Band 38, Heft 5

Obesity is a complex, chronic condition characterised by excess adiposity. Rates of obesity in childhood and adolescence are increasing worldwide, with a corresponding increase in adulthood. The aetiology of obesity is multifactorial and results from a combination of endocrine, genetic, environmental and societal factors. Population level approaches to reduce the prevalence of childhood obesity worldwide are urgently needed. There are wide-ranging complications from excess weight affecting every system in the body, which lead to significant morbidity and reduced life expectancy. Treatment of obesity and its complications requires a multi-faceted, biopsychosocial approach incorporating dietary, exercise and psychological treatments. Pharmacological treatments for treating childhood obesity have recently become available, and there is further development of new anti-obesity medications in the pipeline. In addition, bariatric surgery is being increasingly recognised as a treatment option for obesity in adolescence providing the potential to reverse complications related to excess weight. In this review, we present an update on the prevalence, aetiology, complications and treatment of childhood obesity.

Objectives This study aimed to explore the relationships between sleep parameters, chronotype preferences, and glycemic control in children and adolescents with type 1 diabetes (T1DM), compared to healthy peers. Methods A total of 96 children and adolescents with T1DM and 95 healthy controls aged 8–18 years participated in this case-control study. Anthropometric measurements were collected, and participants completed the Munich Chronotype Questionnaire and the Pittsburgh Sleep Quality Index (PSQI). Glycemic control was assessed using HbA 1c levels. Results Children with T1DM demonstrated significantly shorter sleep durations, poorer sleep quality, and a later chronotype compared to controls (p<0.05). Poor glycemic control (HbA 1c >7.5 %) was observed in 72.9 % of the T1DM group, with 34.3 % exhibiting very poor control (HbA 1c >9 %). Logistic regression identified poor sleep quality (PSQI score, OR: 1.47, p<0.001) and later chronotype (OR: 5.14, p<0.01) as independent predictors of poor glycemic control. Generalized linear modeling (GLM) further revealed significant associations between HbA 1c levels, insulin dosage (p<0.001), and chronotype (p=0.090). Conclusions Late chronotype and poor sleep quality are closely linked to suboptimal glycemic control in pediatric T1DM populations. These findings underscore the importance of integrating sleep-focused strategies into routine diabetes management.

Objectives The primary objective is to determine the risk factors underlying the development of childhood and adolescent obesity. The secondary objective is to determine the predictors of metabolic syndrome (MetS) in childhood and adolescent obesity and its metabolic alterations in the South Indian population. Methods This is a cross-sectional study conducted over two years. We have screened 3,195 school children and adolescents from lower and lower-middle socioeconomic groups. From this pool, by random cluster sampling technique, we have included 166 overweight and obese individuals and 38 control subjects. We have analyzed their sociodemographic, dietary, lifestyle, anthropometric, clinical, and metabolic parameters. Results The prevalence of overweight and obesity in rural areas was 14.2 and 7.6 %, respectively, and in urban areas, it was 16.1 and 8.8 %, respectively. The age distribution of the control and study group is 12.3 ± 1.5 and 13.0 ± 1.9 years with a male-to-female ratio of 1.4:1 and 1.6:1, respectively. Our study found a higher average consumption of energy-dense food and screen time in the obese group compared to the control group. The average outdoor play time was 1.5 h per day in the control group and less than 0.5 h per day in the obese group. In our study, the waist-to-height ratio (WHtR) optimum cutoff value of 0.56, has 95 % sensitivity and 84 % specificity, effectively identifying MetS cases. HOMA-IR optimum cutoff value of 2.25, has 96 % sensitivity and 72 % specificity. The triglyceride-glucose index (TGI) optimum cutoff value of 4.51, has 92 % sensitivity and 88 % specificity indicating a strong balance between correctly identifying positive and negative MetS cases. Conclusions Our study found that even in lower socioeconomic status, there is a higher prevalence of childhood and adolescent obesity due to an urbanized lifestyle in rural areas, a sedentary lifestyle, higher consumption of low-cost energy-dense foods, and higher screening time in this electronic era . We also conclude that WHtR is a simple anthropometric marker that predicts MetS more effectively than BMI and WHR among children and adolescents. HOMA-IR and TGI are effective biochemical markers to identify metabolically unhealthy obesity early.

Objectives The primary goal in managing glycogen storage disorders (GSD) is to implement dietary therapy through regular glucose monitoring while attempting to prevent complications. Self-monitoring of blood glucose is often insufficient for detecting asymptomatic hypoglycemia in patients. Therefore, Continuous glucose monitoring systems (CGMS) play a crucial role in identifying hypoglycemic episodes and providing detailed glucose profiles throughout the day. In this study, CGMS data, laboratory findings, and daily nutritional intake were examined in patients with GSDIa and GSDIII. The lack of similar studies in GSDIII patients in the literature highlights the need for further research in this field. Methods The glucose profiles of 12 patients (7 GSDIa and 5 GSDIII) were analyzed over a 72 h period using CGMS. Nutritional intake, biochemical parameters, and growth parameters were also evaluated. Results This study demonstrated that CGMS detected both hypoglycemia (<70 mg/dL) and hyperglycemia (>150 mg/dL) in GSD patients. Growth retardation was also observed in these patients. As complications of the disease, elevated levels of liver enzymes, cholesterol, triglycerides, and creatine kinase were identified, with fatty liver and hepatomegaly detected in all patients. The patients’ nutritional intake is similar to the recommendations in disease-specific treatment guidelines. Conclusions The primary dietary treatment goal for GSD patients is to maintain normoglycemia. Patients may experience asymptomatic low glucose and/or asymptomatic hypoglycemic episodes during treatment. CGMS enables a more detailed monitoring of glucose profiles, which not only facilitates the precise adjustment of dietary therapy based on detailed results but also helps prevent complications associated with the disease.

Objectives This study aimed to identify clinical, laboratory, and radiological features that could serve as red flags for diagnosing inherited metabolic disorders (IMDs) with hepatic involvement in childhood. Methods We retrospectively reviewed the medical records of 1,237 children from a pediatric metabolism department, with suspected or diagnosed IMDs. Patients with hepatic involvement were divided into two groups: Group 1 (diagnosed with IMDs) and Group 2 (undiagnosed). Demographic, clinical, laboratory, and radiological data were compared between the groups. Results Hepatic involvement was observed in 415 patients (33.5 %), with 206 (49.2 %) diagnosed with IMDs. Group 1 had higher rates of consanguineous marriage and affected siblings. Complex molecule disorders (20.4 %), mitochondrial (16.0 %), and lipid metabolism disorders (16.0 %) were the most common IMDs. Dysmorphic findings were more frequent in Group 1 (28.2 vs. 16.3 %, p=0.004), while diarrhea was less common (4.4 vs. 12.0 %, p=0.005). Ammonia and lactate levels were higher in Group 1 (p<0.001 and p=0.032, respectively). Hepatomegaly was more frequent in Group 1 (53.3 vs. 22.6 %, p<0.001). Pathological abdominal ultrasonography was the only significant multivariate predictor (OR: 89.377, p=0.026). Overall survival was 87.7 %, with no difference between groups. Conclusions Consanguineous marriage, affected siblings, dysmorphic findings, absence of diarrhea, and pathological abdominal USG are key predictors of IMDs in hepatic involvement cases.

Objectives Bone mineral density (BMD) is influenced by factors including age, sex, body composition, and diabetes. However, data regarding these relationships in young individuals is limited. The objective of this study was to address this gap in the literature.  Methods We conducted a post-hoc analysis of participants from six cross-sectional cohort studies, encompassing individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D), as well as controls of healthy weight (HWC) and with obesity (OC). Whole-body dual-energy X-ray absorptiometry (DXA) was employed to measure BMD and body composition. Multiple linear regression models assessed sexual dimorphism in BMD, adjusting for age and exploring effect modification by group and sex. Results A total of 325 participants were included (T1D [n=123, mean age 22.4 years, 50 % male], T2D [n=72, mean age 16.2 years, 33 % male], HWC [n=79, mean age 16.6 years, 41 % male], and OC [n=51, mean age 13.8 years, 53 % male]). Sexual dimorphism in BMD was evident only in T1D and HWC, with males having higher BMD than females (p=0.021; p<0.001, respectively). BMI was positively correlated with BMD in all groups (p<0.001 for HWC; p=0.001 for OC; p<0.001 for T1D; p=0.008 for T2D). Body fat percentage was inversely correlated with BMD in HWC and T1D (p<0.001; p=0.011, respectively), but not in OC or T2D. Additionally, lean mass percentage was significantly associated with higher BMD in HWC and OC (p<0.001; p=0.023, respectively), but not in groups with diabetes. Conclusions Our study documents sexual dimorphism in BMD in youth, with varied associations between body composition metrics and BMD across groups with diabetes and in controls without diabetes, underscoring the importance of understanding these relationships for optimizing bone health during adolescence.

Objectives Familial Male-Limited Precocious Puberty (FMPP) is a rare autosomal-dominant genetic condition with sexual dimorphism. We aim to summarize the clinical characteristics of FMPP patients and emphasize the use of a therapeutic regimen involving letrozole, spironolactone, and GnRHa, to augment clinician’s understanding of the disease, thus enhancing patient care. Methods We retrospectively analyzed the clinical data of 10 FMPP patients and conducted follow-up assessments of adult height in six patients. Results Out of the 10 FMPP cases, five had the LHCGR M398T mutation, three exhibited the LHCGR A564G mutation, and two had the LHCGR T577I mutation. All patients initially presented with symptoms like penile enlargement, frequent erections, and rapid growth. Their median age at diagnosis was 4.67 years with bone age being 9 years. Four patients were untreated with a median adult height of 162 cm. Six patients underwent treatment between ages 3.58 and 5.5 years noting decreased frequency of erections, slower growth rate, and delayed bone age progression. Secondary Central Precocious Puberty (CPP) developed between ages 5 and 6.5 years in all cases, necessitating additional GnRHa treatment. Two treated cases reached an adult height of 176 cm and 173 cm, respectively, without any significant adverse effects. Conclusions The most prevalent genotype among FMPP patients in this study was the LHCGR M398T mutation. Early intervention using a regimen including letrozole and spironolactone, and later GnRHa, appears beneficial in limiting physical signs and improving adult height without major side effects. However, the longer-term effects on fertility require further investigation.

Objectives The objective of this study is to determine the optimal interval between repeat thyroid fine-needle aspiration (FNA) biopsies in children and adolescents and to evaluate whether this has any impact on the final pathological diagnosis. Methods The sample of this retrospective single-center study consisted of 99 patients who had thyroid nodules and underwent thyroid ultrasonography (USG) and FNA biopsy between 2013 and 2023. The interval between FNA biopsies as well as biopsy and surgical cytology results were recorded for each patient. Results The mean age of the sample, 70.7 % of which were females, was 14.04 ± 3.29 years. According to the initial FNA biopsy results, 46.5 % of thyroid nodules were identified as benign, 24.2 % as nondiagnostic, 10.1 % as atypia of undetermined significance, 8.1 % as follicular neoplasm, 6.1 % as suspicious for malignancy, and 5.1 % as malignancy. It was decided to perform thyroidectomy in 34 patients. Conclusions The false-negative rate (6.5 %) we found in patients with a benign initial FNA cytology was slightly higher than the rate stated in the guidelines. Additionally, we determined that performing early (<3 months) repeat FNA biopsy for nondiagnostic nodules did not affect the diagnostic yield of subsequent samples. Therefore, we concluded that repeat FNA biopsy should not be delayed longer than 3 months in nondiagnostic nodules with suspicious USG findings and no longer than 6 months in benign nodules with suspicious USG findings. A shorter interval between FNA biopsies will allow for more timely surgical intervention, especially in patients with malignancy in nondiagnostic and benign nodules.

Objectives Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of fatty acid oxidation, with potentialy fatal outcome. Early diagnosis of MCADD by acylcarnitine analysis on newborn screening using tandem mass spectrometry can potentially reduce morbidity and mortality. In this study, we evaluate the prevalence and genetic background of MCADD in North Macedonia. Methods Medium chain length acylcarnitines, were measured on newborn screening blood spot cards by tandem mass spectrometry. The molecular diagnosis was performed by whole exome sequencing of the ACADM gene, and detected mutations were confirmed with Sanger sequencing in all neonates with positive MCAD screening markers, and their parents as well. Results A total of 52,942 newborns were covered by metabolic screening during the period May 2014–May 2024. 11 unrelated Macedonian neonates were detected with positive MCADD screening markers, and prevalence of 1/4,813 live births was estimated. Molecular analysis of the ACADM gene showed that c.985A>G was the most prevalent mutation occurred on 77.27 % of the alleles, while 18.18 % alleles carried c.244dupT pathogenic variant. Seven patients were homozygous for c.985A>G (63.6 %) while one was homozygous for c.244dupT (9.1 %) variant. Two patients were compound heterozygotes with c.985A>G/c.244dupT genotype (18.2 %), and one patient had c.985A>G allele without detection of the second ACADM mutant allele. Conclusions The NBS estimated prevalence of MCADD in Macedonian population was more frequent than in the other European population and worldwide incidence in general. This is the first report of the genetic background of MCADD in North Macedonia.

Objectives The study aimed to evaluate the impact of antenatal steroid administration, a key intervention for reducing early mortality and morbidity in preterm infants, on the development of metabolic bone disease. Methods This single-center retrospective study was conducted in a Level III neonatal intensive care unit from October 2020 to December 2023. Results It included 173 infants born before 32 weeks of gestation, with a mean birth weight of 1,338 ± 293 g. Metabolic bone disease, diagnosed at four weeks of age based on serum phosphorus and alkaline phosphatase levels, was identified in 26 (15 %) of the infants. Regression analysis examined prenatal factors, including birth weight, intrauterine growth restriction, respiratory distress syndrome, gender, and antenatal steroid exposure, revealing that only lower birth weight was an independent risk factor for metabolic bone disease. Conclusions Antenatal steroid administration did not significantly influence the diagnosis of metabolic bone disease when assessed using biochemical markers at four weeks of age. These findings underscore the importance of birth weight in the risk profile for metabolic bone disease while indicating that antenatal steroids are not a contributing factor.

Objectives We aimed to characterize genetic alterations in Prader-Willi syndrome (PWS) using whole genome microarrays. Methods We performed mRNA expression microarray analysis using RNA isolated from whole blood of 25 PWS patients and 25 age-matched controls. After preprocessing the data to reduce heterogeneity, differentially expressed genes (DEGs) between groups were identified using a linear regression model package. Reactome pathway analysis was performed for upregulated and downregulated genes using EnrichR. Correlations between gene expression levels and clinical factors were estimated using Spearman’s rank correlation coefficient. Results Of 21,488 probes examined in the microarray analysis, 4,156 were detected. Fifty-two genes had different expression levels in children with PWS compared with healthy controls (36 genes upregulated and 16 downregulated). Twelve genes were upregulated and 13 were downregulated in obese PWS patients compared with normal-weight PWS (NW-PWS) patients. The C-type lectin domain family 4 member D (CLEC4D) was upregulated in both PWS (vs. control) and obese-PWS (vs. NW-PWS) patients, and CLEC4D expression was also correlated with body mass index-standard deviation score in PWS patients. Among the genes upregulated in obese PWS vs. NW-PWS, Annexin A3 (ANXA3), potassium inwardly rectifying channel subfamily J member 15 (KCNJ15), and selenium binding protein 1 (SELENBP1) were upregulated in obese-control vs. NW-control. Gene ontology analysis revealed that upregulated DEGs were significantly enriched in biological processes, including pathways involved in myeloid dendritic cell activation associated with CLEC4D. Conclusions This study revealed differences in gene expression between obese and NW-PWS patients. The regulation of macrophage infiltration by CLEC4D suggests a possible mechanism associated with obesity-related complications in PWS.

Objectives Subsequent to early life feeding issues, children with Prader–Willi syndrome (PWS) develop hyperphagia and severe obesity. Growth hormone (GH) therapy has been approved in PWS to improve growth, body composition, and BMI. We aimed to clarify the role of age at GH therapy onset on growth and BMI trajectories in children with PWS. Methods We analyzed height and BMI in 114 patients (58 boys) from REPAR – Czech national GH registry. From them, 69 started GH therapy prior to 2 y/o (age 0.8 ± 0.4 years; mean ± SD; early-onset group [EO]), and 45 later (age 7.1 ± 4.1 years; late-onset group [LO]). Results Height-SDS before therapy was similar in all (EO: −1.9 ± 1.2 [mean ± SD]; LO: −1.7 ± 1.1). After the first year of GH therapy, height-SDS in the EO group increased to −1.0 ± 1.2, in the LO group to −0.9 ± 1.1. After 5 years, height fully normalized in all (−0.1 ± 1.1 SDS). The LO children were already obese at treatment initiation (BMI-SDS: 2.9 ± 2.2), and their BMI-SDS decreased after 1 year of GH therapy by 0.9 (p=0.003). The weight in EO children was below average before GH treatment (BMI-SDS: −0.9 ± 1.2) and their BMI-SDS increased to the overweight range of 1.3 ± 2.2 (p<0.001) within the oncoming 3 years. Albeit BMI-SDS was around the obesity limit in most children after 5 years on GH therapy, the highest lifetime BMI-SDS was lower in EO (2.2 ± 2.6) than in LO (3.7 ± 2.2; p<0.001). Conclusions GH treatment in PWS normalizes body height. After 5 years of GH therapy, BMI-SDS in EO and LO groups are similar; however, the EO group is exposed to lower maximal BMI-SDS values.

Objectives Neonatal severe hyperparathyroidism (NSHPT) is a rare condition characterized by inactivating mutations in the calcium-sensing receptor ( CaSR ) gene, leading to significant hypercalcemia and related complications. Case presentation We present a case of a six-day-old male infant with weakness, jaundice, and hypotonia, later diagnosed with NSHPT due to a known homozygous CaSR mutation (c.242T>A; p.I81K). Initial laboratory findings revealed markedly elevated serum calcium levels and high parathyroid hormone levels which were compatible with primary hyperparathyroidism. After initial management, bisphosphonates were administered, resulting in the patient remaining normocalcemic for 11 months, although hyperparathyroidism persisted. Then, due to the ongoing hyperparathyroidism, cinacalcet was added and continued for nine months. Finally, a total parathyroidectomy was performed. Postoperatively, the patient developed hypoparathyroidism, necessitating long-term supplementation with calcium and calcitriol. By the last follow-up at 3 years, the patient exhibited normal growth parameters and no neurodevelopmental deficits. Conclusions This case underscores the importance of early diagnosis and intervention in NSHPT and highlights the critical role of medical treatment, surgical management and long-term follow-up in optimising patient outcomes. Continued research is essential to enhance understanding and treatment strategies for NSHPT.

Objectives Niemann–Pick type C (NPC) is a rare, autosomal recessive, neurodegenerative disorder caused by biallelic pathogenic variants in the NPC1 or NPC2 genes, leading to lysosomal lipid accumulation. NPC has an incidence of 1 in 100,000 live births and presents with a wide range of symptoms affecting visceral organs and the central nervous system. We aim to describe the diverse clinical presentations of NPC through case studies. Case presentation We report seven NPC patients from five families, showcasing the variability in clinical manifestations. The most common finding was hepatosplenomegaly (70 %), followed by prolonged jaundice (57 %) and neonatal cholestasis. Pulmonary alveolar proteinosis (PAP) was observed in three patients with biallelic pathogenic variants in the NPC2 gene. Neurological symptoms, including vertical gaze palsy and epilepsy, were noted in patients with juvenile onset form. Genetic analyses identified a novel homozygous c.315del (p.Thr106ProfsTer5) variant in the NPC2 gene, associated with early infantile onset. Conclusions NPC presents with diverse clinical findings across ages. Early hepatic symptoms in infants and neuropsychiatric issues in older patients warrant a high index of suspicion for NPC in such cases. A multidisciplinary approach is crucial for patient management, and further research is needed to clarify genotype–phenotype relationships in NPC.

Objectives HSD3B7 deficiency is a genetic disorder caused by mutations in the HSD3B7 gene, leading to impaired bile acid synthesis and the accumulation of toxic intermediates. Affected patients typically present with cholestatic liver disease, including jaundice and progressive liver dysfunction. Case presentation This case series describes three pediatric patients from two families diagnosed with HSD3B7 deficiency, each demonstrating varying clinical severity and outcomes. All cases exhibited cholestasis with normal GGT levels and elevated AST/ALT. Case 1, a male infant, also presented with craniosynostosis and failure to thrive, responding well to cholic acid therapy. Case 2, a female infant and first cousin of Case 1, had mild cardiac abnormalities and showed slight improvement with ursodeoxycholic acid and vitamin supplementation. Case 3, a male infant with a compound HSD3B7 and ATP8B1 mutation, progressed to fulminant liver failure, ultimately requiring a liver transplant. A novel c.531 + 1G>C variant was identified in Cases 1 and 2, contributing to understanding genotype–phenotype correlations in bile acid synthesis disorders. Conclusions Early diagnosis and treatment with bile acid therapy are crucial for improving outcomes, although some cases may necessitate liver transplantation. This series emphasizes the need to consider bile acid synthesis disorders in the differential diagnosis of cholestasis.