Volume 36, Issue 7

Fetal programming occurs during the gestational age when exposure to environmental stimuli can cause long-term changes in the fetus, predisposing it to develop chronic non-communicable diseases (CNCD) in adulthood. Herein, we summarized the role of low-calorie or high-fat diets during pregnancy as fetal programming agents that induce intrauterine growth restriction (IUGR), amplified de novo lipogenesis, and increased amino acid transport to the placenta, which favor the CNCD onset in the offspring. We also outlined how maternal obesity and gestational diabetes act as fetal programming stimuli by reducing iron absorption and oxygen transport to the fetus, stimulating inflammatory pathways that boost neurological disorders and CNCD in the progeny. Moreover, we reviewed the mechanisms through which fetal hypoxia elevates the offspring’s risk of developing hypertension and chronic kidney disease in adult life by unbalancing the renin-angiotensin system and promoting kidney cell apoptosis. Finally, we examined how inadequate vitamin B12 and folic acid consumption during pregnancy programs the fetus to greater adiposity, insulin resistance, and glucose intolerance in adulthood. A better understanding of the fetal programming mechanisms may help us reduce the onset of insulin resistance, glucose intolerance, dyslipidemia, obesity, hypertension, diabetes mellitus, and other CNCD in the offspring during adulthood.

Objectives Data on the prevalence, clinical features and risk factors associated with paediatric diabetic neuropathy (DN) are scarce. Methods We retrospectively analysed data from the DPV registry, including patients under 20 years of age, treated for type 1 diabetes mellitus (T1D) between 2005 and 2021. Patients with non-diabetic neuropathy were excluded. Data came from centres in Austria, Germany, Luxembourg and Switzerland. Results 1,121 of the 84,390 patients included had been diagnosed with DN. Univariate analysis showed patients with DN to be older and predominantly female, with a longer duration of T1D, higher insulin dosages per kg and day, lower rates of insulin pump therapy, higher postprandial glucose-, higher HbA 1c -and higher cholesterol levels, and higher diastolic and systolic blood pressure values. There was also a larger proportion of smokers and higher prevalence of diabetic retinopathy. Median duration of diabetes at diagnosis of DN was 8.3 years. Multivariable analysis, adjusted for demographics revealed an increased risk for DN among female patients and those who were older, underweight (BMI-SDS), smoked cigarettes or had a longer duration of T1D or higher levels of HbA 1c and postprandial blood glucose. The presence of retinopathy and higher cholesterol levels were also linked to increased risk while not-using insulin pump therapy was not. Conclusions DN can develop after just a short duration of T1D. Prevention may be achieved by a lowering of HbA 1c -and postprandial glucose levels through improved glycaemic control. This warrants further investigation. The slight female predominance suggests further hormonal and genetic etiological factors.

Objectives Neurocognitive functions of children with type 1 diabetes mellitus (T1D) are reported to be poorer than those of healthy peers. The aim was to investigate the effects of age of onset of diabetes, metabolic control, and type of insulin regimen on neurocognitive functions in children and adolescents with T1D. Methods Forty-seven children aged 6–18 years, with T1D for at least five years, were included. Children with a known psychiatric disorder or chronic diseases other than T1D were excluded. Intelligence via the Wechsler children’s intelligence scale (WISC-R), short-term memory via the audio-auditory digits form B (GISD-B) test, visual motor perception via the Bender Gestalt test, and attention via the Moxo continuous attention and performance test, timing, hyperactivity, and impulsivity (Moxo-dCPT) were assessed. Results Compared with the T1D group, healthy controls had higher scores in terms of verbal intelligence quotient (IQ), performance IQ, and total IQ mean scores on WISC-R (p=0.01, p=0.05 and p=0.01, respectively). On the MOXO-dCPT test, the T1D group had higher impulsivity compared to the control group (p=0.04). Verbal IQ was better in the moderate control group than in the poorer metabolic control (p=0.01). Patients with no history of diabetic ketoacidosis (DKA) had higher performance, verbal and total intelligence scores than the group with history of DKA. Conclusions Poor metabolic control and a history of DKA in children with T1D adversely affected neurocognitive functions. It would be beneficial to consider the assessment of neurocognitive functions in T1D and to take the necessary precautions in follow-up.

Objectives The prevalence of childhood obesity increases globally, and noninvasive methods are needed to identify metabolic dysfunction and obesity-related complications such as pediatric metabolic associated fatty liver disease (MAFLD). We investigated whether uric acid (UA) and the macrophage marker soluble form of cysteine scavenger receptor CD163 (sCD163) can be used as biomarkers for deteriorated metabolism or pediatric MAFLD in children with overweight or obesity. Methods Cross-sectional clinical and biochemical data from 94 children with overweight or obesity was included. Surrogate liver markers were calculated, and correlations were investigated using Pearson’s or Spearman’s correlation test. Results UA and sCD163 correlated with BMI standard deviation score (r=0.23, p<0.05; r=0.33, p<0.01) and body fat (r=0.24, p<0.05; r=0.27, p=0.01). UA correlated with triglycerides (ρ=0.21, p<0.05), fat free mass (r=0.33, p<0.01), and gamma-glutamyl transferase (r=0.39, p<0.01). sCD163 correlated with the pediatric NAFLD fibrosis score (r=0.28, p<0.01) and alanine aminotransferase (r=0.28, p<0.01). No correlation was found between UA and pediatric MAFLD. Conclusions UA and sCD163 was identified as markers of a deranged metabolic profile, thus acting as easily accessible biomarkers for obesity and an obesity-related deranged metabolism. Furthermore, increasing levels of sCD163 could be a useful biomarker of pediatric MAFLD. Future prospective studies are warranted.

Objectives Fabry disease is an X-linked lysosomal disorder caused by decreased or absent alpha galactosidase enzyme. The enzyme deficiency leads to progressive accumulation of globotriaosylceramide (Gb-3) and its deacetylated form lyso-Gb3 in various tissue lysosomes that results in primarily lysosomal deterioration and subsequently mitochondrial, endothelial, and immunologic dysfunctions. Methods The endocrinological, metabolic, immunological and HLA status of 12 patients were evaluated. Results A total of 11 patients (91.6 %) had immunologic and/or endocrinologic abnormalities. fT4, anti-TPO, and anti-TG levels were increased in 1, 2, and 2 patients, respectively. Three patients had elevated proinflammatory cytokines. ANA profile, p-ANCA and c-ANCA were positive in 1, 1, and 2 patients, respectively. Tissue transglutaminase antibody was negative in all patients however P5 was diagnosed with Celiac disease at the age of 12 and on gluten free diet. All patients had distinct types of HLA apart from 2 patients with anti-TG and anti-TPO positive and there was no relationship between the HLA types and the autoimmunity biomarkers. Conclusions FD may have impact on endocrinologic and immunologic abnormalities even in the patients under ERT, therefore prevalence of these abnormalities may be higher in ERT naïve patients. However, apparently, they are less likely to cause clinical symptoms. Certain HLA alleles may contribute to the direct impact of immunological pathogenesis in FD by developing abnormal autoimmune biomarkers. To the best of our knowledge, this is the first study investigating HLA status of FD patients; therefore further studies are needed to elucidate the underlying mechanism of action.

Objectives The study purpose is to correlate clinical findings with rates of differentiated thyroid cancer (DTC) in a cohort of children presenting with thyroid nodules at a single institution since the adoption of the 2015 American Thyroid Association (ATA) Guidelines Task Force on Pediatric Thyroid Cancer . Methods Clinical, radiographic, and cytopathologic findings were retrospectively analyzed in a pediatric cohort (≤19 years) identified with ICD-10 codes for thyroid nodules and thyroid cancer from January 2017 until May 2021. Results We analyzed 183 patients with thyroid nodules. The mean patient age was 14 years (interquartile range 11–16) with a female (79.2 %) and white Caucasian (78.1 %) predominance. The overall DTC in our pediatric patient cohort was 12.6 % (23 out of 183). Most of the malignant nodules measured from 1–4 cm (65.2 %) with TI-RADS score of ≥4 (69.6 %). Among the fine-needle aspiration results (n=49), the highest frequency of DTC was within the malignant category (16.33 %), followed by suspicious for malignancy (6.12 %), then atypia or follicular lesion of undetermined significance (8.16 %), and lastly follicular lesion or neoplasm and benign with 4.08 % and 2.04 % respectively. Of the forty-four thyroid nodules that underwent surgical intervention, pathology was remarkable for 19 papillary thyroid carcinoma (43.18 %) and 4 follicular thyroid carcinoma (9.09 %). Conclusions Based on the analysis of our pediatric cohort in the southeast region at a single institution, adoption of the 2015 ATA guidelines could lead to an increased accuracy in detecting DTC while reducing the number of patients requiring interventions, such as FNA biopsy and/or surgeries. Further, based on our small cohort, it would be reasonable for thyroid nodules 1 cm or less to be monitored clinically with physical exam and ultrasonography, with further therapeutic or diagnostic intervention considered based on concerning features or parental shared decision making.

Objectives Ketone production is a physiological phenomenon that occurs during beta-oxidation of free fatty acids. Distinguishing physiologic ketosis from pathologic over-production/underutilization of ketones is critical as part of the diagnostic evaluation of disorders of carbohydrate metabolism, but there is limited literature on normal ketone production with fasting. Our aim is to measure fasting serum beta-hydroxybutyrate (BHB) concentrations in healthy children after an overnight fast. Methods Children ≤18 years of age were prospectively recruited from elective procedures through our surgery centers. Exclusion criteria included a history of diabetes, hypopituitarism, adrenal, metabolic or inflammatory disorders, dietary restrictions, trauma, or use of medications that might affect blood glucose. Serum glucose, cortisol, and BHB were assessed after an overnight fast. Results Data from 94 participants (mean 8.3 ± 5.7 years, 54 % male, 46 % female, were analyzed. Children ≤3 years of age (19) have significantly higher mean (0.40 ± 0.06 mmol/L) and median (0.4, IQR 0.2–0.6 mmol/L) BHB concentrations compared to children >3 years of age (75) with mean (0.21 ± 0.02 mmol/L) and median BHB (0.1, IQR 0.1–0.2 mmol/L) (p<0.0001). Fasting BHB levels of >1.0 mmol/L was rare (2 %, N=2) and 74 % (N=70) of participants had BHB levels <0.3 mmol/L. Conclusions BHB concentrations are significantly higher in young children (≤3 years of age) compared to older children. Fasting BHB levels >1.0 mmol/L are rare within our population and therefore may identify a value above which there may a greater concern for pathologic ketotic hypoglycemia. It is imperative to establish the normative range in children to differentiate physiological from pathological ketotic hypoglycemia.

Objectives Asians are particularly susceptible to obesity-associated disorders and rapid progression of obesity from childhood to adulthood. Data on the association between adipocytokine parameters, particularly adipocytokine ratios, and cardiovascular risk factors in childhood remain limited. Herein, we assessed the association of resistin, adiponectin, and leptin levels and leptin/adiponectin and resistin/adiponectin ratios with selected cardiovascular risk factors and the influence of unhealthy weight on such associations in children aged 9–10 years. Methods We included 380 children aged 9–10 years from three public elementary schools in Japan. Results The body mass index (BMI) was significantly higher in male preadolescents than in female adolescents (median 16.5 kg/m 2 vs. 16.2 kg/m 2 , p=0.032). No differences in height, weight, waist circumference (WC), waist/height ratio (W/Hr), total cholesterol and high-density lipoprotein cholesterol levels, or atherosclerosis index (AI) were observed between the sexes. Of the adipocytokine levels and ratios analyzed, only the leptin level and leptin/adiponectin ratio (L/Ar) were strongly and significantly positively correlated with the cardiovascular risk factors WC, W/Hr, and BMI (all p<0.05). The AI was not strongly correlated with any adipocytokine levels or ratios. Apart from the strong positive correlation between the L/Ar and W/Hr, no other significant associations were observed between any of the adipocytokine levels or ratios and the selected cardiovascular risk factors. Conclusions Our findings confirmed the value of adipocytokine ratios in risk assessment in pediatric populations, with leptin levels and leptin/adiponectin ratios strongly correlating with risk factors in children aged 9–10 years.

Objectives Compare the efficacy and safety of daily vs. monthly oral vitamin D 3 in treating symptomatic vitamin D deficiency in infants. Methods 90 infants with symptomatic vitamin D deficiency were randomized into Daily (D) [46 infants] and Bolus (B) [44 infants] groups to receive oral vitamin D 3 , daily (2000 IU/day) and bolus (60,000 IU/month) for three months respectively. Both groups received daily oral calcium @50 mg/kg/day. Serum calcium (Ca), phosphate (P), alkaline phosphatase (ALP), 25-hydroxy cholecalciferol [25(OH)D], parathyroid hormone (PTH) levels, urine calcium: creatinine ratio and radiological score were assessed at baseline, 4 and 12 weeks. At the end of 12 weeks, 78 infants were available for evaluation of efficacy and safety of both regimens. Results Both regimens led to a statistically significant increase in Ca and P levels and fall in ALP and PTH levels from baseline to 4 and 12 weeks of therapy, with no inter-group difference. Infants in group D had statistically significant higher mean 25(OH)D levels as compared to group B at 4 weeks (group D 130.89 ± 43.43 nmol/L, group B – 108.25 ± 32.40 nmol/L; p – 0.012) and 12 weeks (group D – 193.69 ± 32.47 nmol/L, group B – 153.85 ± 33.60 nmol/L; p<0.001). Eight infants [group D – 6/41 (14.6 %); group B – 2/37 (5.4 %), p=0.268] developed mild asymptomatic hypercalcemia without hypercalciuria at 12 weeks that corrected spontaneously within a week. Conclusions Both daily and monthly oral vitamin D 3 in equivalent doses are efficacious and safe for treating symptomatic vitamin D deficiency in infants.

Objectives Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder marked by massive cytokine release from macrophage and T-cell activation. Hallmarks include fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogemia, and elevations in ferritin and soluble IL-2 receptor. Given the association of HLH with inflammation and glucocorticoid therapy, the development of hyperglycemia is not unexpected. Descriptions of the prevalence of secondary diabetes in youth diagnosed with HLH are lacking. Methods Retrospective review from 2010 through 2019 of hospitalized youth 0–21 years diagnosed with HLH. The primary outcome of interest was the development of secondary diabetes, defined as a serum glucose 200 mg/dL or higher necessitating insulin therapy. Results Of 28 patients with HLH, 36 % (n=10) developed secondary diabetes. The only risk factor associated with secondary diabetes was an infectious cause of HLH (60 % vs. 27.8 %, p 0.041). Intravenous regular insulin was used in 80 % of patients with a mean duration of 9.5 days (2–24 days). Most (70 %) needed insulin within 5 days of starting steroids. Stays in the ICU were longer (median 20 vs. 3 days, p 0.007) and intubation more likely (90 vs. 45 %, p 0.041) among those with secondary diabetes. Mortality was high (16–30 %) regardless of insulin use (p 0.634). Conclusions One-third of hospitalized pediatric patients with HLH developed secondary diabetes requiring insulin therapy. Insulin is typically started within 5 days of initiating steroids, limited to IV infusions, and often is not needed by discharge. Secondary diabetes was associated with longer ICU stays and heightened risk of intubation.

Objectives Isolated ACTH deficiency (IAD) is defined as an impaired secretion of ACTH from the pituitary gland without any other anterior pituitary hormonal deficits. The idiopathic form of IAD has been described mainly in adults and is thought to be caused by an autoimmune mechanism. Case presentation Herein, we present an 11-year-old _prepubertal previously healthy boy, who suffered a severe hypoglycemic episode short after the initiation of thyroxine for autoimmune thyroiditis and was finally diagnosed with secondary adrenal failure due to idiopathic IAD, after all other etiologies were excluded, thought an extensive diagnostic work-up. Conclusions Idiopathic IAD is a rare entity of adrenal insufficiency in pediatrics that should be considered as an etiology of secondary adrenal failure in children, when clinical signs of glucocorticoid deficiency are present and other causes are excluded.

Objectives Transient infantile hypertriglyceridemia (HTGTI) is caused by mutations in the glycerol-3-phosphate dehydrogenase 1 ( GPD1 ) gene. HTGTI is characterized by hypertriglyceridemia, hepatomegaly, hepatic steatosis and fibrosis in infancy. Here, we reported first Turkish HTGTI patient with a novel mutation of GPD1 , having hypertriglyceridemia, hepatomegaly, growth retardation and hepatic steatosis. He is the first case who needs transfusion until 6th month in GPD1. Case presentation A 2-month-27-day-old boy, who had growth retardation, hepatomegaly and anemia suffered to our hospital with vomiting. Triglyceride level was 1603 mg/dL (n<150). Liver transaminases were elevated and hepatic steatosis was developed. He needed transfusion with erythrocyte suspension until 6th month. Etiology could not be elucidated by clinical and biochemical parameters. A novel homozygous c.936_940del (p.His312GlnfsTer24) variant was detected in the GPD1 gene by Clinical Exome Analysis. Conclusions GPD1 deficiency should be investigated in the presence of unexplained hypertriglyceridemia and hepatic steatosis in children especially in infants.

Objectives Severe vitamin C deficiency, or scurvy, presents as a syndrome of multisystem abnormalities associated with defective collagen synthesis and antioxidative functions. The many clinical features of scurvy lead to frequent misdiagnoses, as they can often point to other diseases, such as vasculitis, venous thrombosis and musculoskeletal disorders. As such, an extensive workup is recommended in cases in which scurvy is suspected. Case presentation A 21-month-old male patient and a 36-month-old female patient presented with difficulty in walking, painful joint movements, irritability, gingival hypertrophy and bleeding. After exhaustive investigations and risky invasive procedures, vitamin C deficiency was diagnosed in both cases, and the symptoms improved dramatically with vitamin C treatment. Conclusions The importance of taking a dietary history in pediatric patients is highly recommended. In cases where scurvy is considered, serum ascorbic acid levels should be checked to confirm the diagnosis prior to conducting invasive tests.

Osteopetrorickets is a rare complication of autosomal recessive (“malignant”) osteopetrosis. Its prompt diagnosis is essential, because early suspicion of infantile osteopetrosis enables treatment with human stem cell transplantation, depending on the gene involved. It is important to identify not only the characteristic radiological changes of rickets, but also the coexistence of increased bone density, so as not to miss this very rare entity. Herein, a brief case report is presented.