Band 33, Heft 12

Objectives Thyroid cancer is the most common pediatric endocrine neoplasm representing 3% of all malignancies in children. Hashimoto’s thyroiditis (HT) is also a common disorder in the pediatric age range. Patients with HT frequently develop enlarged thyroid with nodules. We aimed to provide a literature review on the frequency of papillary thyroid carcinoma (PTC) in patients with HT. Content A literature search of the PubMed database between 2000 and 2020 was performed, using the relevant keywords “papillary thyroid carcinoma,” “Hashimoto’s thyroiditis” and “children”. We followed the PRISMA statement guidelines during the preparation of this review. Six studies (n=2,065 patients with HT) were retained for the final analysis. The follow-up of the patients with HT was from 2 to 10 years. PTC was diagnosed in 0.67–7.87% of the HT patients included in these studies. In patients with HT and nodules, the percentage of PTC varied between 5.13 and 35%. The overall occurrence of PTC in patients with HT was 3.07%. Summary and Outlook The number of patients developing thyroid nodules in relation to HT was increased. The development of PTC in children with HT appeared to be higher than in the normal population.

Objectives Phenylalanine (Phe) hydroxylase (PAH) deficiency leads to hyperphenylalaninemia (HPA) and tyrosine (Tyr) depletion. We investigated Tyr homeostasis in patients with PAH deficiency and the effect of a slow-release amino acids therapy in phenylketonuria (PKU). Methods We performed four complementary investigations: (1) Tyr concentrations were monitored in 114 patients (10.6 ± 11.9 years) with PKU on dietary treatment supplemented with traditional amino acid formulations (n=52, 1175 samples) or non-PKU HPA on a free diet (n=62, 430 samples); (2) Tyr metabolism in PKU was quantitatively evaluated in three patients by a simple Tyr oral loading test (100 mg/kg); (3) diurnal and (4) long-term Tyr concentrations were evaluated in 5 and 13 patients with PKU, respectively, who switched from traditional to slow-release amino acids therapy. Results 1) Tyr concentrations in the PKU population were subnormal and significantly lower than in non-PKU HPA (p<0.01); (2) the response to a Tyr loading test in PKU was normal, with basal Tyr concentrations reached within 12 h; (3) the diurnal metabolic profile in patients on slow-release amino acids therapy revealed higher morning fasting and nocturnal Tyr concentrations with respect to traditional therapy (p<0.01); (4) this picture was confirmed at follow-up, with normalization of morning fasting Tyr concentrations in patients on slow-release amino acids therapy (p<0.01) and unchanged Phe control (p=0.19). Conclusions Slow-release amino acids therapy can improve Tyr homeostasis in PKU. If associated to optimized Phe control, such a metabolic goal may allow long-term clinical benefits in patients with PKU.

Objectives Treatment of children with Hashimoto thyroiditis (HT) and particularly of those with coexistent diabetes mellitus type 1 (TIDM) and normal/mildly elevated serum TSH is controversial. The aim of the study was to evaluate the natural course of HT in children with TIDM compared with children with no other coexistent autoimmunity and investigate for possible predictive factors of thyroid function deterioration. Methods Data from 96 children with HT, 32 with T1DM (23 girls, nine boys) mean (sd) age: 10.6 (2.3) years, and 64 age and sex-matched without T1DΜ (46 girls, 18 boys), mean (sd) age: 10.2 (2.9) years were evaluated retrospectively. They all had fT4 and TSH values within normal ranges and available data for at least three years’ follow-up. Results During the follow-up period, 11 children (34.4%) with TIDM exhibited subclinical hypothyroidism and two children (6.2%) progressed to overt hypothyroidism compared to 12 (18.8%) and two (3.1%) among children without TIDM, respectively. Among children with HT, a higher percentage (40.6%) of children with T1DM progressed to subclinical or overt hypothyroidism, compared with children (21.9%) with similar characteristics but without TIDM or other coexistent autoimmunity. Conclusions The annual conversion rate from euthyroidism to hypothyroidism in children with T1DM was significantly higher compared to sex and age-matched children without TIDM. Prospective randomized trials are needed to support the view of an earlier intervention therapy even in milder degrees of thyroid failure in these children.

Objectives Glycated hemoglobin (HbA1c) has proven to be indicative in the development of microvascular complications. In this study, the contribution of HbA1c variability to microvascular complications was evaluated. Methods Twenty-one cases with type 1 diabetes mellitus (T1DM) who developed microvascular complications and 39 cases without complications, that were similar in terms of gender, age of diagnosis, insulin treatment, insulin doses (U/kg), and mean HbA1c levels were included. Results Mean age of T1DM diagnosis was 5.87 ± 3.93 years in the complication group and 4.63 ± 3.33 years in the control group. Nephropathy was detected in 17 cases, neuropathy in 8 cases, and retinopathy in 1 case. Nephropathy occurred at a mean age of 11.52 ± 4.12 years and neuropathy at 14.13 ± 5.68 years. The mean HbA1c during follow-up was similar in the group with complications and the control group (8.60 ± 0.63 vs. 8.84 ± 1.32). Adjusted HbA1c-standard deviation (SD) and HbA1c-variation coefficient (CV) values were 1.30 ± 0.65 and 14.36 ± 6.23 in the group with complications (p=0.014), and 0.91 ± 0.37 and 10.59 ± 4.01 in the control group (p=0.013). In the Receiver Operating Characteristic (ROC)-analysis for microvascular complications, the limit value HbA1c-CV was 11.99 (sensitivity: 61.9%, specificity: 71.9%). This value for HbA1c-SD was 0.9699 (sensitivity: 71.43%, specificity: 66.67%) Conclusions This study has shown that long-term fluctuations in HbA1c are associated with the development of microvascular complications in type 1 diabetes.

Objectives Monogenic diabetes includes a group of heterogeneous diabetes types. We aimed to identify the frequency, clinical and molecular features of monogenic diabetes in a Korean pediatric cohort. Methods A retrospective cohort and multicenter study of Korean children suspected to have monogenic diabetes, managed by four pediatric endocrine centers in the southeast region of South Korea, from February 2016 to February 2020. We recruited 27 pediatric Korean patients suspected to have monogenic diabetes who had at least two of the following three criteria (age at diagnosis, family history, and clinical presentation). Targeted exome sequencing was conducted in these patients. The functional consequences of the variants were predicted by bioinformatics and protein structure analysis. Results Molecular genetic analysis identified 16 patients (59.3%) with monogenic diabetes. We identified a total of eight unique variants, including five novel variants ( HNF4A c.1088C>T, CEL c.1627C>T and c.1421C>T, PAX4 c.538+8G>C, INS c.71C>T). We also identified two potential candidate gene variants for monogenic diabetes, namely c.650T>C in the SLC2A2 gene and c.629G>A in the PTF1A gene. Other variants were identified in the WFS1 and NPHP3 genes in two rare genetic disorders. Variant-positive individuals had a lower presence of autoantibody positivity at the time of diagnosis and higher glycosylated hemoglobin levels at last follow-up when compared to variant-negative patients (p<0.001 and p=0.029, respectively). Conclusions These results further expand the spectrum of known variants as well as potential candidate gene variants associated with monogenic diabetes in Korea.

Objectives Copeptin, the C-terminal part of arginine-vasopressin, is increased in hypertensive adolescents and closely associated with metabolic syndrome (MS). We aimed to investigate whether serum copeptin can be used to differentiate masked hypertension (MHT) and MS, and the role of sodium intake, natriuretic peptide response and renin-angiotensin-aldosterone system in MHT and MS in obese youth. Methods Obese children aged 10–18 years with normal office blood pressure measurements were included. Patients with MHT and normotension and those with MS and non-MS were evaluated separately. Biochemical parameters, copeptin, brain natriuretic peptide (BNP), aldosterone, renin, urine sodium, and protein were evaluated. Echocardiography, fundoscopic examination, and ambulatory blood pressure monitoring were performed. Results There were 80 (M/F=39/41) obese patients with a mean age of 13.78 ± 1.93 years. The cases with MHT, MS, and concomitant MHT and MS were 53,24, and 13%, respectively. Copeptin levels were similar among patients with and without MHT or MS (p>0.05). However, multivariate analysis revealed that copeptin significantly increased the probability of MHT (OR 1.01, 95% CI=1.001–1.018, p=0.033). Copeptin was positively correlated with daytime systolic and diastolic load, aldosterone, BNP, and urine microalbumin/creatinine levels (p<0.05). Linear regression analyses revealed that copeptin was significantly correlated with BNP regardless of having MHT or MS in obese youth. In the MHT group, 24-h sodium excretion was not significantly correlated with BNP. Conclusion Copeptin may be a beneficial biomarker to discriminate MHT, but not MS in obese children and adolescents. An insufficient BNP response to sodium intake might be one of the underlying causes of MHT in obese cases.

Objectives Acanthosis nigricans is a skin symptom in obesity that helps to identify patients at high risk for dyslipidemia, hypertension, insulin resistance, and diabetes. It is the most important complication of obesity in metabolic syndrome. Studies investigating the relationship between acanthosis nigricans and metabolic syndrome in obese children are insufficient. In our study, the relationship of acanthosis nigricans and metabolic syndrome was evaluated in children. Methods Obese children aged between 6 and 18 years old, who were examined in the pediatric endocrinology outpatient clinic, were included. The patients’ anthropometric measurements and laboratory results were recorded. Modified IDF (International Diabetes Federation) criteria for children were used in metabolic syndrome classification. Results A hundred and forty-eight obese children were evaluated. The mean age of the cases was 11.91 ± 2.94 years old. Of the cases, 56.1% were female (n=83) 43.9% (n=65) were male. In 39.9% (n=59) of cases, acanthosis nigricans was determined. Acanthosis nigricans was mostly located in the axillary area (27.1%) and the neck (16.9%). In 55.9% of the cases, it was located in more than one area. The relation of regionally detected acanthosis nigricans and metabolic syndrome was not significant (p=0.291). Metabolic syndrome was detected in 14% of 136 patients according to IDF criteria. Acanthosis nigricans and metabolic syndrome combination was present in 27.7%; however, 6.7% of the metabolic syndrome patients did not have acanthosis nigricans. There was a strong relation between metabolic syndrome and the presence of acanthosis nigricans (p=0.003). Conclusions In our study, a correlation between acanthosis nigricans and metabolic syndrome was detected. Acanthosis nigricans is a skin sign that can be easily detected by clinician. It is an important and easy-to-detect dermatosis that helps determine patients at risk of metabolic syndrome in obese children.

Objectives Determine the intake and percentage of adequacy of macronutrients and their association with cardiovascular risk factors in a sample of Colombian schoolchildren. Methods Cross-sectional study nested in a prospective population-based cohort in schoolchildren between 6 and 10 years of age; cardiovascular risk markers and anthropometric measures were measured. Macronutrient intake was established through a food consumption frequency questionnaire (FFQ). The percentage of adequacy was evaluated by comparison with the dietary reference intakes (DRI) and the recommendations for energy and nutrient intake (RIEN) for the Colombian population. Linear regression analysis was performed to assess the association between daily macronutrient/energy intake and cardiometabolic risk factors. Results A total of 1,282 school children (51.09% boys and 48.91% girls; mean age 8.4 ± 1.4 years). The percentage of energy adequacy was 107% (Q1=87.5; Q3=127.2). The macronutrients in overadequacy were proteins and carbohydrates. The total fiber had a low adequacy around 26.0% (Q1=15.8; Q3=38.6). Fat intake was positively associated with BMI, insulin, and HOMA-IR index, while carbohydrate consumption was related to these same factors, although negatively in tight models. Conclusions Schoolchildren in this study had an inadequate protein, carbohydrate, and fiber intake. The results suggest a significant positive and negative relationship between the consumption of both fat and carbohydrates and cardiometabolic risk factors such as BMI, insulin levels, and HOMA-IR.

Objectives Idiopathic short stature (ISS) is a recognized, albeit a controversial indication for treatment with recombinant human growth hormone (rhGH). The objective of the present study was to conduct a systematic review of the literature and meta-analyses of selected studies about the use of rhGH in children with ISS on linear growth and adult height (AH). Methods A systematic literature search was conducted to identify relevant studies published till February 28, 2017 in the following databases: Medline (PubMed), Scopus and Cochrane Central Registry of Controlled Trials. After exclusion of duplicate studies, 3,609 studies were initially identified. Of those, 3,497 studies were excluded during the process of assessing the title and/or the abstract. The remaining 112 studies were evaluated further by assessing the full text; 21 of them fulfilled all the criteria in order to be included in the current meta-analysis. Results Children who received rhGH had significantly higher height increment at the end of the first year, an effect that persisted in the second year of treatment and achieved significantly higher AH than the control group. The difference between the two groups was equal to 5.3 cm (95% CI: 3.4–7 cm) for male and 4.7 cm (95% CI: 3.1–6.3 cm) for female patients. Conclusion In children with ISS, treatment with rhGH improves short-term linear growth and increases AH compared with control subjects. However, the final decision should be made on an individual basis, following detailed diagnostic evaluation and careful consideration of both risks and benefits of rhGH administration.

Objectives In general population, there are three phases in the human growth curve: infancy, childhood and puberty, with different main factors involved in their regulation and mathematical models to fit them. Achondroplasia children experience a fast decreasing growth during infancy and an “adolescent growth spurt”; however, there are no longitudinal studies that cover the analysis of the whole post-natal growth. Here we analyse the whole growth curve from infancy to adulthood applying the JPA-2 mathematical model. Methods Twenty-seven patients, 17 girls and 10 boys with achondroplasia, who reached adult size, were included. Height growth data was collected from birth until adulthood. Individual growth curves were estimated by fitting the JPA-2 model to each individual’s height for age data. Results Height growth velocity curves show that after a period of fast decreasing growth velocity since birth, with a mean of 9.7 cm/year at 1 year old, the growth velocity is stable in late preschool years, with a mean of 4.2 cm/year. In boys, age and peak height velocity in puberty were 13.75 years and 5.08 cm/year and reach a mean adult height of 130.52 cm. In girls, the age and peak height velocity in puberty were 11.1 years and 4.32 cm/year and reach a mean adult height of 119.2 cm. Conclusions The study of individual growth curves in achondroplasia children by the JPA-2 model shows the three periods, infancy, childhood and puberty, with a similar shape but lesser in magnitude than general population.

Objectives While the benefits of diabetes camp programs are well established, minority youth are underrepresented in camp attendance. No research to date has explored barriers to camp attendance or potential disparities in those barriers. Further, little is known about sources families prioritize in seeking diabetes information and support. Methods This was a prospective survey of families of children with type 1 diabetes (T1D) using convenience sampling during normally-scheduled clinic visits. Thirty-nine children and their caregivers completed the survey. Results were analyzed for prevalence and mean number of reported barriers, benefits, and diabetes information networks. Results Age range was 5–15 years and mean duration of diabetes was 2.9 years (0.4–9y). The most prevalent barriers were location, cost, and concern about sending children to overnight camp. Caregivers had high level of knowledge of camp benefits. Participants reported engaging with the diabetes community through interactions with their diabetes team, Facebook groups, and the JDRF. Conclusion Increasing awareness, transportation assistance, and scholarship funding all may increase accessibility of diabetes camps. Diabetes clinic and online or social media groups are both acceptable means of disseminating information about diabetes camp. Further research is indicated to verify if these results are applicable to the larger diabetes community.

Objectives Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes that is usually diagnosed in the first six months of life. Case presentation We report on a male infant with neonatal diabetes who presented with diabetic ketoacidosis at two months and 16 days. A novel homozygous missense mutation (c.259T>G) was identified in the ABCC8 gene. In this case, insulin was replaced with glimepiride at a dosage of 0.49 mg/kg/day at five months, and this achieved metabolic control and satisfactory growth as observed at follow-up. Conclusions This report improves our understanding of the mutational spectrum of ABCC8, which is normally associated with NDM, and shows that the treatment regimen for this condition can be successfully switched from insulin therapy to the use of sulfonylurea.

Objective 3-M syndrome is characterized by severe short stature, syndromic features, and characteristic radiographic findings. Growth hormone (GH) has been used with variable success. Recombinant human insulin like growth factor-1 (rhIGF-1) has never been utilized. Case presentation We describe a child with severe growth retardation, macrocephaly, and skeletal abnormalities with evidence of GH insensitivity subsequently treated with rhIGF-1. He developed morbid obesity and comorbidities including voracious appetite, acanthosis nigricans, tonsillar hypertrophy, and severe obstructive sleep apnea with minimal height improvement. Genetic testing done at 11.5 years revealed a compound heterozygous mutation (c.2112G>A(p.W704X) and c.2559delC) in the CUL 7 gene consistent with 3-M syndrome-1. rhIGF-1 therapy was discontinued. Conclusions This case highlights the novel use of rhIGF-1 therapy on a child with 3-M syndrome-1 with minimal height benefit but accelerated weight gain and serves as a reminder of the importance of re-evaluating therapy efficacy and side effect profile.

Objectives Variants in fibroblast growth factor receptor-1 ( FGFR1 ) may either cause isolated hypogonadotropic hypogonadism (IHH) or Kallmann syndrome (KS). Although the relationship of genes classically involved in IHH with combined pituitary hormone deficiency (CPHD) is well established, variants in FGFR1 have been presented as a rare cause of this phenotype recently. Case presentation Herein, we report an adopted 16-year-old male presented with delayed puberty and micropenis. He had undergone surgery for bilateral undescended testes in childhood. He was normosmic, and the pituitary imaging was normal. However, hypogonadotropic hypogonadism and growth hormone deficiency were detected, associated with a heterozygous nonsense variant (c.1864 C>T, p.R622X) in FGFR1 . Conclusions FGFR1 variants are among the causes of IHH and KS, which are inherited in an autosomal dominant manner and can be associated with midline defects. It should also be kept in mind that CPHD may be associated with FGFR1 variants in a subject with normal olfactory function.

Objectives Osteogenesis imperfecta type VI (OI VI) follows a progressive and severe course, yet unlike other forms of severe OI it has a later onset of fractures, and extra-skeletal findings are not part of the clinical picture. Another difference is that there is an increase in unmineralized osteoid tissue in OI VI, which hinders the effect of bisphosphonates-the current standard of treatment for OI. Therefore, the response to standard treatments in OI VI is not satisfactory. Herein, we report long-term follow-up of two cases with novel SERPINF1 mutations, who show great variation in their treatment response to bisphosphonates. Case presentation The first case was given pamidronate at the age of 15 months when he could sit independently, followed a fluctuating course under treatment, fracture rate did not decrease, however he was able to mobilize with walker at the age of 10 years. On the other hand, the second case developed severe deformities and became wheelchair-bound under pamidronate, thus the treatment was switched to denosumab. Unfortunately, there was no improvement under denosumab after 15 months too, and since bone pain increased, denosumab treatment was stopped. He was put on zoledronic acid instead. Conclusion SERPINF1 transcript amount may be an important factor to explain the variation in response to pamidronate therapy. In OI VI patients, the factors affecting the clinical course should be identified and new or combined treatment options should be established.