Band 38, Heft 6

Introduction Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease beginning before 16 years. Inflammatory cytokine, medication, and genetic factors may lead to puberty disorders in children with JIA. The main objectives of this systematic review were to elucidate the impact of JIA on puberty and identify the influential factors that disrupt puberty. Content A systematic literature review was performed on pubertal disorders from Medline, Google Scholar, and Scopus databases. This systematic review followed the preferred reporting items for systematic review guidelines. The initial search yielded 4,011 articles: identified by Google Scholar (3,880), PubMed (99), and Scopus (940). Finally, 11 articles were retained. Summary and Outlook The age of menarche onset, Tanner stage, and pubertal signs were later compared with controls. The mean age of menarche onset ranged from 12.0 ± 0.3 to 13.39 ± 0.93 years for the JIA girls. This delay was more reported in the polyarticular and oligoarticular subtypes. Menstrual irregularities, metrorrhagia with irregular cycles, primary oligomenorrhea, and secondary amenorrhea were also reported. Factors found to influence delayed menarche and puberty were steroid use, JIA subtype, disease duration, and age at onset. Any studies have focused on the effect of puberty on JIA outcomes. Overall, our review revealed that pubertal disorders are frequent in JIA patients with polyarticular and systemic subtypes. However, some influencing factors remain editable if well-assessed and controlled.

Introduction Inflammatory bowel diseases (IBDs) have an increasing incidence in the pediatric population. The dysabsorptive effects of this condition often lead to a decrease in linear growth. However, the effectiveness and safety of growth hormone (GH) therapy in this population is still a topic of debate, with studies showing conflicting results. Content MEDLINE, Embase, and Cochrane Library databases were systematically searched according to the PRISMA guidelines. All experimental studies featuring children with IBD receiving GH therapy were included. In addition, a trial sequential analysis (TSA) was conducted to determine the sample size required for each outcome. The prospective registry was carried out under protocol CRD42024563079. The total data set comprised eight studies involving 127 patients with IBD, 78 (61.41 %) of whom received GH therapy, with a mean follow-up duration of 1.3 years. A statistically significant effect of GH was found in increasing the height standard deviation score (HtSDS) of children with IBD (standardized mean difference – SMD=1.07; CI=0.58, 1.56; p<0.0001). When comparing children who received GH with controls, no significant improvement in HtSDS was observed (SMD=0.18; CI=−0.73, 1.08; p=0.70). However, meta-regression analysis indicated that a longer follow-up was associated with a greater improvement in the HtSDS (p=0.04). Regarding height velocity (HV), a significant increase was found when comparing measurements before and after the initiation of hormone therapy (mean difference – MD=4.09; CI=2.58, 5.60; p<0.0001). An increase in HV was also noted in children receiving GH compared to the control group (MD=4.47; CI=2.03, 6.90; p=0.0003). No significant changes in the Pediatric Crohn’s Disease Activity Index (PCDAI) were detected, comparing values before and after the start of treatment (MD=−10.09; CI=−22.29, 2.10; p=0.10). The overall prevalence of any adverse effect was estimated at 15.51 % (95 % CI: 2.32–58.70 %). Most common reaction was itching at injection sites. TSA indicated a low risk of overestimating or underestimating the intervention’s effect on the analyzed outcomes. Summary Our study points to the effectiveness and safety of GH therapy in children with IBD and growth impairment. Outlook Further randomized controlled trials (RCT) with standardized methodologies and extended follow-up periods are necessary to confirm these findings.

Introduction Neonatal hypoglycaemia is the most common metabolic disorder of various causes, relatively rare being MODY (Maturity Onset Diabetes of the Young). Content Data search of relevant articles focused on hypoglycaemia in carriers of selected MODY gene mutations published from 2007 to 2022 was performed in databases Medline, PubMed, Cochrane and UptoDate based on key words: ‘hyperinsulinemic hypoglycaemia’, ‘congenital hyperinsulinism’, ‘MODY’, ‘ HNF4A mutation’, ‘ HNF1A mutation’. Summary Loss of function of HNF4A and HNF1A genes comprises approximately to 5.9 % of diazoxide responsive hyperinsulinemic hypoglycaemia, which may appear in 15 % HNF4A mutation carriers. A typical finding of HNF4A mutation carriers with neonatal hypoglycaemia was a birth weight above 4000 g or above 97th percentile. Outlook Although mutations in MODY genes represent a rare cause of neonatal hypoglycaemia, they should be considered in the differential diagnosis, particularly in cases of persistent hypoglycaemia requiring intensive care.

Objectives Newborns of diabetic and obese/overweight mothers face long-term metabolic risks. Untargeted cord blood metabolomic analysis using quadrupole time-of-flight liquid chromatography/mass spectrometry (Q-TOF LC/MS) was performed to explore metabolic alterations and pathways in these high-risk infants. Methods Cord blood samples were collected from 46 newborns born to mothers with gestational diabetes (10), obesity (14), overweight (18), type 2 diabetes mellitus (3), type 1 diabetes mellitus (1), and 20 newborns born to healthy mothers. Q-TOF LC/MS was used to investigate the alterations in cord blood metabolomic profiles. Data processing was conducted using MZmine 2.53. Putative metabolites were idendtified using MetaboAnalyst 6.0. Results Distinct metabolite profiles were observed between diabetes and control groups. Significant identical trend in 19 metabolites were determined in both diabetes and obesity + overweight group vs. control group. Key pathways included steroid and bile acid biosynthesis. Upregulated oxidative stress, clues to sphingophospholipid metabolism, high levels of dihomo-gamma-linolenic acid (DGLA), pantothenic acid, and TRH were detected. The kynurenine pathway was prominent in the diabetes group. Conclusions Estrogen metabolites from the 16- and 2-pathways may indicate metabolic risk, with increased downstream flux under diabetic conditions. Accelerated bile acid synthesis may alter fetal metabolic programming, since bile acids play crucial roles in cellular energy regulation and signaling. Elevated pantothenic acid, essential for the production of coenzyme-A, suggests significant alterations in carbohydrate, protein, and fat metabolism. High serum DGLA levels emerge as a potential biomarker for metabolic abnormalities. Increased plasma kynurenines could predict cardiovascular risks. Larger targeted studies are required to validate these metabolic profiles and pathways.

Objectives The COVID-19 pandemic brought about major changes, such as lifestyle changes, modification in telecommunication, as well as increased mental and psychological burden. This has raised concerns regarding its impact on the quality of life of children and adolescents with type 1 diabetes. To detect the impact of COVID-19 pandemic on children and adolescents with type 1 diabetes in terms of lifestyle changes and telecommunication service using a predesigned questionnaire, as well as quality of life using the Pediatric Quality of Life Inventory (PedsQL). Methods A cross-sectional study including 286 participants with type 1 diabetes at the Pediatrics and Adolescent Diabetes Unit was conducted from March to August 2022. A predesigned questionnaire was used to collect data about lifestyle, telecommunication service, and quality of life using PedsQL. Results Results show that most of the participants (62.2 %) food consumption increased during the lockdown period. Moreover, results also reveal that 79.7 % of the participants were informed about the telecommunication service, 93.4 % of them actually used it, and 88.6 % thought it was simple. As regards the quality of life, there was a statistically significant difference in PedsQL total score between the younger and older groups, with a p-value=0.009 indicating a better quality of life in the older group. Conclusions The COVID-19 pandemic influenced the lifestyle of children and adolescents with type 1 diabetes. Their food consumption increased, the telemedicine service was easy to use and appealed to the majority, and the quality of life of older participants was better.

Objectives Clinical (assessing breast development), laboratory (FSH, LH, estradiol, and GnRH stimulation test), and radiological methods (bone age and pelvic ultrasonography) are used to distinguish central precocious puberty (CPP) from premature thelarche (PT). We examined also via bioelectrical impedance analysis (BIA). Methods The fat mass (FM), fat-free mass (FFM), muscle mass (MM), bone mass (BM), total body water, and percentages (%), basal metabolic rate, phase angle (PhA), muscle-to-fat ratio (MFR), sarcopenic index, and segmental body proportions were determined via Tanita MC-780 MA model measuring device. Results A total of 111 girls, 34 with CPP, 35 with PT, and 42 with healthy controls, were included. Although the baseline weight, height, and BMI SDS of the groups were not statistically different, the FM (%) was found to be lower (p=0.021), and the FFM (%) (p=0.021), MM (%) (p=0.015), BM (%) (p=0.022), and MFR values (p=0.017) were higher in CPP group. In CPP group, right arm FM (%) (p=0.016), left arm FM (%) (p=0.007), and trunk FM (%) (p=0.008) were lower than other groups. Conclusions We detected a MFR cutoff value of (2.96) with 58.8 % sensitivity and 58.4 % specificity, a cutoff value of (3.57) with 50 % sensitivity and 82 % specificity to differentiate CPP cases from others (PT and healthy controls). These rates are relatively low, but these are the first results in this field and may be guiding for studies conducted in large series.

Objectives Hypergonadotropic hypogonadism is a characteristic clinical manifestation of Turner syndrome (TS). While up to 30 and 20 % of people with TS will have spontaneous thelarche and menarche respectively, there is a lack of evidence to predict who will retain sufficient ovarian function to achieve these outcomes. The aim of this study was to determine if follicle-stimulation hormone (FSH) and/or luteinizing hormone (LH) concentrations measured in infancy would accurately predict later spontaneous thelarche or menarche. Methods Patients with a diagnosis of Turner syndrome with FSH and/or LH clinically measured prior to three years of age and now ≥10 years of age with documented pubertal assessment were included (n=33). Differences in infant gonadotropin values were determined for patients with vs. without spontaneous thelarche/menarche using Kruskal-Wallis tests. The optimal threshold of infant LH and FSH to predict spontaneous thelarche and menarche was then determined by maximizing the sum of sensitivity and specificity. Results The prevalence of spontaneous thelarche and menarche were 21.2 and 15.2 % respectively. An infant LH value greater than 0.5 mIU/mL predicted lack of spontaneous thelarche with an estimated accuracy of 94 % and lack of spontaneous menarche with an estimated accuracy of 96 %. An infant FSH value greater than 37.4 mIU/mL predicted lack of lack of spontaneous thelarche with an accuracy of 97 % and lack of spontaneous menarche with an accuracy of 100 %. Conclusions Infant gonadotropin concentrations accurately predict spontaneous later thelarche and menarche for persons with TS.

Objectives Central precocious puberty (CPP) is one of the common endocrine diseases in pediatrics. However, the molecular mechanisms regulating development of CPP have remained unclear. The purpose of this study was to discover the key pathways and hub genes related to CPP. Methods We analyzed two public datasets (GSE7142 and GSE8310) to identify differentially expressed genes in the progression of CPP. Then, we screened out overlapping differential genes from these two datasets and performed a series of bioinformatics analyses to explore promising targets and molecule mechanism of CPP. Results We identified 30 down-regulated overlapping DEGs between GSE7142 (CPP/no CPP) and GSE8130 (EP/JUV) datasets and 17 down-regulated overlapping DEGs between GSE7142 (CPP/no CPP) and GSE8130 (LP/JUV) datasets. KEGG signaling pathway shows that calcium signaling pathway is suppressed continuously in early and late pubertal of CPP patients. MAPK signaling pathway also plays an important role in the occurrence and development of CPP. Eventually, we screened out 2 hub genes ( FGFR2 and FLT1 ) highly related to CPP, which may provide a new directions for the diagnosis and treatment of CPP. Conclusions While further validation is needed, we provide useful and novel information to explore potential signaling pathways and candidate genes for CPP diagnosis and treatment options.

Objectives Few studies have investigated the effect of growth hormone (GH) therapy on bone health and body composition in children with idiopathic short stature (ISS). Therefore, this study aimed to evaluate the short-term effects of GH treatment on bone mineral density (BMD) and prepubertal body composition in children with ISS. Methods The study included 53 prepubertal children with ISS (mean age, 6.3 ± 1.5 years). Their BMD was compared to that of 20 healthy prepubertal children matched for chronological age. Of the 53 children with ISS, 11 received GH therapy for 1 year. Anthropometric measurements and bone age assessments were conducted, and body composition was analyzed using dual-energy X-ray absorptiometry at 6-month intervals. Results At baseline, lumbar spine and femoral neck BMD Z scores, adjusted for height, showed no significant differences between the ISS and control groups. However, bone mineral apparent density (BMAD) Z scores were significantly lower in children with ISS compared to controls. Over 12 months of GH therapy, no significant changes were observed in lumbar spine or femoral neck height-adjusted BMD Z scores. Nevertheless, GH treatment led to a significant reduction in percent body fat for chronological age and an increase in lean body mass after 1 year. Conclusions Prepubertal children with ISS exhibited lower BMAD at the lumbar spine compared to healthy controls. Although short-term GH therapy did not significantly alter bone density, it positively impacted body composition. These findings provide valuable clinical insights into bone health and body composition in children with ISS.

Objectives Polycystic ovary syndrome (PCOS) is known one of the most common causes of menstrual irregularities and hyperandrogenism in adolescents. We compared cases with increased risk for PCOS (presence of clinical hyperandrogenemia (CH) and/or biochemical hyperandrogenemia (BH) along with menstrual irregularity (MI)) and cases with only MI. Methods Patients were divided into four subgroups. Those with only MI (n=130), CH+MI (n=68), BH+MI (n=25), and CH+BH+MI (n=31). Age, weight, height, and body mass index were recorded. The CH was assessed by the presence of persistent acne, hirsutism, or androgenic alopecia. Modified Ferriman Gallwey (mFG) score was used to evaluate hirsutism. Cases with total testosterone levels above 55 ng/dL were considered to have BH. Results We observed that basal LH and LH/FSH ratio do not provide insight into CH. Unlike, DHEA-S (p=0.006), total testosterone (p=0.003), and free androgen index (FAI) (p=0.027) are relatively high in patients with CH. Polycystic ovarian morphology (PCOM) is lower in cases with only MI compared to cases with increased risk of PCOS (43.3 vs. 56.7 %, p=0.096). We predicted that 28.05 μg/L for Total testosterone, 75.9 for FAI, and 192.9 μg/dL for DHEA-S could be used as a cut-off value with a sensitivity and specificity over 60 %, ​​to distinguish MI from increased risk for PCOS. Conclusions After excluding other secondary endocrinological causes of MI in the first years, routine use of total testosterone, DHEA-S, and FAI is sufficient to distinguish cases presenting menstrual disorders due to anovulation from increased risk of PCOS.

Objectives Glucocorticoid excess or deficiency with hyperandrogenism may cause cardiovascular morbidity in patients with congenital adrenal hyperplasia (CAH) due to failing to mimic physiological circadian rhythm. This study aimed to evaluate the cardiac function in pediatric patients with CAH treated with conventional hydrocortisone treatment and its relation to hydrocortisone dose and therapy duration. Methods Twenty-three pediatric patients with CAH, aged 3–16 years, and 21 age- and gender-matched healthy controls were enrolled to the study. All the patients were evaluated by physical examination, electrocardiogram (ECG), conventional echocardiography, and tissue Doppler imaging (TDI). Results The mean Sm (systolic myocardial velocity) in the CAH group was 7.96 ± 1.22 cm/s, which was significantly lower than that in the control group (p=0.034). The mean systolic excursion in the CAH group was 14.17 ± 1.92 mm, which was significantly lower than that in the control group (p=0.046). The tricuspid-derived early diastolic myocardial velocity (Em) and the tricuspid-derived E/Em ratio were significantly higher in the CAH group than in the control group (p=0.003 and 0.008, respectively). No signs of left ventricular hypertrophy or dilatation were detected on ECG and echocardiography. Conclusions Long-term conventional hydrocortisone therapy even within the recommended therapeutic range may adversely affect cardiac functions in children with 21-hydroxylase deficiency.

Objectives To describe the clinical and genetic profiles of eight patients diagnosed with Congenital Lipoid Adrenal Hyperplasia (CLAH) at a tertiary center in North India. Methods A retrospective analysis of eight children with genetically confirmed CLAH diagnosed between January 2020 and June 2024 was conducted. Data on clinical presentation, anthropometry, biochemical parameters, genetic mutations, and treatment were reviewed. Results Seven patients exhibited the nonclassical phenotype, while one had the classical form. The median (IQR) age at symptom onset, presentation, and diagnosis was 2.50 (1.25–3.82) years, 5.40 (1.70–8.37) years, and 6.31 (4.20–9.12) years, respectively. Skin hyperpigmentation was observed in 100 % of patients, failure to thrive in 75 %, dehydration in 50 %, seizures in 62.5 %, and hypotension in 25 %. Biochemical abnormalities included hyponatremia and hypoglycemia in 62.5 % each, and hyperkalemia in 37.5 % of cases. Genetic analysis identified missense variants in the STAR gene, with six patients carrying the p.Arg188Cys variant, suggesting a founder effect. All patients received glucocorticoid and mineralocorticoid replacement. None of the patients had genital ambiguity or hypogonadism. Conclusions Nonclassical CLAH appears to be more prevalent in the Indian population than previously recognized. Genetic testing facilitates accurate diagnosis and management in resource-limited settings. Lifelong follow-up is essential for monitoring pubertal and gonadal function.

Objectives 17α-Hydroxylase and 17,20-lyase are enzymes encoded by the CYP17A1 gene mapped at chromosome 10q, and are required for the synthesis of sex steroids and cortisol. 17α-hydroxylase deficiency causes a decrease in cortisol and androgen with a subsequent overproduction of adrenocorticotrophic hormone (ACTH), gonadotropin, and 11-deoxycorticosterone. However, isolated 17,20-lyase deficiency is a rare condition that results in sex steroid deficiency with normal serum cortisol. This case series aims to report a novel canonical splice site CYB5A variant causing isolated 17,20-lyase deficiency and highlight the utility of steroid metabolomics in diagnosing 17α-hydroxylase and isolated 17,20-lyase deficiencies. Case presentation We describe four patients with ambiguous genitalia who were accurately diagnosed through steroid metabolomics using liquid chromatography- mass spectroscopy (LC-MS). Genetic testing identified a novel homozygous likely pathogenic 5′ canonical splice site variant, c.129 + 1G>A in intron 1 of CYB5A gene, resulting in isolated 17, 20 lyase deficiency. Conclusions Here, we report four patients with 46, XY disorder of sexual development (DSD) from two families with 17α-hydroxylase deficiency and isolated 17,20-lyase deficiency due to cytochrome b5 variant with a variable spectrum of under-virilization who had received inadequate treatment for a prolonged period of time due to incorrect diagnosis.

Objectives Here we present a case of 46,XY disorder of sex development (DSD) in which three variants were detected in the SRY , DHX37 , and POR genes. Case presentation A patient with 46,XY karyotype and female phenotype presented at 15 years 3 months of age due to absence of puberty. She exhibited facial signs such as midfacial hypoplasia, long face, proptosis, bulbous nose, mild prognathism and skeletal signs such as scoliosis, pectus carinatum, arachnodactyly and her sex development remained prepubertal. The patient was found to have hypergonadotropic hypogonadism, elevation of 17-OH progesterone and progesterone levels, low anti-mullerian hormone and inhibin B levels, and absence of gonads and a hypoplastic uterus on pelvic ultrasound. Whole exome sequencing revealed a novel hemizygous missense variant in the SRY gene (c.247C>T, p.Pro83Ser), a homozygous missense variant in the POR gene (c.1355C>T, p.Pro452Leu), and a novel heterozygous missense variant in the DHX37 gene (c.1325A>G, p.His442Arg). Conclusions Our patient is the first case in which the coexistence of variants in the SRY , DHX37 and POR genes was detected. This case suggests that a combined phenotype characterized by DSD and alterations in adrenal function may result from genetic variants in the SRY , DHX37 and POR genes involved in gonadal development and synthesis of adrenal hormones.

Objectives To present a patient diagnosed with single, large-scale mitochondrial DNA (mtDNA) deletion (SLSMD), a rare and progressive multisystem disorder. Diverse initial symptoms, evolving and overlapping phenotypes, along with genetic heterogeneity present significant challenges for diagnosis. Case presentation A 3.2-year-old girl presented with seronegative insulin-dependent diabetes, short stature, skin pigmentation anomalies, and macrocytic anemia. The anemia resolved spontaneously, but the macrocytosis persisted. Over time, diagnosis of corneal dystrophy and sensorineural hearing loss were established. Although no classical biochemical features of mitochondrial disease were present, comprehensive molecular mtDNA analysis was performed from peripheral blood. The results revealed a single mtDNA deletion of 7.423 bp, with 37 % of heteroplasmy, confirming the diagnosis of SLSMDs. Conclusions The occurrence of diabetes mellitus as presenting endocrine manifestation of SLSMDs at an early age is uncommon. Macrocytosis, as well as hair and skin pigmentation changes, may be the early indicators of mitochondrial diseases. A cluster of symptoms including antibody-negative diabetes, short stature, and signs of sporadic dysfunction of organs with high energy demand, suggest a distinct pattern commonly observed in mitochondrial disorders.