denote pre-treatment BGL, 2–2.5 h post-treatment and BGL within 2.5–4 h post-treatment; respectively. The two groups were compared regarding two outcome measures: Outcome no. 1: BGL2 ≥ 45 mg/dL and outcome no. 2: BGL3 ≥ 45 mg/dL. Compared to i.v. glucose, the i.m. glucagon group had significantly more infants with BGL2 ≥ 45 mg/dL (40% vs. 76%, p = 0.028), and marginal significant difference regarding BGL3 ≥ 45 mg/dL (62% vs. 77%, p = 0.08). Univariate analysis showed that i.m. glucagon, male gender, vacuum extraction, cesarean delivery and one or more NH risk factors were significantly associated with outcome measure no. 1. I.m. glucagon, small for gestational age status, cesarean delivery, BGL1 and NH risk factors were associated with outcome measure no. 2. Multi-variate analysis showed that i.m. glucagon was significantly and independently associated with BGL2 ≥ 45 mg/dL. I.m. glucagon is worth consideration as a treatment option for NH.

GATA6 gene variants come along with possible features such as pancreas agenesis/hypoplasia, neonatal diabetes and congenital heart defect. Congenital hypothyroidism, and hepatobiliary and gut abnormalities are also detectable. Children with congenital heart defects and neonatal diabetes were already described in 1970. GATA6 variants can be due to de novo variants or due to inherited variants. To date, 11 cases due to an inherited variant have been described. Herein we present a novel heterozygous GATA6 variant (c.1291C > T p.[Gln431*]) in a boy with transient neonatal diabetes, diaphragmatic hernia, congenital heart defect and early-onset scoliosis. The same variant was also present in the mother. At the age of 3 years, a random evaluation revealed a hemoglobin A 1c (HbA 1c ) level of 7.8% (62 mmol/mol) without any diabetes-related symptoms. He was started on insulin therapy and HbA 1c normalized. A short review of the literature of hereditary cases of the GATA6 variant revealed the variable phenotypic spectrum and showed that patients with a mild phenotype are likely to have children with a more severe phenotype.

Nephrogenic diabetes insipidus (NDI) is a rare inherited disorder most often caused by mutations in the arginine-vasopressin receptors or aquaporin channels, which subsequently impairs the water reabsorption in the kidney. This case report describes a 15-year-old female diagnosed with NDI after an acute gastroenteritis and multiple fluid boluses leading to intractable emesis. Gene testing reveals our patient is compound heterozygous for novel AQP2 gene mutations with a cytosine-to-thymine substitution at nucleotide position 277 and adenine-to-cytosine substitution at nucleotide position 659. Therefore, we report a novel AQP2 gene mutation in an adolescent patient which is outside the common age for diagnosis.

Background Stroke and other neurologic complications are rare in pediatric type 1 diabetes mellitus (T1DM) without severe diabetic ketoacidosis (DKA) or poor glycemic control. Case presentation A previously healthy, 10-year-old female presented with acute thalamic stroke, non-acidotic new T1DM diagnosis and negative hypercoagulopathy workup. She received routine insulin therapy and aspirin, and returned to neurologic baseline within a year without stroke recurrence. Conclusions The contribution of non-acidotic hyperglycemia to stroke risk is better described in adults. Even though unable to prove causality, this case should at least raise awareness of the possible association of pediatric new-onset diabetes and stroke for optimal outcomes.

Background Neurosarcoidosis is not a common entity from an endocrinology standpoint. Prompt diagnosis is essential in order to determine appropriate treatment and to establish prognosis. Case presentation Our case illustrates the difficulties encountered in making a diagnosis of sarcoidosis in an adolescent who presented with polyuria, polydipsia and hypernatremia. She developed panhypopituitarism and her deficits did not improve after treatment. Conclusion Pediatric endocrinologists diagnose and treat panhypopituitarism associated with many conditions. Neurosarcoidosis should be considered as part of the diagnosis in patients with panhypopituitarism, especially if there is evidence of multi organ disease. Case reports can effectively address the gap in knowledge due to the limited exposure of physicians to this field, especially in children.