Band 38, Heft 2

Objectives We performed a meta-analysis to compare the effects of orlistat on body mass index and serum lipids in overweight and obese adolescents. Methods The meta-analysis was conducted to identify randomized controlled trials (RCTs) published up to 1 August 2024. PubMed, Embase, and Cochrane Library databases were searched. The outcome measures body mass index (BMI) and serum lipids, such as total cholesterol (TC), total triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The review of publications was conducted in accordance with the guidelines set forth in the Cochrane Handbook and the Preferred Reporting Project for Systematic Review and Meta-Analysis (PRISMA). Results This study has been registered with INPLASY (number INPLASY202480052). A total of 696 patients were included in five randomized controlled trials. The orlistat group reduced BMI compared to placebo in the short term (MD=−0.73, 95 % CI: −1.44 to −0.02, p=0.04, I 2 =73 %) but appeared to have little effect in the long term (MD=−1.72, 95%CI: −3.55 to 0.12, p=0.07, I 2 =84 %). The exciting thing is that orlistat can significantly improve blood lipid levels in children, TC (MD=−8.11, 95 % CI: −10.88 to −5.33, p<0.05, I 2 =0 %), TG (MD=−3.22, 95 % CI: −5.58 to −0.86, p<0.05, I 2 =0 %), LDL (MD=−6.06, 95 % CI: −8.75 to −3.37, p<0.05, I 2 =0 %), and HDL (MD=0.87, 95 % CI: 0.13–1.61, p<0.05, I 2 =31 %). Conclusions Orlistat has been linked to alter lipid levels in obese or overweight children. However, the evidence regarding its efficacy in reducing BMI is inconclusive, with inconsistent findings across short and long-term studies. Further randomized controlled trials are necessary to ascertain its long-term impact on prognosis.

Objectives Idiopathic central precocious puberty (iCPP) is the most common cause of precocious puberty in girls. However, research on the psychological outcomes of iCPP girls is limited. To evaluated the psychological characteristics in iCPP girls in comparison to prepubertal girls throughout the first diagnosis and six-month follow-up period. Methods Eighty-five girls, age 6–8 years, and their caregivers were enrolled to the prospective cohort study. Three Thai-standardized questionnaires were used as psychological assessment tools, including Children’s Depression Inventory (CDI), Parent Screen for Child Anxiety Related Disorders (SCARED) and Parent-Strengths and Difficulties Questionnaire (SDQ). Results Forty-six iCPP and 39 prepuberty girls were enrolled at baseline. No significant differences in psychological and behavioral problems between iCPP and prepuberty girls. However, the iCPP group exhibited a significantly higher proportion of “risk and problem” for emotional problems compares to the prepuberty group (7 vs. 0, p=0.01) while the prepuberty group exhibits the significantly proportion of “risk” for peer problems (6 vs. 0, p=0.007). At baseline, twelve percent of iCPP girls exhibited depression and mean CDI score was 8.1 ± 7.2 and 3.7 ± 2.3 (p=0.007) in iCPP and prepuberty group, respectively. At the 6-month follow-up, there was no significant difference in psychological outcomes between two groups. Conclusions There were no significant differences in psychological and behavioral problems in iCPP girls compared to prepubertal girls. However, the higher prevalence of emotional problems and depression observed in iCPP girls constitutes significant psychological issues that necessitate close monitoring.

Objectives Limited data are available on the hormonal response of children to venepuncture or intravenous cannulation (IVC). Catecholamines (epinephrine (E) and norepinephrine (NE)) have been traditionally recognized as stress hormones. Copeptin, the carboxyl-terminus of the arginine vasopressin (AVP) precursor peptide, is also a known marker for stressful stimuli, including myocardial infarction, critical illness, and sepsis. We aimed to measure the above stress markers in response to IVC in the pediatric population. Methods We measured plasma E, NE and serum copeptin concentrations in 100 children aged 5–17 years undergoing endocrine testing. Labs were drawn 1–3 min (min) after placement of IV cannula (baseline or 0 min) and then re-measured 20 min later (+20 min) while subjects rested in a quiet room. Results Between 0 and 20 min, the median (IQR) NE (n=99) changed from 349 (244, 482) pg/mL to 253 (184, 348) pg/mL (p<0.001); E (n=54) changed from 57 (43, 116) pg/mL to 57 (38, 96) pg/mL (p=0.024); Copeptin changed from 9.4 (6.3, 15.2) pmol/L to 9 (5, 13) pmol/L (p<0.001). The mean decrease (delta) was 106 pg/mL for NE (28 %, p<0.001), 16 pg/mL for E (18 %, p=0.042) and 2.7 pmol/L for copeptin (17 %, p=0.012). There was no correlation between the decrease (expressed as a percentage) in NE vs. E, E vs. copeptin, and NE vs. copeptin. Conclusions Our data suggest that the stress of IVC induces a rapid increase in NE, E, as previously described, as well as copeptin levels. The copeptin decrement, concordant with the catecholamine trend in the minutes after IVC, supports this peptide (and AVP) as a rapid response marker of stress, and has unclear practical implications for copeptin measurements in evaluating fluid and sodium metabolism disorders in children.

Objectives The aim of this study was to assess the impact of pre-operative imaging regarding selecting cases of children’s who underwent laparoscopic adrenalectomy due to adrenal masses in two tertiary medical centers. Methods We performed a retrospective review of all laparoscopic adrenalectomy performed at two tertiary medical centers in Israel between 2017 and 2023. Results Sixteen (n=16) patients, 10 girls and six boys, underwent laparoscopic adrenalectomy through a transperitoneal approach. The median age was 10 years (range: eight months to 17.3 years). Six masses were incidentalomas. Preoperative imaging (ultrasonography, CT, and MRI) demonstrated a mass in the right adrenal (n=9) and left adrenal (n=7), with tumor sizes ranging from 1.8 to 5.3 cm in maximum diameter. Operative results showed minimal blood loss and no conversions to laparotomy. There were no postoperative complications. Pathological diagnoses included neuroblastoma (n=8), cortical hormone-secreting tumors (n=3), pheochromocytoma (n=2), adrenal cortical adenoma (n=2), and adrenal metastatic Ewing sarcoma (n=1). Eleven masses were defined as benign and five as malignant tumors. Conclusions Laparoscopic adrenalectomy appears to be a safe and effective technique in selected cases with adrenal masses. Among our cohort, malignant masses were more common compared to the predominantly benign adrenal masses seen in adults. Vascular encasement was a major factor in determining the feasibility of the laparoscopic approach, with preoperative imaging playing a critical role in this assessment.

Objectives Subclinical hypothyroidism (SCH) is defined by elevated thyroid-stimulating hormone (TSH) levels (>5 mUI/L) and normal total and free thyroxine levels (fT4). There is ongoing debate over whether mild SCH should be treated. This study aims to assess the clinical course of normoponderal pediatric patients with SCH. Methods Retrospective study, involving normoponderal children and adolescents with SCH, followed at the Pediatrics Department of Hospital de Braga, from December 2007 to December 2022. Results We identified 47 children and adolescents with confirmed SCH. No sex predominance was found. The median age at diagnosis was 11 years. Most cases were idiopathic (59.6 %) and diagnosed during puberty (57.5 %). The majority (46.8 %) experienced spontaneous remission, while 38.3 % required levothyroxine (LT) therapy. Discharged patients were followed for a median of 25 months. No significant differences were seen in body mass index z-score, fT4 levels, heart rate, blood pressure, or lipid parameters. Significant differences were found in thyroid-stimulating hormone (TSH) levels and LT dosage. Thyroid peroxidase antibody (TPOAb) positivity was significantly correlated with SCH’s natural history. Although initial TSH levels were not significantly associated with SCH’s natural course, they predict treatment need. Individuals with initial TSH levels >6.47 mUI/L were more likely to require therapy. In the third year of follow-up, a significant strong negative correlation was found between TSH levels and high-density lipoprotein cholesterol. Conclusions SCH was self-limiting and benign in most cases. TPOAb positivity was a predictor of SCH’s natural history, and the need for treatment was predicted by initial TSH levels.

Objectives Auxology is essential for monitoring congenital adrenal hyperplasia (CAH). Data from prospective studies of newborn screening (NBS) are scarce. Methods Analysis of data extracted from a population-based prospective long-term follow-up survey study of children detected through NBS in Bavaria in 1999–2018. The study is based on standardized parent or patient questionnaires, supplemented by medical reports. Height, weight, and treatment data of 146 children/adolescents with classical CAH were analyzed. The entire observation period up to the age of 18 years was completed by 55 patients. Standard Deviation Scores (SDS) for height/body-mass-index (BMI) at different ages and the deviation of the height SDS at age 18 years from the parental target-height SDS were calculated. Results Male and female patients with CAH showed different and altered growth patterns, resulting in a median [IQR] SDS deviation from target height of −0.81 [−1.05, −0.41] in males and −0.35 [−0.90, 0.02] in females. BMI-SDS values were significantly (p<0.05) increased in males aged 6–16 years and in females aged 2 and 8–12 years. The average total steroid dose was higher in males (p<0.001). For deviations from target height, significant associations were found with sex (p<0.05) and adherence (p<0.01), but not with mutation group or steroid-dose. For BMI, none of the parameters showed a significant correlation. Conclusions Early treatment after NBS has helped to improve, but not to normalize, the development of height and weight in patients with CAH. Optimizing monitoring and treatment, preferably sex-specific, remains a challenge for clinical practice and research.

Objectives Exocrine pancreatic insufficiency has been demonstrated in type 1 diabetes (T1D); lower concentrations of pancreatic enzymes have been associated with metabolic risk (MR). Influence of puberty and MR factors on serum concentrations of amylase and lipase remain unexplored in Indian youth with T1D. 1) To characterize and predict determinants of serum amylase and lipase concentrations in adolescents/youth with T1D. 2) To assess relationship between amylase, lipase, and prevalence of MR. Methods Cross sectional, observational study on 291 (155 girls) adolescents/youth (10–24 years) with T1D. History, examination, body composition, biochemistry (glycated hemoglobin [HbA1c], thyroid stimulating hormone [TSH], lipids). Results Mean age, diabetes duration and HbA1c were 15.3, 7.0 years and 10.0 ± 2.1, respectively. Relative risk of lower amylase/higher lipase concentrations (<median) in participants with poor glycemic control (HbA1c>9.5 %) was 1.42 and 1.34, respectively, though these did not reach statistical significance. In pubertal participants, amylase was lower and lipase higher; association was not found with MR. Higher TSH and lower serum calcium were significantly associated with higher lipase (p<0.001). Conclusions We have characterized amylase and lipase concentrations across puberty; poor glycemic control tended to be associated with lower amylase and higher lipase, though these findings did not reach statistical significance. Amylase and lipase concentrations should be monitored in Indian adolescents with T1D, particularly in those with poor metabolic control, puberty, uncontrolled hypothyroidism, or reduced calcium intake, while further longitudinal and larger studies are needed to generalize these findings.

Objectives Graves’ disease is the leading cause of hyperthyroidism in children. Only a small percentage of pediatric patients achieve remission with anti-thyroid drug treatment (ATD), and both definitive therapies (thyroidectomy, or radioiodine thyroid ablation) cause lifelong hypothyroidism. Our objective was to evaluate the outcome of patients with pediatric Graves’ disease (PGD), treated at a single tertiary center, focusing on response to medical treatment, remission rate, adverse reactions (AR), definitive treatment (DT), and potential predictive factors for remission. Methods Data from clinical charts of 130 patients diagnosed with PGD between 2006 and 2021 were collected: epidemiological, clinical, biochemical characteristics, outcome, remission, adverse reactions (AR), and DT were registered. Predictive factors at diagnosis were evaluated for 88 patients diagnosed at our center. Results Our patients were 78 % female, 98 % Hispanic, with a median age of 12.7 years (range 1.7–17.3 years). Fourteen (11 %) had Down syndrome. Severe thyrotoxicosis (FT4>5.5 ng/dL) was seen at diagnosis in 66 %. Initially, 129/130 received ATD; during the study, 17 participants (13 %) reached remission, with a median ATD duration of 3.1 years (range 1.3–6.1 years). The chance of remaining hyperthyroid was 65 %. Only one patient relapsed 1.3 years post-ATD. Forty-six percent (59/129) needed DT, 31 % (40/129) were lost to follow-up, and 10 % (11/129) remained on ATD. AR affected 26 % of the patients and most (74 %) occurred within the first 3 months, half of them severe enough to discontinue ATD. No significant predictive factors were identified. Results ATD, our first-line treatment, resulted in low remission rates for Hispanic pediatric patients with severe thyrotoxicosis at diagnosis. Poor adherence issues contributed to the indication of DT (46 %) and loss to follow-up (31 %) during the studied period. Based on our findings, DT should be considered at 4 years of ATD in persisting PGD. Conclusions ATD, our first line treatment, resulted in low remission rates for Hispanic pediatric patients with severe thyrotoxicosis at diagnosis. Poor adherence issues contributed to the indication of DT (46 %) and loss to follow-up (31 %) during the studied period. Based on our findings, DT should be considered at 4 years of ATD in persisting PGD.

Objectives Mutations in the AVPR2 gene are the most common cause of nephrogenic diabetes insipidus (NDI). In-frame deletions of the AVPR2 gene are a rare variant that results in NDI. We report a novel variant of the p.H138del in an NDI family with twin male patients and three female carriers of different clinical phenotypes. Methods The proband’s blood genome was sequenced with a panel, and the variants were classified according to ACMG/AMP (2015) guidelines. X chromosome inactivation (XCI) was analyzed in the peripheral blood of his mother, grandmother, and maternal aunt, respectively. The haplotypes of the X chromosome were determined using their STR loci. Results A novel in-frame deletion in the AVPR2 gene was detected in monozygotic-twin boys, and his mother, grandmother, and maternal aunt were heterozygous carriers. The two boys showed typical NDI, and their mother and grandmother presented polydipsia, polydipsia, and polyuria, but the maternal aunt did not have similar symptoms. The blood XCI results of the mother, grandmother, and maternal aunt showed random inactivation (36.18 , 48.37, and 49.30 %, respectively). The X haplotype indicated that the variant of the mother and grandmother was on their activated X chromosomes(Xa), while the maternal aunt’s variant was on her inactivated X chromosome(Xi). Conclusions In-frame deletion of the AVPR2 gene within its functional domain can significantly affect protein function, which is one of the vital causes of NDI. The clinical variability of female carriers of AVPR2 is associated with underlying environmental and epigenetic factors or complex recombination of the X chromosomes.

Objectives Copeptin is secreted in isomolar amounts along with AVP. Its stability makes it a perfect biomarker of AVP deficiency. In children, dynamic GH tests were shown to stimulate copeptin. Here, we retrospectively studied the effect of clonidine on copeptin release. Methods This is a monocentric retrospective analysis of donated residual serum samples from 42 children with suspected growth hormone deficiency (GHD) who underwent clonidine stimulation between 2020 and 2023. Copeptin was measured in baseline, 30-, 60-, 90- and 120-min samples by BRAHMS Copeptin proAVP Kryptor immunofluorescence assay. Results There were 20 patients with GHD and 22 without; no patient had polyuria-polydipsia syndrome. Median age was 6.7 years (quartiles; 5.6–7.8), and the median height was −2.92 SDS (−3.42 to −2.34). The median baseline level of copeptin was 5.6 pmol/L (3.4–9.6). Median copeptin mildly decreased to 4.5 pmol/L (3.0–10.0) after 30 min; this change was not significant (p=0.45). Thereafter, median values remained low at 4.6, 4.6, and 4.6 pmol/L (60, 90, and 120 min). There was no correlation between baseline copeptin levels and the diagnosis of GHD. Conclusions The clonidine stimulation test does not stimulate copeptin release and is not suitable for the assessment of AVP deficiency in children.

Objectives Sialidosis type 1 is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the NEU1 gene, which encodes the sialic acid-degrading enzyme α-neuraminidase. Sialidosis type 1 is a milder form with a late-onset phenotype, characterized by progressive myoclonic epilepsy and ataxia with cherry-red spots. Sialidosis type 2 is an early-onset and more severe form presenting with dysmorphic features, hepatosplenomegaly and cognitive delay. Clinical diagnosis is usually supported by increased urinary bound sialic acid excretion and confirmed by genetic analysis or demonstration of α-neuraminidase enzyme deficiency in cultured fibroblasts. The aim of this study was to present a case of type 1 sialidosis, review the literature, and investigate genotype–phenotype correlations, symptom frequencies, and race-specific mutations in patients diagnosed with type 1 sialidosis. Case presentation We report herein a family of four Turkish siblings affected with sialidosis type 1 associated with a homozygous variant, c.403G>A p. (Asp135Asn), in the NEU1 gene. A systematic literature review on sialidosis type 1 was carried out, by the PubMed database was searched using keywords included sialidosis and/or NEU1 gene. We selected case reports or series that included genetically confirmed type 1 sialidosis from 1996 to 2023. So far, nearly genetically confirmed 80 patients from unrelated 65 families, more than 40 NEU1 disease causing mutations, have been identified in patients with sialidosis type 1. Among the reported mutations, missense variants are the most common, and few nonsense, frameshift, exonic duplications or small deletions have been reported. c.239C>T p. (Pro80Leu) variant in Chinese and Japanese patients, c.649G>A p. (Val217Met) variant in Japanese patients, c.880C>T p. (Arg294Cys) variant in Indian patients, c.629C>T p. (Pro210Leu) variant in Ecuadorian patients, c.982G>A p. (Gly328Ser) variant in Italian patients, and c.403G>A p (Asp135Asn) and c.625del p. (Glu209Serfs*94) variants in Turkish patients were found higher. Conclusions Race-specific variants were found with higher percentages in certain populations.

Objectives Hypothalamic hamartoma (HH) is a rare condition that causes epilepsy and central precocious puberty (CPP) at an early age. In this report, we describe a child with CPP secondary to HH and discuss the current literature. Case presentation A 26-month-old girl was brought to our hospital for evaluation of breast enlargement. Her parents were first-degree relatives. Her breast development was categorized as Tanner stage 3, and her bone age was 7 years/4 months. Laboratory investigations were consistent with CPP. Brain magnetic resonance imaging (MRI) revealed a smooth, spherical lesion in the hypothalamus, located in the tuber cinereum and measuring 11 × 9 × 10 mm. The lesion was identified as a HH. The patient was started on gonadotropin-releasing hormone analogue therapy, specifically 200 μg/kg/month of leuprolide acetate (3.75 mg depot) administered intramuscularly every 28 days. During the 2-year follow-up, her breast development remained at Tanner stage 3, and she did not develop axillary or pubic hair. Her bone age was 7 years/6 months (chronological age; 4 years/2 months). 2-year follow-up MRI showed no change in the size or contours of the HH compared with the initial diagnosis. No side effects from the medical treatment were observed during the follow-up period. Conclusions In patients under the age of 4 years showing signs of CPP, HH should be considered as diagnosis. All patients receiving medical treatment should be closely monitored.

Objectives Kallmann syndrome (KS) is a rare genetic disorder marked by hypogonadotropic hypogonadism and either anosmia or hyposmia. It exhibits genetic heterogeneity, with mutations identified in only 30 % of cases, involving various genes such as KAL1, FGFR1, FGF8, CHD7, and SOX10. Here, we present a case of gonadotropin deficiency associated with KS, observed in both a mother and her daughter, the latter conceived through assisted reproductive technology using the mother’s ovum. Case presentation A 12-year-old female presented with short stature and lack of growth over the past year. Initial laboratory testing revealed mildly elevated TSH (8.348 uIU/mL), normal free T4 (0.9 ng/dL), and positive thyroid antibodies, including elevated TPO (629 IU/mL). Her growth hormone peak response to stimulation testing was 12.8 ng/mL, and GnRH stimulation indicated a peak LH value of 1.78 mIU/mL and a peak FSH value of 2.83 mIU/mL, consistent with hypogonadotropic hypogonadism (HH). Genetic testing identified a novel heterozygous variant in the SOX10 gene, predicted to be damaging, and also present in her mother, who had Kallmann syndrome. The patient was initiated on low-dose estrogen therapy with estradiol patches to stimulate growth and pubertal development. Conclusions This case highlights the transmission of a novel SOX10 mutation in a mother-daughter pair through assisted reproductive technology, bypassing the typical infertility-related barriers to genetic inheritance in KS. The autosomal dominant inheritance pattern observed in this family emphasizes the importance of genetic counseling when reproductive assistance is considered. This case also suggests that SOX10 mutations may contribute more broadly to the pathogenesis of KS and related HH.

Objectives Sepiapterin reductase deficiency (SRD) is a rare dopa-sensitive neurotransmitter disorder caused by autosomal recessive mutations in the sepiapterin reductase gene. The triad of paroxysmal stiffening, oculogyric crises, and hypotonia are highly suggestive in some patients. However, in other patients, the clinical picture may be nonspecific and remain under-recognized and misdiagnosed as cerebral palsy. Case presentation We present a nine-month-old boy who initially presented with hypotonia and developmental delay, diagnosed as vitamin B12 deficiency. Upon he did not respond to vitamin replacement treatment, he was diagnosed with SRD by whole-exome sequencing (WES). The boy improved dramatically under treatment with L-dopa, 5-hydroxytryptophan and BH4. Conclusions We aim to emphasize that SRD can present with nonspecific symptoms, leading to a diagnostic delay for this rare but treatable disease. Moreover, our case is the first to demonstrate the clinical benefit of BH4 add-on treatment. Early intervention is crucial for good outcome and neurodevelopment.