Band 34, Heft 9

Objectives Metabolic syndrome (MetS) is systemic metabolic disease that results from insulin resistance or obesity. Numerous meta-analyses have investigated the effect of exercise on different populations, but none were aimed at the effect of aerobic exercise alone on obese children. This review systematically assessed and performed a meta-analysis on the effect of aerobic exercise on obese children with MetS. Content MEDLINE via PubMed, Embase, SPORTDiscus, and the Cochrane library were searched and screened from inception to 20 October 2020 for randomized controlled trials. The inclusion criteria were obese children who met the criteria for MetS and aged 5–19 years old in an aerobic exercise group. The meta-analysis included eight trials with a total of 197 participants. Aerobic exercise significantly improved the waist circumference (mean difference [MD]=−3.97; 95% confidence interval [CI]=−6.12 to −1.83; p<0.01), body mass index (standardized MD [SMD]=−0.5; 95% CI=−0.70 to −0.29; p<0.01), triglyceride (SMD=−24.6; 95% CI=−33.85 to −15.35; p<0.01), high-density lipoprotein cholesterol (SMD=2.36; 95% CI=0.44 to 4.27; p<0.01), and systolic blood pressure (SMD=−6.90; 95% CI=−10.46 to −3.35; p<0.01). Summary Based on the results of this meta-analysis, during the intervention period of the included studies, aerobic exercise alone mainly affected the lipoprotein, blood pressure, and body dimensions but cannot completely cure the MetS of obese children. Outlook The effects of different types of aerobic exercise on obese children with MetS and exercise dose to cure the MetS of obese children needs to be further studied.

Objectives Non-alcoholic fatty liver disease (NAFLD) is a common obesity-related comorbidity in childhood. In this study, we aimed to evaluate predictors of NAFLD by comparing clinical, endocrine and metabolic findings in obese children with and without hepatosteatosis. Methods Two hundred and eight obese children aged 6–18 years were included. The patients were divided into group 1 (patients with NAFLD, n=94) and group 2 (patients without NAFLD, n=114). Anthropometric measurements, pubertal stage, lipid profiles, fasting glucose and insulin, homeostatic model of assessment for insulin resistance (HOMA-IR), uric acid, total bilirubin, alanine aminotransferase (ALT), blood urea nitrogen, thyroid-stimulating hormone and free thyroxine parameters were compared retrospectively. Results The mean body weight, body mass index (BMI), height, tri-ponderal mass index (TMI), insulin, HOMA-IR, triglyceride, ALT and uric acid values were significantly higher, while high-density lipoprotein-cholesterol (HDL-C) values were significantly lower in group 1. The 70.7% of obese children with hepatosteatosis and 83.9% of those without hepatosteatosis were correctly estimated by parameters including age, gender, ALT, HDL-C, fasting insulin and uric acid values. Conclusions Since obesity-associated hepatosteatosis induces various long-term metabolic impacts in children, early detection is of critical importance. Age, gender, TMI, BMI, ALT, HDL-C, fasting insulin and uric acid values may help to predict the risk of hepatosteatosis. Besides, we assessed whether TMI compared to BMI does not have a better utility in estimating obesity-induced hepatosteatosis in children. This is the first study to show the association between TMI and hepatosteatosis in children.

Objectives Our study aims to assess the impact of lockdown during the coronavirus disease 2019 pandemic on glycemic control and psychological well-being in youths with type 1 diabetes. Methods We compared glycemic metrics during lockdown with the same period of 2019. The psychological impact was evaluated with the Test of Anxiety and Depression. Results We analyzed metrics of 117 adolescents (87% on Multiple Daily Injections and 100% were flash glucose monitoring/continuous glucose monitoring users). During the lockdown, we observed an increase of the percentage of time in range (TIR) (p<0.001), with a significant reduction of time in moderate (p=0.002), and severe hypoglycemia (p=0.001), as well as the percentage of time in hyperglycemia (p<0.001). Glucose variability did not differ (p=0.863). The glucose management indicator was lower (p=0.001). 7% of youths reached the threshold-score (≥115) for anxiety and 16% for depression. A higher score was associated with lower TIR [p=0.028, p=0.012]. Conclusions Glycemic control improved during the first lockdown period with respect to the previous year. Symptoms of depression and anxiety were associated with worse glycemic control; future researches are necessary to establish if this improvement is transient and if psychological difficulties will increase during the prolonged pandemic situation.

Objectives To review the data of infants and children with suspected monogenic diabetes who underwent genetic testing. Methods Monogenic diabetes is a rare form of diabetes resulting from mutations in a single gene. It can be caused by dominant as well as recessive modes of inheritance. In a country like Pakistan where interfamily marriages are common the incidence of genetic disorders is increased. As Pakistan a resource-poor country, the diagnosis of insulin-dependent diabetes is often delayed and a genetic diagnosis of monogenic diabetes is extremely difficult. Children with clinical diagnosis of monogenic and syndromic diabates were recruited and blood samples were sent for genetic analysis. Results One thousand sixty four new cases diagnosed with type 1 diabetes were registered at the National Institute of Child Health, Karachi, in the last 10 years. Of these 39 patients were selected for genetic testing who were diagnosed with diabetes/had a sibling diagnosed with diabetes before the age of nine months (n = 27) or had extra pancreatic features ( n= 12). We identified mutations in 18/27 cases diagnosed with diabetes before nine months of age. The most common genetic subtype was WolcottRallison syndrome caused by EIF2AK3 mutations (seven cases). KCNJ11 mutations were identified in two cases, ABCC8 mutations were identified in four cases from three families, GCK and INS mutations were each identified in two cases, and one SLC2A2 mutation was identified in one case. A genetic diagnosis was made in 12/12 children from six families with diabetes diagnosed after the age of nine months who had extrapancreatic features. Six patients had genetically confirmed Wolfram syndrome ( WFS1 ), three had thiamine-responsive megaloblastic anemia ( SLC19A2 ) and three were diagnosed with histocytosis lymphadenopathy plus syndrome ( SLC29A3 ). Conclusions Genetic testing is essential to confirm a diagnosis of monogenic diabetes which guides clinical management and future counselling. Our study highlights the importance of diagnosing monogenic diabetes in the largely consanguineously-married population of Pakistan.

Background Craniosynostosis is an underdiagnosed complication associated with hypophosphatemic rickets. The study aims to describe the clinical and auxological characteristic of children with hypophosphatemic rickets and craniosynostosis, describe the usual treatment, and compare the characteristics with those of children without craniosynostosis. Methods and patients An observational and retrospective cohort study was conducted. Clinical notes and cranial images were reviewed. Out of 96 children, only the 50 patients who had skull images were included. Results Out of 50 patients, 26 (15 males) had craniosynostosis (52%). No differences were observed in birth size, age, height, body proportions, alkaline phosphatase, serum phosphate, or percent tubular reabsorption of phosphate at first appointment among children with or without craniosynostosis. Among patients with craniosynostosis, dolichocephaly was prevalent. The sagittal suture was affected in all patients with craniosynostosis, with 19 of 26 children (73%) affected with isolated scaphocephaly. Pan-sutural craniosynostosis was present in 7 children (27%). None of the children had microcephaly, 7 of them presented macrocephaly and, in the remaining subjects, head circumference was normal. Five patients had undergone at least 1 cranial remodeling surgery. One patient with craniosynostosis was diagnosed with a Chiari I malformation. Molecular characterization of PHEX gene was performed in 14 cases. Conclusions Craniosynostosis is an underdiagnosed complication of hypophosphatemic rickets. Many patients with normal head size and growth may go undiagnosed, thus it is important to consider this association for early diagnosis and possible surgical treatment. A multidisciplinary approach is necessary for a correct long-term follow-up.

Objectives Acromesomelic dysplasia, type Maroteaux, is an autosomal recessive skeletal dysplasia caused by biallelic loss of function variations of NPR2 , which encodes a cartilage regulator C-type natriuretic peptide receptor B. NPR2 variations impair skeletal growth. It is a rare type of dwarfism characterized by shortening of the middle and distal segments of the limbs with spondylar dysplasia. Methods We performed detailed clinical and radiological evaluation and sequence analysis for NPR2 . Results Herein, we report nine patients from eight families with two novel NPR2 pathogenic variants. Conclusions This study describes typical clinical phenotypes of Maroteaux type acromesomelic dysplasia, and enriches the variant spectrum of NPR2 by reporting one nonsense and one missense novel variant. We emphasize the importance of detailed clinical evaluation before genetic testing in diagnosing rare skeletal disorders.

Background The aim of this study was to describe the incidence and spectrum of early clinical presentations of congenital adrenal hyperplasia (CAH) in an unscreened population. Methods A national retrospective observational study was undertaken to identify all children diagnosed with CAH in the Republic of Ireland, between January 2005 and December 2019. Reporting clinicians completed anonymized clinical questionnaires. Results There were 103 cases of CAH reported and 69 cases met the study inclusion criteria. The estimated annualized incidence of CAH in the Republic of Ireland was 1:14,754 or 0.07 cases per 1,000 live births. Forty-seven children presented clinically in the first six months of life, but only 17 of these had a confirmed diagnosis by day 10. Of these early presentations, there were 28 infants with salt-wasting, 15 females presented with virilized genitalia and four infants were detected due to a family history of CAH. Female infants presented at a median age of 0 days [IQR 0–1] and males at 14 days [IQR 9–21]. Seventy-eight percent of salt-wasting presentations occurred after day 10. Delays in clinical presentation, biochemical diagnosis and treatment initiation were identified. Conclusions The incidence of CAH is higher in Ireland than in other unscreened populations. In the absence of screening, clinicians should be aware of the possibility of CAH and appropriate investigations should be urgently requested. Life-threatening salt-wasting is the most frequent clinical presentation and many cases could be detected prior to decompensation if newborn screening were introduced.

Objectives Although new-born screening (NBS) for classical congenital adrenal hyperplasia (C-CAH) has been available for decades, it is not widely implemented. We assessed the usefulness of introducing NBS for C-CAH, by analyzing presenting status of infants with C-CAH, over the past two decades, in Sri Lanka. Methods This retrospective clinic-based study, from the largest tertiary children’s hospital in Sri Lanka, analyzed initial presenting features of children with C-CAH from 1999 to 2018, in the absence of NBS for CAH, and included gender-based comparisons. Results Features suggestive of impending adrenal-crisis were seen at initial presentation in >80 % (dehydration 70%, hyponatremia 65%, hyperkalemia 47%, vomiting 45%, hypoglycemia 22%, collapse 20%). Hyperpigmentation was seen in 78%, and consanguinity in 27%. There were fewer affected males (n = 12) compared to females (n = 28). Most girls (96%) had virilized genitalia, and 16 faced uncertainty about gender at birth. Median age at diagnosis was 20 days. More than 70% of children had SW-CAH (males = 9 and females = 20). There were fewer males with SW-CAH, and all had features of impending adrenal crisis, including severe hyponatremia in 50%, while 62% of girls also developed hyponatremia and 33% had hyperkalemia, prior to treatment. Treatment of SW-CAH was initiated at a median age of 30 days in boys, and 10 days of age in girls. Conclusion Many boys and girls with C-CAH from Sri Lanka presented late with impending adrenal crisis. Males were diagnosed later, and some possibly succumbed to C-CAH undiagnosed. These findings support including CAH in NBS programs to avert preventable childhood morbidity and mortality.

Objectives An increase in the incidence of congenital hypothyroidism (CH) with eutopic gland has been reported worldwide due to neonatal screening programs. In this study, we aimed to determine the prevalence of transient CH (TCH) and to investigate predictive factors that could distinguish between permanent and transient CH in patients with eutopic thyroid glands. Methods We retrospectively reviewed 508 children treated for CH with eutopic thyroid glands between June 1998 and June 2020 in Jiangxi Newborn Screening Center. All patients were treated with levothyroxine and underwent Diagnostic re-evaluation after 2–3 years of age. Patients were classified as having TCH or permanent CH (PCH) during follow-up. Results Of the 508 patients initially treated for CH with a normally located gland, 335 patients (65.9%) were classified in the TCH group and 173 (34.1%) in the PCH group based on the defined criteria. Multivariate analysis revealed that TCH was associated with a lower levothyroxine dose at 24 months of age (p<0.001) and a lower likelihood of having a first-degree family history of CH (p=0.026) than PCH. Gender, prematurity, low birth weight, initial CH severity such as serum TSH and FT4 levels, or bone maturation delay at diagnosis had no effect. Receiver operating characteristics curve analysis showed that a cutoff of 2.3 μg/kg/day for levothyroxine dose requirement at 24 months of age had a sensitivity of 71% and a specificity of 70% for predicting transient CH, with values below this threshold considered predictive of transient CH. Conclusions TCH presents a significant portion of patients with CH. The levothyroxine dose requirement at 24 months of age has a predictive role in differentiating TCH from PCH in CH patients with eutopic thyroid glands.

Objectives To report two novel mutations in the BCKDHB gene with Maple syrup urine disease (MSUD) and compare their data with 52 cases of MSUD reported in the available Chinese literature. Methods Clinical data of a case of a newborn with MSUD was retrospectively studied. Literatures on MSUD in the local medical journals from January 1990 till December 2019 in China were reviewed. Results Two novel BCKDHB mutations c.90_91insCTGGCGCGGGG (p.Phe35TrpfsTer41) and c.80_90del (p.Ala32PhefsTer48) were identified. We found a total of 52 cases of MSUD reports so far. A total of 49 cases had the symptom of poor feeding (94.2%), 50 cases showed poor responses to stimulation (96.2%), 21 cases had odor of maple syrup (40.3%), 29 cases had seizures (55.7%), and 13 cases had respiratory failure (25.0%). The average of the blood ammonia was 127.2 ± 75.0 μmol/L. A total of 18 cases reported the gene testing, among of them 9 cases of BCKDHA mutations, 6 cases of BCKDHB mutations, and 2 cases of DBT mutations. A total of 13 cases (25%) were treated with mechanical ventilation, 50 cases (96.2%) with protein-restricted diet and l -carnitine, 29 cases with thiamine, and only 2 cases were treated with blood purification. Finally, 19 patients (36.5%) were died, 21 cases (40.4%) were improved after treatments. Conclusions The clinical phenotype of neonatal MSUD in China belongs to the classical type currently. Suspected patients should have blood or urine branched-chain amino acid levels tested and brain MRI as early as possible to enable early diagnosis, thus improvement in prognosis.

Objectives This study aimed to evaluate the biochemical factors, genetic mutations, outcome of treatment, and clinical follow-up data of Iranian patients with tetrahydrobiopterin (BH4) deficiency from April/2016 to March/2020. Methods Forty-seven BH4 deficiency patients were included in the study and underwent biochemical and genetic analyses. The clinical outcomes of the patients were evaluated after long-term treatment. Results Out of the 47 (25 females and 22 males) BH4 deficiency patients enrolled in the study, 23 were Dihydropteridine reductase (DHPR) deficient patients, 23 were 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficient patients, and one was GTP-Cyclohydrolase 1 deficiency (GTPCH-1) patient. No clinical symptoms were observed in 10 of the DHPR deficient patients (before and after the treatment). Also, most patients diagnosed at an early age had a proper response to the treatment. However, drug therapy did not improve clinical symptoms in three of the patients diagnosed at the age of over 10 years. Also, 16 PTPS deficiency patients who were detected within 6 months and received treatment no clinical symptoms were presented. One of the patients was detected with GTPCH deficiency. Despite being treated with BH4, this patient suffered from a seizure, movement disorder, mental retardation, speech difficulty, and hypotonia. Conclusions The study results showed that neonatal screening should be carried out in all patients with hyperphenylalaninemia because early diagnosis and treatment can reduce symptoms and prevent neurological impairments. Although the BH4 deficiency outcomes are highly variable, early diagnosis and treatment in the first months of life are crucial for good outcomes.

Objectives X-linked adrenoleukodystrophy (X-ALD), is a peroxisomal inborn error of metabolism caused due to the loss of function variants of ABCD1 gene that leads to accumulation of very long chain fatty acids (VLCFAs) in several tissues including the neurological system. Childhood cerebral X-ALD (CCALD) is the most common and severe form of X-ALD, if left untreated. Allogenic hematopoietic stem cell transplantation (HSCT) is the only available therapy that halts neurological deterioration in CCALD. We present 12 patients with several subtypes of X-ALD that were followed-up in a single center. Methods Data of 12 patients diagnosed with X-ALD were documented retrospectively. Demographics, age of onset, initial symptoms, endocrine and neurological findings, VLCFA levels, neuroimaging data, molecular genetic analysis of ABCD1 gene, and disease progress were documented. Results Mean age of initiation of symptoms was 7.9 years and mean age of diagnosis was 10.45 years. Eight patients had the CCALD subtype, while two had the cerebral form of AMN, one had the adult form of cerebral ALD, and one patient had the Addison only phenotype. The most common initial symptoms involved the neurological system. Loes scores varied between 0 and 12. Seven patients with CCALD underwent HSCT, among them three patients died. The overall mortality rate was 25%. Conclusions Patients with X-ALD should be carefully followed up for cerebral findings and progression, since there is no genotype–phenotype correlation, and the clinical course cannot be predicted by family history. HSCT is the only available treatment option for patients with neurological deterioration.

Objectives Previous reports indicate that growth hormone (GH) treatment for Prader–Willi syndrome (PWS) improves bone mineral density (BMD) only when initiated at a young age and not when initiated in adulthood. However, there are no data on BMD during long-term GH treatment of Japanese children and adolescents with PWS. Thus, this study aimed to investigate BMD changes among patients with PWS, who were undergoing GH treatment from childhood to adolescence. Methods Sixty-seven pediatric patients with PWS who had GH treatment initiated during childhood between January 2003 and June 2020 were evaluated. To avoid underestimation, we used total body BMD, which was evaluated using dual-X-ray absorptiometry adjusted for the BMD z-score using patient height, sex, and age. Results In both sexes, age was negatively correlated with the BMD-standard deviation score (SDS) (male: r =−0.156 [p=0.042]; female: r =−0.197 [p=0.043]), which started to decrease in childhood. Conclusions The BMD-SDS of patients with PWS decreases gradually despite GH treatment. As there are no clear recommendations about monitoring of bone health in patients with PWS, further studies are needed to improve the guidelines for screening of BMD and treatment of patients with PWS.

Objectives Congenital disorders of glycosylation (CDGs) are rare inherited metabolic disorders associated with facial dysmorphism and in the majority of the patients, there is an important neurological impairment. Epilepsy was a main concern in rare forms of the disease. There are two groups of the disease: CDG-I results from the defects in glycan addition to the N-terminal and CDG-II occurs due to defects in the processing of protein bound glycans. SLC35A2-CDG is a rare form of CDG caused by mutations in the X-linked gene that encodes a UDP-Galactose transporter. The manifestations of the disease include seizures, failure to thrive, delayed myelination, and cerebral atrophy. Case presentation We describe herein a severe female child with intractable seizures, microcephaly, growth retardation, hypotonia, global developmental delay, facial dysmorphism, skeletal findings, cerebral/cerebellar atrophy, and thin corpus callosum, and a mildly affected male carrying a novel variant with seizures and mild global developmental delay who were found by whole exome sequencing (WES) for SLC35A2 mutations previously not reported. Conclusions Our findings expand the number of reported cases and add novel variants to the repertoire of SLC35A2-CDG.

Objectives 5α-reductase type 2 deficiency due to biallelic SRD5A2 variants is a common form of 46,XY disorders of sex development. Case presentation A Chinese neonate presented with ambiguous genitalia. He carried a homozygous likely_pathogenic SRD5A2 variant (c.650C>A, p.A217E). His apparently nonconsanguineous parents were heterozygotes for the variant. The variant has previously been identified in two Chinese patients. Our patient carried 14.2 Mb loss-of-heterogeneity regions distributed in the genome. The SRD5A2 variant in this family was invariably coupled with two polymorphisms in exon 1 and intron 1. In the patient, blood testosterone (T)/5α-dihydrotestosterone (5αDHT) ratios were elevated before and during mini puberty, and were higher when measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) than measured by conventional immune assays. Conclusions This study provides evidence for the founder effect of an SRD5A2 variant. Furthermore, our data indicate that there is a need to establish a new reference value for T/5αDHT ratios using LC-MS/MS.

Objectives Thyroid storm (TS) is a rare but life-threatening condition caused by decompensated hyperthyroidism. There is no consensus on how to diagnose pediatric TS. We report three pediatric cases of TS presenting with central nervous system (CNS) and gastrointestinal (GI) symptoms as the initial presentation of Graves’ disease. Case presentation They were previously healthy adolescents without family history of thyroid disease. CNS symptoms varied from agitation to coma. GI symptoms included abdominal pain, vomiting, and diarrhea. Their laboratory studies revealed thyrotoxicosis and positive result of thyroid-stimulating antibody (TSAb). They were admitted to the intensive care unit (ICU) and received the combination of an antithyroid drug, Lugol’s solution, a beta antagonist, and hydrocortisone. The most severe case was a 13 year-old Japanese girl who presented with loss of consciousness and hemodynamic shock. She died after 5 days of intensive treatment. Conclusions Pediatricians should consider TS in the differential diagnosis when a patient exhibits both CNS and GI symptoms.

Objectives Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant condition caused by heterozygous gain-of-function mutations in the human ALB gene. Case presentation We report, a three-year-old boy with FDH due to p.R242P (or p.R218P without signal peptide) mutation in the ALB gene with a phenotype characterized by extremely high serum total and free thyroxine concentrations. His parents had normal thyroid function tests (TFT), so the mutation detected in this patient is assumed “ de novo ”. Although the most frequent variant was p.R242H in Caucasians and p.R242P in Japanese, our patient had p.R242P variant. Conclusions Early identification of FDH is fundamental to prevent unnecessary repeats of TFT with different methods. We encourage the ALB gene hot spot sequencing initially and indicate that this molecular diagnosis is a rapid and simple method to diagnose FDH in individuals with euthyroid hyperthyroxinemia.

Objectives Congenital disorders of glycosylation (CDGs) are a group of genetic disorders due to hypoglycosylation of proteins and lipids. A type I pattern is associated with defects in glycan assembly and transfer (CDG-I; cytosol; and endoplasmic reticulum defects), a type II pattern is seen in processing defects of the Golgi apparatus. MAN1B1-CDG is an autosomal recessive CDG-II due to mutations in the α 1,2-mannosidase gene (MAN1B1), mainly characterized by psychomotor disability, facial dysmorphism, truncal obesity, and hypotonia. Case presentation Three patients (two males and one female), with MAN1B1-CDG who had elevated transaminase levels are presented. All patients had presented due to dysmorphic and neurological findings and hypertransaminasemia was remarkable. A type 2 pattern was found on serum transferrin isoelectrofocusing analysis of the presented cases. MAN1B1-CDG was confirmed by genetic analysis. Conclusions Although the cause of the increased serum transaminase levels in the present patients is not clear, no evidence for an infection or underlying liver pathology could be identified. In order to know if this is a consistent feature, we suggest measuring serum transaminase levels regularly in MAN1B1-CDG patients.