Band 35, Heft 5

Obesity is an epidemic disease that can increase the incidence of type 2 diabetes, cardiovascular disease, malignancy, hypertension, and other health problems that affect the musculoskeletal system. There is a complex interaction between obesity and bone metabolism. In children with obesity, the peroxisome proliferator-activated receptor gamma pathway causes the differentiation of mesenchymal stem cells into adipocytes via osteoblasts, in which results in low bone mass and osteoporosis. Systemic inflammation in obesity has negative effects on bone metabolism. An increase in the number and size of adipose tissue and adipocytokines secreted from adipocytes affect the bone mass of the whole body with hormonal and biochemical effects. The skeletal effects of obesity are mediated by higher oxidative stress and increased production of proinflammatory cytokines. Osteoporosis due to obesity has increased morbidity and mortality in recent years, resulting in important health problems in developed and developing countries.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is one of the severe cutaneous adverse drug reactions (SCARs) with high mortality rate and variable long term sequelae, especially in thyroid dysfunction and thyroiditis. In this article, we review clinical course, culprit drugs, onset of diagnosis, and type of thyroid dysfunction in DRESS patients. There were a total of 51 cases including 12 children (aged less than 18 years old) and 39 adults from our review. The most common thyroid dysfunction was Hashimoto’s thyroiditis (41/51=80.4%) including anti-thyroid antibody positive (29/51=56.9%), possible/compatible with Hashimoto’s thyroiditis (12/51=23.5%) both in the children (n=12) and adult (n=39), Graves’ disease/hyperthyroidism (7/51=13.7%) and non-specific hypothyroidism (3/51=5.9%), respectively. The most common culprit drugs and onset of thyroid dysfunction after DRESS diagnosis in children aged less than 18 years include antiepileptic drugs (phenytoin, phenobarbital, carbamazepine) (range 0–8 months, median 2 months) and sulfa groups (sulfasalazine, sulfamethoxazole, sulfonamide) (range 1–4 months, median 2 months). Data of prevalence, type, and clinical course of thyroid dysfunction from DRESS is important for clinicians to recognize for monitoring its sequelae and provide plans for treatment.

Objectives The aim of the present study was to analyze the moderating effect of maturation on the relationship between body fat and insulin resistance, in children from 9 to 12 years. Methods Maturity offset, homeostasis model assessment index of insulin resistance (HOMA-IR), and body fat percentage (BF%) were estimated in 127 children. Skeletal maturation indicator (SMI) was estimated in 105 participants. A moderation analysis based on a linear regression and on Johnson-Neyman technique was performed using a 95% confidence level. Results BF%, insulin levels, and HOMA-IR values were lower in late maturers than on-time maturers (p<0.05). SMI moderated the relationship between BF% and HOMA-IR index in 11.1% of boys and in 32.5% of girls (p<0.05). Also, the highest values of HOMA-IR index were observed at −1 year to achieve the peak height velocity, in girls (p<0.05). Conclusions Maturation process has a moderation effect on the relationship BF% and insulin resistance, particularly in early maturers; furthermore, it was independently associated with HOMA-IR.

Objectives Children with type 1 diabetes (T1D) having diabetic nephropathy (DN) are at increased risk of developing end stage renal disease. The present study aimed to determine the prevalence of DN and its predictors in Indian children and youth with T1D. Methods This cross-sectional study included 319 children and youth (2.6–21 years) with T1D having disease duration of at least 2 years. Demographic data and laboratory findings were obtained using standard questionnaires and protocols. Diagnosis of diabetic nephropathy was based on albuminuria on two occasions within a period of 3 months. Results The prevalence of DN in our study subjects was 13.4%. 7.5% subjects were known cases of diabetic nephropathy on treatment with enalapril. Hypertension was found in 14.3% subjects with DN in contrast to 4.1% without DN (p<0.05). Duration of diabetes and estimated glucose disposal rate were the important predictors of DN. Interestingly, of the 43 children with DN, 11.3% (n=8) were under 10 years age. Conclusions We found a high prevalence of DN in children and youth with T1D including in children under the age of 10 years. Early screening and timely intervention are required to retard the disease progression and avoid end stage renal disease.

Objectives The exact mechanism of partial clinical remission in type 1 diabetes mellitus (T1DM) has not been elucidated yet. The severity of the inflammation at the time of diagnosis may affect the occurrence or duration of this phase. We aimed to investigate the relationship between hematological inflammatory parameters at the time of diagnosis in T1DM and (i) daily insulin requirement during the follow-up and (ii) the presence of partial clinical remission period, which was determined according to insulin dose-adjusted HbA 1c levels. Methods A single-center retrospective study was conducted, including children who were diagnosed with T1DM, were positive for at least one autoantibody, and were followed up for one year in our clinic between 2010 and 2020. Results Sixty-eight patients (55.9% female, 64.7% prepubertal) were included in the study, whose mean age was 8.4 ± 4.2 years. A total of 38 patients (55.9%) had partial clinical remission. None of the initial hematological indices were associated with the occurrence of partial remission. Initial neutrophil/lymphocyte ratio (NLR) and derived-NLR (d-NLR) levels were significantly lower (p=0.011 and 0.033, respectively) and lymphocyte/monocyte ratio (LMR) levels were significantly higher (p=0.005) in patients who showed an insulin requirement of <0.5 IU/kg/day at the 3rd month after diagnosis. Conclusions Initial hematological parameters were not found as a predictor of partial clinical remission period in T1DM in children. However, a lower NLR and d-NLR, or a higher LMR at the time of diagnosis can be used as an indicator of a low daily insulin need at the 3rd month of T1DM.

Objectives Emerging evidence suggests a fat depot-specific relationship with bone mineral density (BMD) in children, particularly in those who are overweight/obese. However, this has not yet been investigated in detail in children with Prader–Willi syndrome (PWS), a genetic syndrome characterized by a decreased lean mass (LM) and increased fat mass (FM). The objective of this study is to investigate the relationships of LM and FM, particularly fat distribution, with bone mineral parameters. Methods This is a retrospective and cross-sectional study. Forty-seven prepubertal Japanese children with PWS (22 males, mean age: 6.86 years) were included. No subjects had type 2 diabetes mellitus or osteoporotic medications. LM, FM, and BMD and bone mineral content in the total body less head and the lumbar spine were measured using dual-energy x-ray absorptiometry, in addition to subcutaneous/visceral adipose tissue (SAT/VAT), and the ratio of VAT to SAT (V/S) by computed tomography at the umbilical level. Bone mineral apparent density was calculated to correct for bone size. Results LM positively correlated with bone mineral parameters after controlling for age, sex, growth hormone (GH) treatment, and FM. Although FM did not correlate with bone mineral parameters, compartment-specific analysis revealed that SAT positively and V/S negatively correlated with bone mineral parameters after controlling for age, sex, GH treatment and LM. Conclusions A compartment-specific effect of FM on bone mineral parameters was noted such that SAT was a positive predictor for BMD independent of LM in prepubertal children with PWS.

Background Unlike in Western countries, the use of diabetes technologies has been limited in Turkey, or at least until the last few years. This low adoption frequency may be attributed to the lack of experience of pediatric diabetes teams in working with new technologies. The aim of this study is to evaluate the attitudes, experiences and self-efficacies of pediatric endocrinology fellows and attending physicians in terms of use of continuous subcutaneous insulin infusion (CSII) therapy and continuous glucose monitoring (CGM) systems. Methods The questionnaire used in this study consisted of 63 questions including 10 questions evaluating the demographic characteristics and experience of the participants, 33 Likert-type questions related to self-competency, 17 yes/no questions and 3 open-ended questions which evaluated attitudes towards our study area. This questionnaire was e-mailed to pediatric endocrinology fellows and attending physicians working in Turkey. Results A total of 24 fellows and 28 attending physicians working in the field of pediatric endocrinology participated in the survey. Of the respondents, 61% reported that there was no formal training curriculum regarding diabetes technology at their institutions. The mean scores obtained from the Likert scale questions measuring self-competency in using CSII and CGM were 3.8 and 3.3 out of 5, respectively. Of the respondents, 55% judged themselves to be under-skilled in interpreting pump reports while 39% of the respondents reported themselves as being under-skilled in interpreting CGM reports. Conclusions While it is true that training programs for using diabetes technology have been established by the National Pediatric Endocrinology Association in Turkey, the development of a specific curriculum for institutions that provide pediatric endocrinology fellowship training in this framework will increase the self-confidence of pediatric endocrinologists in this matter and this will ultimately contribute to the improvement of the metabolic control of children with diabetes.

Background Existing various and complicated metabolic syndrome (MetS) definitions have contributed to the difficulty in assessing MetS in children and adolescents, and therefore it is urgently needed to develop a convenient and effective screening tool for pediatric MetS. This study aimed to identify the optimal adiposity measure to screen for pediatric MetS. Methods The cross-sectional data was collected from 8,150 children and adolescents aged 7–17 y living in southern China. Anthropometric indices, blood lipids, and serum glucose were determined. Results of two commonly used MetS definitions were compared: International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel Ⅲ (NCEP-ATP) modified by Cook. Receiver operating characteristic curve analyses were performed and areas under the curve (AUCs) were calculated to determine the optimal index for MetS screening. Results MetS prevalence assessed by NCEP-ATP was significantly higher than that by IDF (6.2% vs. 1.5%, p<0.001). Waist-to-height ratio (WHtR) showed the highest screening power for MetS defined by both IDF and NCEP-ATP (AUC 0.932 and 0.900, respectively), and its optimal cut-off point was 0.48 by both IDF and NCEP-ATP definition (sensitivity 0.944 and 0.847, specificity 0.800 and 0.830, respectively), regardless of age or sex. When taking sex diversity into account, the optimal WHtR cut-off point was 0.49 (IDF) or 0.50 (NCEP-ATP) in boys, and 0.46 (both definitions) in girls. Conclusions Among children and adolescents aged 7–17 y in southern China, a WHtR greater than 0.48 can be a simple but effective screening tool for MetS.

Objectives The prevalence of mental health issues has increased at an alarming rate during the COVID-19 pandemic. Furthermore, an exacerbated psychosocial burden in populations with chronic disease is observed. This cross-sectional study evaluated the psychosocial factors of pediatric type 1 diabetes (T1D) during the COVID-19 pandemic. Methods During April 2020, 15 min phone interviews were performed for pediatric T1D group (n=100) and healthy comparison group (n=93) to assess psychosocial functioning during the acute lockdown phase of the pandemic. The patient health questionnaire-4 was utilized to assess anxiety and depressive symptoms. An additional questionnaire to assess specific concerns related to T1D and COVID-19 was administered to the T1D group to explore potential causes for increased psychosocial burden. Results T1D was associated with a five-times higher risk of anxiety symptoms. Increased anxiety symptoms in T1D group appear to be, at least in part, due to fear of higher risk of severe COVID-19 infection and uncertainty regarding access to diabetes supplies. Conclusions This study provides a snapshot of mental well-being in a diverse population of patients with T1D in the acute phase of a crisis and underscores the need for timely, accurate medical information and distribution of medical resources for pediatric T1D population.

Background Adrenal insufficiency (AI) is a life-threatening condition caused by an impaired secretion of the adrenal glucocorticoid and mineralocorticoid hormones. It comprises a heterogeneous group of primary, secondary and acquired disorders. Presentation differs according to the child’s age, but it usually presents with nonspecific and insidious symptoms and signs. The main purpose of this study was to describe and compare patients with primary or secondary AI. Methods Retrospective analysis of all patients with adrenal insufficiency followed at the Pediatric Endocrinology Unit in a tertiary care Portuguese hospital over the last 30 years. Data on family history, age at the first manifestation and at etiological diagnosis, and clinical presentation (symptoms, signs and laboratory evaluation) was gathered for all patients. Results Twenty-eight patients with AI were included; 67.9% were male, with a median (25th–75th percentile, P25–P75) age of 1 (0.5–36) month at the first presentation. The principal diagnostic categories were panhypopituitarism (42.9%) and congenital adrenal hyperplasia (25%). The most frequent manifestations (75%) were vomiting and weight loss. They were followed for a median (P25–P75) period of 3.5 (0.6–15.5) years. In respect to neurodevelopmental delay and learning difficulties, they were more common in the secondary AI group. Conclusions Despite medical advances, the diagnosis and management of AI remains a challenge, particularly in the pediatric population, and clinicians must have a high index of suspicion. An early identification of AI can prevent a potential lethal outcome, which may result from severe cardiovascular and hemodynamic instability.

Objectives The aim of our study was to define the genotype–phenotype correlations of mutations in the PAH gene among the Turkey’s Central Anatolian region. Methods Demographic characteristics of 108 patients with hyperphenylalaninemia (HPA) and 94 patients whose diagnosis was confirmed by PAH gene analysis (Sanger DNA Sequence Analysis and Next-Generation Sequencing) were determined retrospectively. Blood phenylalanine levels were analyzed using the high-performance liquid chromatography method. Results Mild HPA-not-requiring-treatment (NT) was found in 50.9% of the patients, and a classical phenylketonuria (PKU) phenotype was found in 25.9%. Forty-seven types of variants were identified. The predominant variants were p.Ala403Val (9.9%), p.Ala300Ser (9.4%), and c.1066-11G>A (splicing) (9.4%). Missense mutations accounted for 68% of mutations and attenuated the clinical impact; splice variations were found in 14.8% of cases with severe features. The p.Thr380Met allele was specific to the mild HPA-NT group. The c.1066-11G>A (splicing) allele was associated with classical PKU, whereas the p.Arg408Trp allele was linked to severe symptoms. Three variations of unknown clinical significance were discovered: c.706+4A>T (splicing), c.843-5T>C (splicing), and p.Thr323=. Of these variants, the patient who was homozygous for the c.843-5T>C (splicing) allele related to the classical PKU phenotype. 70% of the patients who underwent tetrahydrobiopterin (BH4) test were responsive. Phenotypes that responded to BH4 treatment were mostly mild phenotypes. Conclusions The PAH genotype is the main factor that determines the phenotype of PKU. Establishing the relationship between the identified genetic mutations and phenotypic characteristics will provide very important data for each patient in terms of the specific management style.

Background Babies born small for gestational age (SGA) are at risk of obesity and metabolic syndrome (MetS). Spexin (SPX) is a novel peptide implicated in food intake and obesity. Spexin levels are lower in obese subjects. This study investigated the potential association of SPX and some obesity related peptides such as leptin and active ghrelin with size at birth and MetS components in prepubertal children born term and either SGA or appropriate for GA (AGA). Secondary aim was to identify whether any of the investigated peptides were associated with MetS components. Methods We conducted a cross-sectional study of 37 consecutive (median age: 5.6 y) SGA- and 50 (median age: 5.9 y) AGA-born children. Clinical evaluations were performed using standard methods. Several biochemical variables (SPX, total leptin, and active ghrelin levels) were analyzed. Age-dependent cut-off values were used to define MetS components, including excess adiposity, hypertension, insulin resistance, and dyslipidemia. The associations between the assessed clinical and laboratory variables and MetS components were investigated. Results Children born SGA had higher frequencies of MetS components than AGA-born peers (p < 0.01). None of the investigated peptides were different between children born SGA and AGA after correcting for body mass index (p > 0.05 for all). Serum SPX levels were lower in children with at least one metS component than those without MetS components (p = 0.018). Conclusions Size at birth had no association with serum SPX. Serum SPX levels are decreased in prepubertal children with MetS components.

Objectives Genetic factors have a key role in childhood obesity with higher rates in children than adults. Among the monogenic types of non-syndromic obesity, melanocortin-4 receptor (MC4R) deficiency is the most frequent cause. Beside pathogenic variants, single-nucleotide polymorphisms in MC4R gene are also associated with lower energy expenditure. The aim of this study was to estimate the frequency of MC4R variants and polymorphisms in a cohort of Turkish children and adolescents with severe early-onset obesity, and to understand the clinical features of patients. Methods Patients, 1–17 years of age, with the onset of obesity before 10 years of age and a body mass index (BMI) standard deviation score (SDS) of >2.3, and who had a family history of early-onset obesity in at least one of their first-degree relatives were included in the study. Beside routine blood tests genetic analyses for MC4R gene were performed. Results Analyses of MC4R revealed previously known variations in three (3.5%) patients, and pathogenic polymorphisms related with obesity in four (4.7%) patients. BMI SDS values were between 2.8 and 5.5 SDS in the pathogenic variant carrier group, and 2.8–4.9 SDS in the polymorphism group. Mean BMI SDS in variant-negative group was 3.4 ± 0.82. Conclusions Investigation of the MC4R in individuals with early-onset obesity and presence of obesity first-degree relatives is important. Hypertension is a rare comorbidity compared to other causes. Contrary to studies reporting that insulin resistance was absent or very rare, we found it as a frequent finding in both pathogenic variants and polymorphisms of MC4R.

Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine metabolism, mostly caused by PAH gene variants. The aim of this study was to identify the frequency of PAH gene variants in Turkish population with PKU. In 433 patients with PKU, PAH gene was examined using next generation sequencing (NGS) method. IVS10- 11G>A, p.R261Q, p.A300S, p.A403V, and p.T380 variants, which are the most common variants in this study, constituted 45,9% of the variants in our study. Nine novel variants p.A34V, K73Qfs*4, R157H, R261S, p.T266I, p.S310P, T328A, p.F351I, and K363N were identified. This study determines the most common PAH variants in Turkey and shows that PKU can be screened before marriage with the screening kits. Identification of the PAH gene variant spectrum is important for early diagnosis, understanding molecular mechanisms, clinical follow-up, treatment, and genetic counseling. And the novel variants found this study are important for further studies.

Objectives Primary hypertriglyceridemia is a rare condition in children. Hypertriglyceridemia induced pancreatitis is most commonly reported in adults, accounting for third most common cause after gallstones and alcohol consumption. The study aims to highlight the frequency of hypertriglyceridemia induced pancreatitis in a cohort of children presenting in a tertiary care hospital. Methods A retrospective review of paediatric patients with pancreatitis was conducted in Shifa International hospital, Islamabad, from 2013 to 2020. All patients under 18 years of age who fulfilled the inclusion criteria were included. Medical records of patients were checked for symptoms, signs, age, growth parameters and laboratory investigations. Patients who had HTG were reviewed in detail for family history of pancreatitis or dyslipidemias. Results We found a cohort of 6 patients with primary hypertriglyceridemia after excluding secondary causes. Out of these 6 patients, 4 (66.6%) were male and 2 (33.3%) were female. Minimum age of our patient was 2 months and maximum was 17 years with a mean age of 6.5 years. Two patients presented less than one year of age. Mean triglyceride levels was 1,599 + 523 mg/dL. Four patients (66.6%) had acute pancreatitis, one each (16.6%) had recurrent and chronic pancreatitis. Family history was positive for hyperlipidaemia in two patients who had positive consanguinity. Patients with positive family history were symptomatic at earlier age. Conclusions This is the first study to highlight primary hypertriglyceridemia presenting as pancreatitis in paediatric population from Pakistan. All patients had triglycerides level of greater than 1000 mg/dL.

Objectives Diabetes mellitus (DM) is widely known to have a detrimental effect on bone health and is associated with increased fracture risk. Recently, the Wnt/beta-catenin signaling pathway and its inhibitors sclerostin and dickkopf-1 (Dkk-1) were found to be involved in the control of bone mass. The present study aimed to measure serum sclerostin and Dkk-1 protein levels in children and adolescents with type-1 DM and compare with other bone turnover markers and bone mineral density (BMD). Methods This study was performed on 40 children and adolescents with type-I DM and 40 healthy children and adolescents. Anthropometric measurements and pubertal examination were done. In addition to laboratory analysis, dickkopf-1, sclerostin, cross-linked N-telopeptides of type I collagen (NTx), bone alkaline phosphatase (bALP), and osteocalcin levels were studied. BMD of the participants was measured by calcaneus ultrasonography. Results Dickkopf-1 levels of the children and adolescents with type-1 DM were significantly higher, vitamin D, NTx, osteocalcin, and phosphorus levels were significantly lower than those of the controls (p<0.001). Fasting blood glucose, HbA1c, and insulin were significantly higher in the type 1 DM group (p<0.01). Conclusions Both bone remodeling and its compensatory mechanism bone loss are lower in children and adolescents with type-1 DM than in the controls. Also, higher levels of Dkk-1 play a role in decreased bone turnover in these patients. Since Dkk-1 and sclerostin seem to take a role in treating metabolic bone diseases in the future, we believe that our findings are significant in this respective.

Objectives Niemann–Pick disease type C (NPC) is a lysosomal storage disease due to impaired intracellular lipid trafficking caused by biallelic pathogenic variants in NPC1 or NPC2 genes. NPC is classified according to the age of onset of neurological manifestations. Cholestatic liver disease can be transient or lead to liver failure. Accompanying neurological findings can be observed at any age. In this report, an infant with a homozygous pathogenic variant in NPC1 gene whose diagnosis was eventually confirmed by specific biomarkers is described. Case presentation A sixteen-day-old male was admitted to hospital with prolonged jaundice. He had mild hepatosplenomegaly, conjugated hyperbilirubinemia, elevated liver transaminases, and mild hypoalbuminemia. Cholestasis resolved spontaneously and patient was readmitted due to progressive hepatosplenomegaly without any neurologic findings when he was 8 months old. Molecular investigations detected homozygous c.1123A > C (p.Thr375Pro) pathogenic variant in NPC1 gene. NPC-specific lysosomal biomarkers such as Lysosphingomyelin and Lysosphingomyelin-509 were elevated, confirming the diagnosis. Conclusions The clinical features of NPC are highly heterogeneous, from disease severity or age of onset to disease progression. Patients presenting with transient neonatal cholestasis and should be regularly followed for neurodevelopmental status and visceromegaly. In the case of variants of unknown significance in NPC1 gene, lysosomal biomarkers play an important role when genetic analyses are inconclusive.

Objectives A highly invasive pathological diagnosis is necessary to differentiate central diabetes insipidus (CDI) with a thickened pituitary stalk. Lymphocytic infundibulo-hypophysitis (LIH) due to autoimmune involvement of the pituitary stalk is a differentiating disease, and anti-rabphilin-3A antibody (Rab3A-Ab) positivity was recently reported. Case presentation A 7-year-old boy was diagnosed with CDI after having polyuria for two months. He showed growth hormone deficiency with reduced growth rate. Brain magnetic resonance imaging (MRI) revealed a thickened pituitary stalk. The placental alkaline phosphatase level of the cerebrospinal fluid, tumor marker for germ cell tumors, was below the level of sensitivity. No skin or bone findings suggestive of Langerhans cell histiocytosis were detected. Eight months after CDI onset, Rab3A-Ab was positive, and MRI showed shrinking of the thickened pituitary stalk, leading to the diagnosis with LIH. Conclusions Rab3A-Ab is a useful adjunctive diagnostic tool for childhood-onset LIH.

Objectives Hypoparathyroidism is a rare disorder which is predominantly of idiopathic or genetic origin in children. The diagnosis is made from the biochemical measurement of parathyroid hormone (PTH), and the key findings include a low PTH in combination with hypocalcemia and hyperphosphatemia. However, the level of PTH encountered in patients with hypoparathyroidism may be dependent on the underlying genetic cause of the disorder as well as the biochemical assay used for assessment of PTH. Case presentation A three-year-old child with asymptomatic primary hypoparathyroidism was identified with a homozygous missense variant of PTH . A sudden unexpected high PTH result after a shift from 2nd to 3rd generation PTH assay in the routine laboratory provided a clue on the underlying genetic etiology. Conclusions Pathogenic variants of PTH as a cause of hypoparathyroidism are rarely described. In this case, the child was asymptomatic, and discordant PTH results were seen with different assays.

Objectives Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes present within the first six months of life. NDM can be transient (TNdM) or permanent (PNDM). About 70% of TNDM cases have abnormalities in the imprinted region of chromosome 6q24. In TNDM, diabetes remits at infancy whilst may relapse later in life. Chromosome 6q24 related TNDM usually relapses at the pubertal period, while in some cases, relapse occurs earlier. It has been reported that these cases can respond to sulfonylurea treatment, while more evidence and experience are needed. Case presentation Herein, we reported relapse of diabetes at prepubertal age and its response to sulphonylurea therapy in a case with TNDM due to a homozygous c.7734C>T (p.R228C) variant in the ZFP57 gene. Conclusions A response to the sulphonylurea monotherapy seems not optimal for relapsed TNDM due to chromosome 6q24 abnormalities.