Volume 38, Issue 9

Familial hypercholesterolemia (FH) is a common genetic disorder with a co-dominant inheritance pattern, characterized by persistently elevated levels of atherogenic low-density lipoprotein cholesterol (LDL-C) and a significantly increased risk of premature atherosclerotic cardiovascular disease. Given that the cardiovascular risk associated with elevated LDL-C begins in early childhood and progresses over time, early identification and long-term management are crucial. Implementing effective screening programs, genetic testing, and timely initiation of lipid-lowering therapy are essential strategies to mitigate future coronary events, improve quality of life, and reduce morbidity and mortality. This document outlines strategies and recommendations to improve early detection, genetic screening, and holistic management of individuals affected by FH, with particular emphasis on facilitating a structured transition from pediatric to adult healthcare services to ensure continuity of care and sustained treatment adherence.

Objectives In girls with precocious puberty (PP), adult height prediction (PAH) is crucial in treatment planning, yet the estimations may be prone to inaccuracies. This study aimed to compare the accuracy of two commonly used PAH methods in 6–8-year-old girls diagnosed with idiopathic GnRH-dependent PP. Methods This retrospective study included data on 60 six- to eight-year-old girls diagnosed with PP. Data was collected from medical records. Forty-eight (82 %) girls were treated with GnRH analogues, and 18 (30 %) had data on AH. Bone ages (BA) were assessed with Greulich–Pyle and BoneXpert. PAHs were estimated with Bayley-Pinneau and BoneXpert. Results In girls treated with GnRH-analogue, AH did not significantly differ from the mean PAH calculated by Bayley-Pinneau (mean difference, −0.1 cm ± 6.6 cm (SD); p=0.93). Predicted adult height estimated by BoneXpert was higher than the actual AH (−3.6 cm ± 4.6 cm, p=0.01), but it showed lower variability in individual prediction errors and less bias related to the degree of BA advancement than Bayley-Pinneau. All subjects reached their mid-parental target height range. Conclusions In 6- to 8-year-old girls with signs of idiopathic GnRH-dependent precocious puberty, the potential to reach their growth target remains, and overestimation of residual height growth at diagnosis should be carefully considered before initiating treatment.

Objectives To generate current reference values for height velocity (HV, cm/year) in German children and adolescents and to evaluate the sensitivity of auxological parameters in the evaluation of short stature (referral criteria). Methods The study population consisted of healthy German participants of the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study (1985–2022). In total, data was available from n=453 girls (mean age 9.1 ± 2.4 years) and n=473 boys (mean age of 9.6 ± 2.5 years). As the participants were measured repeatedly, 4,557 HV assessments for girls and 5,224 HV assessments for boys were analyzed (median number of observations in female was nine and in male 11). The reference percentiles were created using the LMS method. The referral criteria of the German Society for Pediatric and Adolescent Endocrinology and Diabetology (DGPAED) and of the Growth Hormone Research Society (GHRS) for further endocrinological evaluation were evaluated in a subsample. Results The specificity of the referral criteria “HV<25th centile for 1 year” (DGPAED) was 10.4 % in girls and 4.3 % in boys. When this criterion was changed to “HV<3rd centile for 1 year” the specificity increased to 75.5 % in girls and 76.1 % in boys. With omission of the 5th criterion (“height> −2.0 SD AND HV< −2.0 over 1 year”) of the six referral criteria of the GHRS, the specificity of the remaining five referral criteria was 91.4 % in girls and 90.5 % in boys. Conclusions New reference centiles for HV are presented. With modification of the already proposed GHRS criteria, the specificity of the assessment of HV in the evaluation of short stature could be increased significantly.

Objectives Congenital hypothyroidism (CH) requires early diagnosis to prevent irreversible neurodevelopmental impairments. This study aimed to determine cutoff values for initial capillary thyroid-stimulating hormone (TSH), first venous TSH, and levothyroxine (LT4) dose at 6 months to differentiate between transient and permanent CH. Methods A retrospective analysis was conducted on 289 patients diagnosed with CH at the Pediatric Endocrinology Clinic of the University of Health Sciences, Umraniye Training and Research Hospital, from January 2014 to September 2021. Patients received treatment and were followed for at least 6 months after treatment discontinuation or remained under therapy. Patients were divided into two groups: permanent CH and transient CH. Initial capillary TSH, first venous TSH, and LT4 dose at 6 months were recorded, and cutoff values were determined using ROC analysis. Results Of the 289 patients, 179 (62 %) had transient CH and 110 (38 %) had permanent CH. The permanent CH group had significantly higher levels of capillary TSH, first venous TSH, and LT4 dose at 6 months (p<0.001). The cutoff values for predicting transient CH were <23.1 mIU/L for capillary TSH, <64.5 mIU/L for first venous TSH, and <3.6 µg/kg/day for LT4 dose at 6 months, all statistically significant. Conclusions Initial capillary TSH, first venous TSH, and LT4 dose at 6 months are reliable predictors for distinguishing between transient and permanent CH. These cutoff values provide clinical guidance, especially for early treatment discontinuation in patients with LT4 doses below 3.6 µg/kg/day, indicating a higher likelihood of transient CH.

Objectives Empty sella turcica (ES) is commonly observed in idiopathic growth hormone deficiency (GHD) in children. This study aims to determine the frequency of ES in children with GHD, assess their pituitary thyroid-stimulating hormone (TSH) and prolactin (PRL) reserves using the thyrotropin-releasing hormone (TRH) stimulation test, and investigate whether ES is associated with a higher prevalence of combined pituitary hormonal deficiencies. Methods TSH and PRL pituitary reserves were assessed through the TRH stimulation test in 22 patients with ES and 31 without this finding (non-ES). All participants had childhood-onset GHD and underwent pituitary imaging, primarily by computed tomography (CT) Anti-thyroid peroxidase (anti-TPO) antibodies were measured in all patients with elevated basal TSH. Results Among 125 children diagnosed with GHD between 1988 and 1996, ES was identified in 29 cases (23 %). Fifty-three patients agreed to participate (86.8 % male), with ES present in 43.5 % of males and 28.6 % of females. No significant differences in TSH and PRL responses to TRH were observed between the ES and non-ES groups. Mildly elevated basal TSH was observed in 50 % of patients with ES and 55 % without ES, most of who tested negative for anti-TPO antibodies. Among patients with elevated basal TSH and hypothyroidism, the majority exhibited exaggerated or delayed TSH responses to TRH and elevated basal PRL, findings suggestive of hypothalamic dysfunction. Four patients presented combined GH, TSH, and PRL deficiencies. Conclusions ES is common in children with GHD but presents distinct features compared to adults. Central hypothyroidism (CeH) was observed in 45.6 % of patients with ES and 54.8 % without ES. Mild TSH elevation was frequent and rarely associated with anti-TPO antibodies, supporting the exclusion of primary hypothyroidism and suggesting underlying hypothalamic dysfunction. Subclinical hormonal abnormalities were also frequent among euthyroid patients. The TRH stimulation test proved valuable in distinguishing hypothalamic dysfunction from pituitary or primary hypothyroidism. Genetic testing for POU1F1 and PROP1 mutations may be warranted in selected cases with combined deficiencies.

Objectives Depression and anxiety are rare disorders that can be seen in childhood. Anxiety disorders are more common. The underlying causes of these mental disorders are generally unknown. Changes in the body caused by hyperandrogenism may lead to mental disorders. In this study, we investigated the association of androgen excess with depression and anxiety in adolescent girls. Methods Adolescent girls with elevated androgen levels were evaluated using the DSC and SCARED scales and underwent a child psychiatric evaluation. Physical examination and the relationship between scale scores and anxiety and depression were investigated. Results Fifty-three girls aged 10–18 (mean 15.09 ± 1.26) with androgen elevation participated in the study. In our study, the frequency of panic disorder, separation anxiety, and eating disorders was shallow, but the frequency of generalized anxiety, social anxiety, and depression was high (21 %, 29%, 23 %). None of our patients had school phobia, bipolar disorder, suicidality, obsessive-compulsive disorder, enuresis, or encopresis. No significant change was observed in scale scores with any androgen elevation. Conclusions In our study, we found that androgen elevation did not change the frequency of mental disorders in adolescent girls. Despite the large number of studies, it is still controversial whether hyperandrogenemia increases mental disorders due to conflicting results between studies.

Objectives Precise and timely diagnosis is essential in the management of children born with atypical genitalia/differences or disorders of sex development (DSD) to provide optimal personalised care. Establishing the diagnosis can be challenging and time-consuming. The human chorionic gonadotrophin (hCG) stimulation test is useful in assessing male gonadal function, and stimulated testosterone: 5α-dihydrotestosterone (T:DHT)>10 suggests 5-alpha reductase type 2 (SRD5A2) deficiency. Methods We report the clinical, hormonal and genetic data of patients with 46, XY DSD with genetically confirmed SRD5A2 deficiency to assess the value of the hCG-stimulated T:DHT ratio in the diagnostic work-up. Additionally, we reviewed the literature on the usefulness of hCG-stimulated androgen ratios in determining DSD aetiology. Results Of 14 patients with genetically confirmed SRD5A2 deficiency, including one novel variant, nine underwent hCG stimulation test: seven in infancy, one at 4 years and one at puberty. A T:DHT ratio above 10 was observed in seven patients (median: 15; range: 10.7–66.5). Two patients, aged one month and 4 years, had ratios of 8.3 and 4.4, respectively. Urinary steroid profiling (GC/MS) suggested SRD5A2 deficiency in all patients who had the testing (n=13). No association was found between T:DHT ratios and age at presentation or external masculinisation score (EMS). Conclusions The hCG stimulation test appears less sensitive than urinary steroid profiling in establishing the diagnosis of SRD5A2 deficiency.

Objectives To explore the clinical spectrum and symptom duration in pediatric adrenocortical tumors (pACTs), with a focus on identifying cases that may reflect gradual tumor progression. Methods We retrospectively analyzed data from 110 pediatric patients with pACTs enrolled in the German Pediatric Oncology Hematology-Malignant Endocrine Tumor (GPOH-MET) studies (1997–2022). Endocrine symptom duration, histopathological classification, and clinical outcomes were assessed. Patients with symptom durations ≥2 standard deviations (SDs) from the mean were defined as outliers and evaluated for potential progression. Results The cohort included 31 patients with adrenocortical adenomas (ACAs), 12 with tumors of uncertain malignant potential (ACx), and 67 with adrenocortical carcinomas (ACCs). Seven patients (6.4 %) showed markedly prolonged symptom duration, including four with ACC. One representative case demonstrated a nearly 5-year course from initial androgen excess to metastatic ACC, with evolving biochemical features and a diagnostic urinary steroid profile indicative of adrenal tumor activity. Conclusions A small subset of pACTs may present with prolonged endocrine symptoms, possibly reflecting gradual tumor evolution. While molecular validation is lacking, these findings support the need for early recognition and further research into the natural history of pACTs.

Objectives Central precocious puberty (CPP) is characterized by the early onset of secondary sexual characteristics before the age of 8 in girls and 9 in boys. While rapid progression of sexual development may indicate an underlying organic cause, such as the presence of anatomical abnormalities of the hypothalamic-pituitary axis, no definitive diagnostic standard exists. Therefore, diagnosis requires a comprehensive assessment incorporating clinical, biochemical, and radiological evaluations. The aim of this study is to identify clinical, hormonal, and radiological factors that differentiate idiopathic from organic CPP, in order to establish predictive criteria for the identification of organic etiology. Methods A multicenter retrospective study was conducted on female patients diagnosed with CPP at two major Italian hospitals between January 2015 and February 2025. Clinical, hormonal, and radiological data were analyzed to differentiate between idiopathic and organic CPP. A total of 134 patients were included, all of whom underwent a GnRH stimulation test for diagnosis. Results Among the 134 patients, 12 (9 %) were diagnosed with organic CPP. Patients with organic CPP were diagnosed at a younger age, exhibited higher growth velocity, and showed elevated basal and stimulated gonadotropin levels. Multivariate analysis identified several significant predictors of organic CPP, including age at diagnosis, LH peak, LH/FSH ratio, height SD, and growth velocity. ROC curve analysis demonstrated that an LH peak >9.1 mIU/mL and growth velocity >1.75 standard deviations (SD) were highly sensitive (80 %) and specific (85 %) indicators of organic CPP. Conclusions Organic CPP is characterized by a younger age at diagnosis, faster progression of puberty, and higher gonadotropin levels compared to idiopathic CPP. An LH peak >9.1 mIU/mL and a growth velocity >1.75 SD should be considered key diagnostic markers for identifying organic causes of CPP and guiding further investigation and treatment.

Objectives The pediatric common variable immunodeficiency (CVID) is the most prevalent symptomatic antibody deficiency characterized by a marked heterogeneity of genetic underpinnings, immune system dysfunctions, and clinical manifestations encompassing susceptibility to infections and immune dysregulation disorders, thus increasing autoimmunity. Endocrinopathies associated with CVID have multifactorial etiology and usually lead to hypofunction of the affected organs. The aim of the study was to evaluate the parameters of endocrine homeostasis in children with CVID and to ascertain whether endocrinopathies are components belonging to the spectrum of organ-specific immunopathologies associated with this condition. Methods The study cohort comprised 22 children (aged 5–17 years) with a confirmed diagnosis of CVID who were undergoing immunoglobulin replacement therapy. A range of anthropometric and hormonal parameters related to growth, thyroid, parathyroid, adrenal glands function, and calcium-phosphate metabolism were assessed. Results Antithyroid peroxidase antibodies were identified in 81.81 % of children, while antipancreatic islet (GAD-Ab) antibodies were present in 59.09 %. Among those without preexisting diabetes, 50 % exhibited low C-peptide levels, while 35 % demonstrated both positive GAD-Ab and low C-peptide, with one case displaying elevated HbA 1c . Vitamin D3 deficiency was identified in 50 % of patients, and 40.91 % exhibited elevated parathormone levels, suggestive of secondary hyperparathyroidism. Conclusions Endocrinopathies, particularly autoimmune thyroiditis, are prevalent in pediatric CVID, reflecting the condition’s immune dysregulation. Regular monitoring of clinical and hormonal parameters is essential for the provision of multidisciplinary care and the enhancement of patient outcomes.

Objectives L-2-hydroxyglutaric aciduria (L2HGA) is a hereditary metabolic disorder characterized by the accumulation of L-2-hydroxyglutaric acid in body fluids, particularly in cerebrospinal fluid, which disrupts neuron function in the central nervous system and triggers oxidative stress. It can cause seizures, developmental disorders, and behavioral abnormalities. Methods The study retrospectively evaluated the demographic information, initial symptoms, clinical characteristics, cranial magnetic resonance imaging (MRI) findings, and post-treatment biochemical changes of 10 cases diagnosed with L2HGA. Results The study included five paediatric and five adult cases with a molecular diagnosis of L2HGA. The mean age at diagnosis was 10.1 years. Convulsion was identified as the primary presenting symptom in 70 % of cases. We identified intellectual disability in 80 % of our cases. In addition to the classic cranial MRI findings of subcortical white matter involvement, basal ganglia involvement was detected in 60 % of cases. We found that 2-hydroxyglutaric acid levels in urine organic acid analysis were significantly decreased riboflavin and carnitine post-treatment, with a mean decrease of 133.89 ± 101.43 mmol/mol creatinine (p=0.017). The most common missense variant identified in the L2HGDH gene was c.905C>T (p.Pro302Leu), occurring at a frequency of 50 % (5/10). The cases did not report significant improvement in their symptoms with treatment. Conclusions L2HGA is a rare metabolic disorder that is more common in communities where consanguineous marriages are prevalent. Early diagnosis enables early treatment and protection of the brain from oxidative stress. As more cases are reported publicly, studies on genotype–phenotype relationships will yield more significant findings.

Objectives Stress hyperglycemia is relatively common in the pediatric emergency department. It is usually associated with severe illnesses such as infections, seizures, and trauma. The association between stress hyperglycemia and future development of type 1 diabetes mellitus is unclear. Different reports have shown controversial results. Methods This was a retrospective follow-up cohort of children admitted to the pediatric emergency department at the Shaare Zedek Medical Center in Jerusalem, Israel during the years 2010–2014 with stress hyperglycemia. The study group was then evaluated over a 10-year period for developing type 1 diabetes mellitus. The study group incidence was then compared to the general population. Results During the study period, there were 1,184 admissions with stress hyperglycemia. The most common diagnoses were infectious (36.5 %) and respiratory (24.3 %) diseases. There were two cases that later developed type 1 diabetes. This resulted in an odds ratio of 14.95 for developing type 1 diabetes in the study cohort (with fatalities removed) compared to the known incidence in Israel at that time (95 % CI, (p<0.01)). Conclusions Children presenting with stress hyperglycemia may be at greater risk for developing type 1 diabetes and should warrant close follow-up and possibly advanced testing to offer early diagnosis.

Objectives We investigated indices of mental health in transgender youth and their primary caregiver during 12 months of GnRHa therapy. Methods Psychological measures were completed at baseline, 6 months, and 12 months by patients and caregivers using validated questionnaires from the Patient Reported Outcomes Measurement Information System and National Institutes of Health Toolbox. One-way repeated-measures ANOVAs were performed to evaluate differences in psychological measures across time. One-sample t-tests compared the sample mean of each measure to the population mean at each time point. Results Of 28 patients enrolled, 16 were treated with a GnRHa alone for 12 months. No significant main effect of time on any measure of psychological functioning in patients or caregivers was found (all ps>0.05). Compared to the general population, transgender youth reported higher levels of psychological stress and lower levels of life satisfaction at all time points, and higher levels of depression and anger at later time points, while caregivers perceived decreased well-being in their child on all measures at all time points. Caregivers reported higher levels of self-reported anxiety at all time points and higher levels of self-reported depression at baseline. Conclusions Transgender youth and their caregivers in the early stages of medical transition experience more challenges related to psychological well-being compared to the general population. However, all measures of psychological well-being remained stable throughout the study.

Objectives In childhood, endogenous hyperinsulinemic hypoglycemia is most commonly associated with congenital hyperinsulinism due to genetic mutations. Pancreatic neuroendocrine tumors, which have an incidence of approximately four cases per million per year, are rare in children. Detecting small lesions is challenging, and clinical suspicion is crucial for early diagnosis. This report aims to emphasize the importance of endoscopic ultrasonography (EUS) in the clinical approach to endogenous hyperinsulinism. Additionally, a focused literature review was conducted to support the diagnostic and therapeutic aspects discussed in the case. Case presentation A 16-year-9-month-old male with no prior medical history was admitted to the emergency department with excessive sweating, speech difficulties, and an inability to wake up, occurring 8 h after a post-training meal. His blood glucose was 35 mg/dL. He had experienced similar episodes previously, resolving with food intake. An extended fasting test revealed hyperinsulinemic hypoglycemia (glucose: 45 mg/dL, insulin: 15.9 µU/mL, ketone: 0.1). Imaging studies (USG, MRI, CT) failed to detect a lesion. EUS identified a 12  ×  9 mm pancreatic body lesion, confirmed as a well-differentiated grade 2 neuroendocrine tumor via fine-needle aspiration biopsy. Laparoscopic enucleation verified the insulinoma diagnosis, with no metastasis or MEN-1 findings. Following surgery, the patient remained asymptomatic with no recurrence of hypoglycemia during a 2-year follow-up. Conclusions Insulinoma should be considered in cases of hypoglycemia triggered by fasting or exercise due to its intermittent insulin secretion. Given the small size of the pancreas and the anatomical differences in children, EUS is a highly sensitive diagnostic tool for detecting small pancreatic tumors, such as insulinoma.

Objectives Treatment-induced neuropathy of diabetes (TIND) is a rare complication of rapid glycemic improvement, characterized by severe shooting pain, predominantly in the lower extremities. This report aims to highlight the clinical presentation of TIND and evaluate the effectiveness of caudal epidural steroid injections (CESI) in managing refractory pain in pediatric cases. Case presentation We describe two pediatric cases of TIND following rapid improvement in glycemic control for type 1 diabetes. Both patients presented with debilitating pain and sleep disturbances that severely impacted their daily activities. Initial management with a combination of analgesics, pregabalin, gabapentin, and duloxetine failed to provide adequate relief. Subsequently, both patients received CESI with bupivacaine and methylprednisolone. Significant symptomatic improvement in pain and sleep was observed within 4–6 weeks post-intervention. At the 6-month follow-up, the pain relief was sustained, and no adverse effects were reported. Conclusions These cases underscore the importance of recognizing TIND as a potential complication of rapid glycemic control and the challenges in its management. CESI appears to be a promising therapeutic option for children with refractory TIND, offering durable pain relief and improved quality of life. Further studies are needed to validate its efficacy and safety in larger cohorts.

Objectives The DNAJC3 gene encodes a protein that acts as a cochaperone of binding immunoglobulin protein (BiP), a major member of the heat shock protein 70 (HSP70) family, which is found in the endoplasmic reticulum (ER) and promotes normal protein folding. Loss-of-function mutations in DNAJC3 lead to early-onset diabetes and multisystemic neurodegeneration. In this article, we report a case of monogenic syndromic diabetes caused by a previously undescribed DNAJC3 variant. Case presentation A 15-year-old 5-month-old girl with polyuria and polydipsia for the last 2–3 months was diagnosed and treated as diabetic ketoacidosis at the center where she was admitted with complaints of general condition disorder and frequent breathing. Her laboratory findings were HbA 1c 15.1 %, serum insulin 7.83 m U/L, C-peptide 0.78 μg/L. Tests for autoimmune diabetes markers were negative. Physical examination revealed severe short stature 141.4 cm (−3.62 SDS). Sensorineural hearing loss developed 5 months after the diagnosis of diabetes and intellectual functions were impaired. Neurologic examination revealed marked ataxia. Monogenic syndromic diabetes mellitus with multisystemic neurodegeneration including juvenile onset diabetes mellitus, ataxia, short stature and sensorineural hearing loss was considered. Exome sequencing and CNV (Copy Number Variation) analysis revealed a novel homozygous c.1244G>C (p.Arg415Pro) variant in DNAJC3 gene. Conclusions This case supports the wide phenotypic spectrum and multisystem involvement potential of DNAJC3 variants and demonstrates the need to increase awareness in the diagnostic process of these rare genetic disorders..

Objectives 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare autosomal recessive organic aciduria. Most patients present within the first year of life with metabolic decompensation, which can cause neurological damage or death if untreated. Case presentation A 20-month-old previously healthy boy was admitted to the hospital after a nocturnal seizure. Upon admission, the child was unconscious and laboratory analysis revealed severe hypoglycemia and metabolic acidosis without ketonuria. Hypoglycemia was corrected with a bolus of 10 % glucose followed by continuous glucose-electrolyte infusion. Status epilepticus was treated with midazolam and phenobarbital. Magnetic resonance imaging (MRI) performed on the second hospital day, revealed bilateral and symmetric T2 hyperintense lesions in the cortex, supratentorial white matter, basal ganglia and central pons, along with slight white matter volume reduction. Urinary organic acids indicated HMGCLD. HMG-CoA lyase activity in immortalized lymphocytes was significantly decreased. Sanger sequencing of the HMGCL gene identified a heterozygous sequence variant, c.796T>C, p.(Cys266Arg). MLPA analysis showed a reduced gene dosage for exons 3 and 4 of HMGCL , consistent with a heterozygous deletion. Upon diagnosis, a low-protein diet was recommended, as well as oral l -carnitine therapy with a high-calorie supplement drink at night. Initially, the child had slightly impaired psychomotor development, which normalized by age 3.5. He was without metabolic crises or seizures since diagnosis. Conclusions In any child presenting with hypoketotic hypoglycemia and metabolic acidosis of unknown etiology, HMGCLD should be considered. Given the rarity of HMGCLD and its sporadic cases across Europe, management should involve a well-experienced multidisciplinary team.