Band 38, Heft 3

Objectives Surgery interventions for thyroid disorders are rare in pediatric population. This study aims to present our institution’s 10-year experience regarding the surgical treatment and outcomes of thyroid pathologies in children and review the literature. Methods All pediatric patients who underwent thyroid surgery at our institution from April 2013 to October 2023 were retrospectively reviewed. Results The study included 57 patients with a median age of 15 years. 38 patients (66.6 %) were female, and 19 patients (33.3 %) were male. The most common indication for thyroid surgery was a nodule (71.9 %), followed by Graves’ disease (10.5 %), multinodular goiter (8.7 %), and familial multiple endocrine neoplasia syndrome (8.7 %). Of the 57 patients, 36 (63.2 %) were diagnosed with thyroid neoplasia, with 28 (77.8 %) having papillary thyroid carcinoma (PTC), three (8.3 %) having medullary thyroid carcinoma (MTC), two (5.6 %) having follicular thyroid carcinoma (FTC). Temporary unilateral vocal cord paralysis and permanent unilateral vocal cord paralysis were seen in three patients (5.3 %) and in two patients (3.5 %) respectively. Persistent hypocalcemia and permanent hypoparathyroidism were noted in two patients (3.5 %), while transient hypocalcemia was observed in 13 patients (22.8 %). The presence of neoplasm did not appear to be associated with the incidence of hypocalcemia or vocal cord paralysis (p=0.115 and 0.652, respectively). Conclusions Thyroid pathologies in pediatric patients necessitate a multidisciplinary approach. Surgical management should be carefully evaluated in accordance with pediatric guidelines. Complication rate significantly decreases when surgery is performed by experienced surgeon.

Objectives The authors sought to assess whether the age of 18 reflects a true pathological inflection point that justifies transitioning between pediatric and adult paradigms of care with differentiated thyroid cancer (DTC). Methods A retrospective chart review was conducted for patients aged 12–24 undergoing hemithyroidectomy or total thyroidectomy for papillary or follicular thyroid carcinoma from 2010 to 2020. Results A total of 153 patients receiving surgery for DTC were assessed for pathological stage, nodal metastasis, and thyroid neoplasm characteristics. When comparing pathologic tumor staging of patients <18 vs. ≥18 years old, there was a significant relationship between age and pT stage (p=0.009), but not between age and pN stage (p=0.319). However, when comparing patients ≤15 vs. >15 years, there was a significant relationship between age and pT stage (p=0.015) and age and pN stage (p=0.016). Patients ≤15 years of age most commonly had stage pT2 tumors (48.9 %, n=22), whereas most >15 years had stage pT1 tumors (37.9 %, n=41). Of patients whose lymph nodes were analyzed, patients ≤15 years were most likely to have pN1b disease (31.1 %, n=14), while patients >15 years were most likely to have pN0 disease (33.3 %, n=36). Conclusions In this sample, separating children and adults at an age of 15, rather than 18, yielded more significant differences in risk of nodal involvement. Markers of invasive histology were more common in patients older than 15, while nodal involvement was more common in patients 15 and under.

Objectives There is limited research on thyroid function in pediatric patients with cystic fibrosis (pwCF). This study aimed to determine the frequency of thyroid dysfunction in children and adolescents with CF and to evaluate iodine deficiency and selenium status in pwCF. Methods Sixty-two CF patients and 62 control subjects were evaluated. The anthropometric measurements, nutritional status, FEV1(Forced-expiratory-volume in 1 s) percentage, thyroid function tests (TSH, FT4, FT3), urinary iodine and selenium levels, hospitalization status in the last six months, antibiotic usage, and colonization status with staphylococcus or pseudomonas were assessed for the cases. Results The mean age of the patient group was 10.84 ± 4.04 years. All CF patients were receiving multivitamin supplementation. Malnutrition was present in 50 % of patients, bacterial colonization in 29 %, FEV1 decrease in 38.5 %, subclinical hypothyroidism (SH) in 12.9 %, iodine deficiency in 87 % and exocrine pancreatic insufficiency in 100 %. T3 levels were found to be higher in pwCF. No significant difference was found between malnutrition and FEV1 and urinary iodine and selenium levels. Compared to the control group, pwCF had lower urinary iodine levels. Conclusions To the best of our knowledge, our study is one of the few in the literature to investigate urinary selenium levels alongside iodine in PwCF. Further research is needed to clarify and interpret elevated urinary selenium levels in this context. It was shown that iodine deficiency and the rate of SH were relatively high in pwCF. However, it was still thought that correcting iodine deficiency in these patients could improve thyroid dysfunction associated with CF.

Objectives The association of celiac disease (CD) in type 1 diabetes mellitus (T1DM) is well-established, yet variation exists in screening practices. This study measures the accuracy of early screening with tissue transglutaminase immunoglobulin A (TTG-IgA) and endomysial antibody (EMA) in newly diagnosed T1DM. Methods This is a retrospective study of children with T1DM between 2013 and 2019 with early CD screening and follow-up. Data elements included anthropometrics, serologies, blood pH, bicarbonate, and Hemoglobin A1c. Celiac serologies were analyzed using chi-square and receiver operating characteristic curves to calculate optimal levels for predicting CD. Results A total of 1,292 children met inclusion criteria with 142 having positive celiac serologies; 47 (33.1 %) of whom were subsequently diagnosed with CD – an incidence of 3.6 %. All subjects with positive EMA and TTG-IgA ≥8 times upper limit of normal were diagnosed with CD. Gastrointestinal symptoms, BMI, and thyroid disease were not statistically significant variables in this cohort, although there was a trend toward CD in lower BMI patients and higher TTG IgA in those with markedly elevated HgbA 1c . Conclusions Early celiac screening in T1DM is reliable and promotes timely CD diagnosis and treatment. Although transient positive celiac serologies were noted, the degree of TTG-IgA elevation and EMA positivity are strong predictors of coexisting CD. Larger prospective studies using these assays will further define the risk stratification algorithm that is needed for our T1DM community.

Objectives The prevalence and predisposing factors to metabolic dysfunction-associated fatty liver disease (MAFLD) in children with type 1 Diabetes (T1D) living in developing countries are unknown. Methods A cross-sectional study was conducted in children with T1D. The presence of liver fat and tissue stiffness were assessed by ultrasonography and shear-wave elastography (SWE), respectively. The SWE values were correlated to body mass index (BMI), glycemic control, disease duration, and gamma-glutamyl transferase (GGT). Healthy non-obese children (n=36) were recruited as controls. Results One hundred children with T1D were grouped (Group A-C) according to the disease duration (<5, 5–10, and >10 years, respectively). The mean diabetes duration and glycated hemoglobin were 5.9 ± 4.0 years and 8.2 ± 0.55 %, respectively. The mean SWE values were significantly higher in the patient groups compared to controls (5.07 ± 0.67, 5.27 ± 0.65, 5.16 ± 0.50, vs. 4.80 ± 0.82 kPa, p-value 0.006). The liver stiffness based on SWE showed a positive but weak relationship with BMI, diabetes duration, glycemic control, and GGT levels. A significantly higher number of children with T1D had MAFLD [9(20 %), 7(24.1 %), 7(26.9 %), vs. 1(3 %), p-value <0.001] based on ultrasonography. Conclusions Children with T1D showed higher liver stiffness values than controls. A weakly positive relationship of liver stiffness was observed with BMI, duration of diabetes, glycemic control, and serum GGT. Approximately one-fourth of children with diabetes showed sonographic evidence of hepatic steatosis. Larger studies are needed to ascertain the effects of obesity, diabetes duration, and metabolic control on the prevalence and progression of MAFLD in children with T1D.

Objectives The gonadotropin-releasing hormone (GnRH) provocation test is crucial for diagnosing central precocious puberty (CPP). However, due to its invasion and high cost, it is essential to find a simpler biomarker. This study aimed to investigate the feasibility of fasting insulin (FINS) and insulin-like growth factor-1 (IGF-1) as potential biomarkers for diagnosing girls with CPP and to analyze their effects on puberty development. Methods From May 2023 to June 2024, we retrospectively analyzed 145 girls in the growth clinic of the Third Affiliated Hospital of Zhengzhou University, including 80 CPP girls as the case group and 65 normal growth and development girls as the control group. Collect their growth and development parameters and blood samples. The levels of FINS, IGF-1, and sex hormones were detected and compared between the two groups. Results Compared with the control group, girls in the CPP group showed higher levels of FINS, IGF-1, and IGF-1 standard deviation score (IGF-1 SDS) (p<0.001). Multivariate logistic regression analysis showed that the risk of CPP increased with the increase of FINS, IGF-1, and IGF-1SDS levels [OR=1.141, 95 % CI=(1.029–1.265), p<0.05; OR=1.062, 95 % CI=(1.011–1.116), p<0.05; OR=1.610, 95 % CI=(1.029–2.520), p<0.05]. The areas under the curve of FINS, IGF-1, IGF-1SDS, and their combination in the diagnosis of CPP were 0.759, 0.716, 0.707, and 0.777, respectively. Conclusions Elevated FINS and IGF-1 levels in girls with CPP indicate their potential as effective biomarkers for early screening and diagnosis of CPP.

Objectives This study aimed to assess differences in insulin-like growth factor 1 (IGF-1) levels following the transition from somatropin to lonapegsomatropin in patients with pediatric growth hormone deficiency (GHD). Secondary objectives included the evaluation of dose titrations based on IGF-1 levels, changes in annualized height velocity (AHV) and body mass index (BMI), and assessing reported adverse effects associated with lonapegsomatropin therapy. Methods A single-center, retrospective review was conducted including patients diagnosed with pediatric GHD initially treated with somatropin who transitioned to lonapegsomatropin between January 1, 2022, and December 31, 2023. Results Fourteen patients (median age: 9 years) were included. The median somatropin dose was 0.18 mg/kg/week (range, 0.09 to 0.29) at the time of transition and patients were initiated on a median lonapegsomatropin dose of 0.23 mg/kg/week (range, 0.15 to 0.26). This resulted in an IGF-1 increase of 2.3 SDS post-switch. Dose adjustments were made based on IGF-1 levels. Five patients required immediate dose reductions; four of these required further adjustments due to persistent elevation. There were no serious adverse effects reported. Conclusions Lonapegsomatropin may be a favorable option to reduce injection burden for those with pediatric GHD, though the manufacturer’s recommended starting dose of 0.24 mg/kg/week may require individualization. Careful monitoring and dose adjustment based on IGF-1 levels are necessary to maintain safety and efficacy.

Objectives To develop a clinical model for predicting the occurrence of Central Precocious Puberty based on the breast development outcomes in chinese girls. Methods This is a retrospective study, which included a total of 1,001 girls aged 6–9 years old who visited the outpatient clinic of Beijing Children’s Hospital from January 2017 to October 2022 for “breast development”. Participants were categorized into pubertal development (PD) cohort and simple premature breast development (PT) according to the criteria, and information was collected and tested for relevant indicators. After dealing with missing data, logistic regression, LASSO regression and random forest were used to screen the variables, and support vector machine models were built with SMOTE oversampling and ten-fold cross-validation to assess the effectiveness of the models in the training and validation sets. Results A total of 1,001 girls were included in the analysis, of whom 369 (36.9 %) were diagnosed with PD and 632 (63.1 %) with PT. Body mass index (BMI), bone age (BA), luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), uterine diameter, and ovary volume were identified as the final predictor variables by three variable screening methods. The AUC of the constructed disease diagnostic model was 0.9457 in the developmental cohort and 0.8357 in the external validation group, and sensitivity analyses revealed that the performance of the constructed models with different variable selection strategies was similar. Conclusions A disease diagnostic model was developed that may help predict a girl’s risk of diagnosing central precocious puberty.

Objectives Premature ovarian insufficiency (POI) affects 1 in 10,000 children, with its molecular causes largely unknown. Adult studies suggest that low androgen levels induce ovarian insufficiency, but data on about this in children is limited. This study aims to assess the prevalence of low androgen levels in childhood POI and its relationship with adrenal insufficiency. Methods Idiopathic POI adolescents were categorized into two groups based on DHEAS and total testosterone (TT) measured by chemiluminescence. Low androgen group (LAG) was defined using cut-offs according to Tanner pubarche staging. Demographic, clinical, and laboratory data were compared. Morning cortisol <7 μg/dL and/or ACTH >96 or <5 pg/mL were planned to undergo ACTH stimulation testing, with a peak cortisol response <18 μg/dL considered insufficient. Results Forty-three adolescents, mean age 15.5 ± 1.3 years with a 46, XX karyotype, normal FMR1 mutation, FSH levels >40 mIU/mL, and low AMH levels were included. In 14 cases (37.8 %), DHEAS and TT were low. In the LAG, pubarche was absent in seven patients, and initial height SDS was significantly lower. Morning cortisol ranged from 7.9 to 23.5 μg/dL, with an ACTH of 29.4 ± 9.7 pg/mL. No differences in adrenal steroids or correlations between DHEAS and ACTH were observed. Conclusions Diminished androgen levels are prevalent in children with idiopathic POI. The potential for this condition to increase the risk of adrenal insufficiency and its impact on secondary ovarian insufficiency remains unclear. This study, the first of its kind in children, underscores the potential role of genetic factors in zona reticularis and ovarian development.

Objectives Tangier disease (TD) is a rare autosomal recessive condition characterized by high-density lipoprotein (HDL) deficiency; involving symptoms of polyneuropathy, hyperplastic orange-yellow tonsils, vision disorder, and sudden cardiac death. The major clinical symptoms of TD may not all be co-present. This study evaluates patients diagnosed with TD in childhood to improve the possibility of early diagnosis of asymptomatic cases by reporting our patients’ clinical characteristics in order to minimize delayed diagnosis and emphasize the importance of TD, easily detected by HDL measurement. Methods This retrospective and cross-sectional study investigated seven patients from three different families diagnosed with TD. Results Four of seven patients were girls. Median age was 5.7 years at symptom onset and 6.5 years at diagnosis. The index case presented with neuropathy findings, and TD was diagnosed based on genetic analysis. Low lipid levels were determined in a sibling and cousins with cardiac death and gait disturbance in the family. TD was confirmed by genetic investigation. Our other patients were evaluated due to anemia, thrombocytopenia, yellow-orange hypertrophy in the tonsils, and organomegaly. Diagnosis was established with genetic analysis and low HDL. No coronary artery disease or ocular involvement was observed in any case. Conclusions All patients presenting with neuropathy and gait disorders should undergo detailed tonsil examinations and HDL tests. Genetic analysis should be carried out if necessary. Family screening should be recommended to patients with consanguineous marriages after diagnosis of TD.

Objectives Differences of sex development (DSD) refer to various congenital conditions affecting the urogenital and hormonal systems. Accurate diagnosis and personalized management are crucial for supporting patients through complex decisions, such as those related to gender identity. Methods This study represents the first comprehensive investigation into DSD in Iran, analyzing patient’s clinical and genetic data between 1991 and 2020. Karyotype analysis was performed on 69 patients without a molecular diagnosis, with sex chromosome DSD excluded. Presence of SRY gene evaluated in all sex reversal patients. Whole exome sequencing (WES) was used for 26 undiagnosed patients, revealing pathogenic variants in WT1 , NR5A1 , DHX37 , AR , CYP17A1 , and LHCGR genes. Results The most common diagnosis was testicular TDSD, identified in 42 patients (60.86 %), with the SRY gene being the primary cause in 36 of these patients. The study highlights the importance of genetic analysis in identifying novel and rare gene variants, particularly within the steroid hormone and gonad differentiation pathways, for both 46, XY and 46, XX DSD. Conclusions These findings emphasize the need for genetic analysis in providing personalized patient care and tailored counseling to help individuals navigate complex decisions, including those involving gender identity.

Objectives Kisspeptin plays a major role in the onset of puberty by stimulating the gonadotropin-releasing hormone (GnRH) neurons. The aim of this study was to investigate whether GnRH inhibits kisspeptin secretion via a negative feedback mechanism and potential associations between kisspeptin levels and other hormones of importance for pubertal onset. Methods Thirteen girls with suspected central precocious puberty underwent a GnRH stimulation test twice in a randomized, placebo-controlled manner. Blood was sampled up to 150 min after an IV injection of either Relefact LHRH ® or saline. The levels of kisspeptin, acylated ghrelin, ultrasensitive oestradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), insulin and glucose were analysed. Results Baseline kisspeptin levels ranged from 9.9 to 201.6 pg/mL. Neither area under the curve for kisspeptin levels nor peaks were significantly lower after the GnRH injection compared to placebo. Baseline kisspeptin and glucose levels tended to be associated (rho=0.55, p=0.051) but no other associations were found between kisspeptin and other hormones. Conclusions Basal levels of kisspeptin vary widely in young girls. We found no evidence of a negative feedback mechanism of GnRH on kisspeptin in this small pilot study. The suggested association between kisspeptin and glucose levels needs further investigations.

Objectives Phenylketonuria (PKU) and tyrosinemia type 3 (HT3) are both rare autosomal recessive disorders of phenylalanine-tyrosine metabolism. PKU is caused by a deficiency in phenylalanine hydroxylase (PAH), leading to elevated phenylalanine (Phe) and reduced tyrosine (Tyr) levels. HT3, the rarest form of tyrosinemia, is due to a deficiency in 4-hydroxyphenylpyruvate dioxygenase (HPD). Case presentation We report a 5-year-old girl diagnosed with both PKU and HT3. She presented with elevated Phe levels in neonatal screening, and subsequent biochemical tests revealed both hyperphenylalaninemia and elevated Tyr levels. Genetic analysis confirmed the diagnoses, identifying homozygous mutations in both the PAH and HPD genes. Dietary management to maintain optimal Phe and Tyr levels proved to be challenging due to the presence of these two coexisting pathologies especially during infections and due to dietary non-compliance, necessitating frequent adjustments in the treatment strategy. Conclusions This case highlights the importance of considering multiple metabolic disorders in patients with unexplained clinical and biochemical findings. Early diagnosis and stringent dietary management are crucial for preventing neurological damage and ensuring favorable outcomes in patients with concurrent metabolic disorders.

Objectives Acrodermatitis dysmetabolica (AD) is a dermatologic manifestation associated with inherited metabolic disorders (IMDs), distinct from acrodermatitis enteropathica, which occurs solely due to zinc deficiency. Case presentation This report presents two pediatric cases: a 30-month-old girl with maple syrup urine disease (MSUD) experiencing AD secondary to severe isoleucine deficiency due to a protein-restricted diet, showing improvement with dietary adjustments, and a 2.5-month-old boy infant with propionic acidemia (PA) who developed AD alongside septic shock, which progressed despite intervention. Conclusions These cases emphasize the importance of identifying AD in IMDs and the critical need for meticulous monitoring of amino acid levels, as deficiencies may lead to severe complications.

Objectives Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder of lipoprotein metabolism associated with significant morbidity and early mortality. The conventional management with lipid-lowering drugs and lipoprotein apheresis is unable to consistently achieve guidelines recommended low-density lipoprotein cholesterol (LDL-C). We aim to describe the efficacy of Evinacumab, a recently approved monoclonal antibody, in lowering LDL-C in an Indian girl with HoFH. Case presentation A 16-year-old girl was diagnosed with HoFH at age two years after the appearance of cutaneous and tendo-calcaneus xanthomas. Genetic testing revealed a pathogenic homozygous deletion in the LDL receptor (LDLR) gene. Despite lifestyle measures, a low-fat diet, and maximum doses of atorvastatin and ezetimibe, her average LDL-C level remained 320.3 mg/dL over the past decade. Her caregivers did not accept LDL-apheresis. She also did not respond to Evolocumab therapy. The patient developed progressive calcific aortic stenosis and concentric left ventricular hypertrophy, necessitating aortic valve replacement surgery at age 16 years. The recent addition of Evinacumab to her lipid-lowering drug regimen, resulted in a significant LDL-C reduction of 76.16 %, bringing levels down to 82 mg/dL. These levels were sustained over the last four months. Conclusions Evinacumab offers a promising option for managing high-risk and difficult-to-treat HoFH patients. This is the first Indian child receiving Evinacumab for HoFH.