Journal of Clinical Research in Pediatric Endocrinology最新文献

Idiopathic hypogonadotropic hypogonadism (IHH) comprises a group of disorders characterized by deficient secretion or action of gonadotropin-releasing hormone (GnRH), leading to impaired pubertal development and infertility. Traditionally, IHH is classified into Kallmann syndrome (KS), associated with anosmia, and normosmic IHH (nIHH), in which olfactory function is preserved. The condition exhibits marked genetic heterogeneity. Advances in next generation sequencing have significantly expanded the genetic landscape of IHH, with pathogenic variants identified in over 60 genes, accounting for up to 50% of cases. Oligogenic inheritance is increasingly recognized, occurring in 10-20% of individuals. The potential for spontaneous or treatment-induced clinical recovery in a subset of patients, along with phenotypic overlap with constitutional delay of growth and puberty (CDGP), presents additional diagnostic challenges. Despite these complexities, genetic studies of IHH have provided critical insights into fundamental neuroendocrine processes, most notably the recent elucidation of the KNDy (Kisspeptin, Neurokinin B, Dynorphin) neurons as the GnRH pulse generator. These discoveries have also informed the development of targeted therapies, exemplified by the recent FDA approval of fezolinetant, a neurokinin B receptor antagonist, for the treatment of menopausal vasomotor symptoms.

CHARGE syndrome is an autosomal dominant disorder caused by variations in the CHD7 gene. The characteristic findings of the syndrome include coloboma (C), heart anomalies (H), choanal atresia (A), growth and developmental delay (R), genitourinary system anomalies (G), and ear anomalies and/or hearing loss (E). A 7.7-years-old male patient was initially referred after a partial empty sella appearance was noted on brain imaging during evaluation for developmental delay at 10 months of age. He had undergone surgery for choanal atresia and congenital heart disease. The patient exhibited severe postnatal growth retardation, hypertelorism, epicanthal folds, cleft palate, a thin upper lip, bilateral ear anomalies, preaxial polydactyly, and bilateral undescended testes. He had motor and mental developmental delay. Ophthalmologic examination showed retinal atrophy and coloboma. Genetic analysis identified a novel heterozygous c.5050+2T>C variant in intron 22 of the CHD7 gene, confirming the diagnosis of CHARGE syndrome. Furthermore, the patient had undergone bilateral orchiopexy at two years of age, and growth hormone therapy was initiated after a diagnosis of complete growth hormone deficiency at 19 months of age. A novel heterozygous variant in the CHD7 gene was identified in a patient, who presented with classical signs of CHARGE sydrome. Early recognition and diagnosis is important to enable initiation of timely treatment of potential complications associated with the disorder.

Objective: Artificial intelligence (AI) is increasingly used in medicine, including pediatric endocrinology. AI models have the potential to support clinical decision-making, patient education, and guidance. However, their accuracy, reliability, and effectiveness in providing medical information and recommendations remain unclear. The aim was to evaluate and compare the performance of four AI models, ChatGPT, Bard, Microsoft Copilot, and Pi, in answering frequently asked questions related to pediatric endocrinology.

Methods: Nine questions commonly asked by parents regarding short stature in pediatric endocrinology were selected, based on literature reviews and expert opinions. These questions were posed to four AI models in both Turkish and English. The AI-generated responses were evaluated by 10 pediatric endocrinologists using a 12-item Likert-scale questionnaire assessing medical accuracy, completeness, guidance, and informativeness. Statistical analyses, including Kruskal-Wallis and post-hoc tests, were conducted to determine significant differences between AI models.

Results: Bard outperformed other models in guidance and recommendation categories, excelling in directing users to medical consultation. Microsoft Copilot demonstrated strong medical accuracy but lacked guidance capacity. ChatGPT showed consistent performance in knowledge dissemination, making it effective for patient education. Pi scored the lowest in guidance and recommendations, indicating limited applicability in clinical settings. Significant differences were observed between AI models (p<0.05), particularly in completeness and guidance-related categories.

Conclusion: The present study highlights the varying strengths and weaknesses of AI models in an area of pediatric endocrinology. While Bard was effective in guidance, Microsoft Copilot excelled at accuracy, and ChatGPT was informative. Future AI improvements should focus on balancing accuracy and guidance to enhance clinical decision-support and patient education. Tailored AI applications may optimize the role of AI in specialized medical fields.

Objective: Familial hypercholesterolemia (FH) is an inherited metabolic disorder that increases cardiovascular risk from childhood. Despite its frequency, pediatric diagnosis and treatment remain inadequate, particularly in developing countries.

Methods: We retrospectively analysed 124 pediatric patients with genetically confirmed heterozygous FH (HeFH). Genetic testing included sequencing of LDLR, APOB, and PCSK9. We assessed clinical features, treatment responses, statin use, and adverse events. A comparative analysis was conducted between different statin types.

Results: Only 28.2% of patients were diagnosed via routine lipid screening, though 90.3% had a positive family history. After diagnosis, 16.1% declined treatment and 41.1% were lost to follow-up. Most genetic diagnoses involved pathogenic LDLR variants; a few cases involved APOB and PCSK9. We identified three novel LDLR variants. Among treated patients, atorvastatin led to a greater median LDL-C reduction. A higher (though not statistically significant) proportion of pitavastatin users reached LDL-C targets. LDL-C reduction was positively correlated with baseline LDL-C levels. For the majority of patients, statins were well tolerated; five patients had transient creatine kinase (CK) elevations that resolved with treatment interruption.

Conclusion: This is the first large pediatric HeFH cohort study from Turkey providing details on both genetic background and treatment outcomes. Despite genetic confirmation, significant gaps remain in early diagnosis, treatment acceptance, and long-term follow-up. Both atorvastatin and pitavastatin proved to be safe and effective. Findings emphasise the need for national screening programmes, family education, dietary counselling, and consistent follow-up.

Objective: Spinal muscular atrophy (SMA) is the most common neurodegenerative disease caused by the absence or insufficiency of the survival motor neuron protein (SMN). hSMN1 is producing fully functional SMN protein but hSMN2 is producing only about 10% functional protein. Deletion or mutation in hSMN1 gene leads to SMA, while the hSMN2 copy number modifies disease severity. Increasing hSMN2 expression has emerged as a potential therapeutic approach. In this study, we investigated the effect of growth hormone (GH) on hSMN2 promoter activity using a reporter in CHO cells.

Methods: Three different hSMN2 promoter regions (588 bp, 1036 bp and 1705 bp) were used to show the effect on gene expression of reporter respond to GH in this study. They were amplified by PCR and cloned into the pGL3 luciferase reporter vector. The ligation reactions were transformed into DH5α cells and positive colonies containing specific hSMN2 promoter inserts were confirmed by PCR with hSMN2-primers. The plasmids carrying hSMN2 promoters were transfected into CHO cells. After transfection, the cells were treated with GH for 24 hours and luciferase activity was measured to assess promoter activity.

Results: All hSMN2 promoter constructs responded to GH. The 1036 bp promoter construct showed the highest luciferase expression upon GH treatment. However, the 1705 bp promoter construct exhibited reduced gene expression compared to the control vector treated with GH.

Conclusion: These findings suggest that GH can modulate hSMN2 expression in hSMN2 promoter dependent manner. GH may be candidate hormone for SMA treatment by enhancing hSMN2 expression.

Diabetic peripheral neuropathy (DPN) is the most common form of acquired neuropathy. In children with type 1 diabetes (T1D), the reported prevalence of DPN varies widely, ranging from 3% to 62%, mainly due to differences in screening methodologies and patient population characteristics. While intraepidermal nerve fiber density (IENFD) assessment via skin biopsy remains the gold standard for detecting small fiber neuropathy, nerve conduction studies (NCS) are the established diagnostic tool for large fiber involvement. However, several novel and non-invasive diagnostic tools have emerged recently, offering improved screening options for early-stage and subclinical DPN. The frequent presence of asymptomatic neuropathy in pediatric populations, combined with its limited treatment options, underscores the importance of early identification of modifable risk factors thus reducing the risk of developing clically significant DPN. This review provides a comprehensive overview of the current evidence on the prevalence, risk factors, and modern diagnostic approaches for DPN in children with diabetes.

Adenylate cyclase 3 (ADCY3) gene alterations have been reported to be associated with obesity. However, few patients with homozygous mutations have been described to date and the follow-up procedure and treatment options are unclear. A 10-month-old female presented with increased appetite and weight gain. She was born from a consanguineous marriage. Weight, height, and head circumference measurements and standard deviation scores (SDS) were 19 kg (+6.98 SDS), 82 cm (+3.53 SDS), and 49 cm (+3.07 SDS), respectively. Laboratory tests revealed a fasting glucose level of 103 mg/dL (5.7 mmol/L), insulin level of 25.39 μIU/mL, and homeostatic model assessment for insulin resistance value of 6.43. Whole-exome sequencing revealed a novel, homozygous c.1102G>A (p.Asp368Asn) variant in ADCY3. Her parents and healthy sister were heterozygous for the variant. At the age of 2.5 years, neurodevelopmental delay was observed. At the age of 3.5 years, the patient’s weight, height, and body mass index values were 49.5 kg (+8.16 SDS), 111 cm (+2.59 SDS), and 40.18 kg/m2 (+6.48 SDS), respectively. Signs of Blount disease and acanthosis nigricans were evident, and she had hyperphagia. She was undergoing speech therapy. Homozygous ADCY3 variants may present with early onset, severe obesity, insulin resistance, and neurodevelopmental delay in children. Severe complications may occur, even at young ages. More data in terms of the optimal treatment and follow-up process of these patients are needed.

Lowering of thyroid-stimulating hormone (TSH) cutoffs in newborn screening programs has created a management dilemma by leading to more frequent detection of neonates with elevated TSH concentrations due to false-positive results, transient neonatal hyperthyrotropinemia (NHT), and milder forms of congenital hypothyroidism. Current consensus guidelines recommend starting treatment if the venous TSH level is >20 mU/L in the face of a normal free thyroxine (FT4) level, which is an arbitrary threshold for treatment decisions. In countries such as Türkiye, where transient NHT may be more common due to iodine deficiency (ID) and/or overload, putting this recommendation into daily practice may lead to unnecessary or over treatment, time-consuming long-term follow-up, and increased workload and costs. In this review, we addressed alternative approaches for infants with elevated TSH concentrations detected at newborn screening. The suggested management approach can be summarized as: Infants with mild NHT (venous TSH <20 mU/L) should be followed without treatment. In moderate NHT (venous TSH 20-30 mU/L), treatment or monitoring decisions can be made according to age, TSH trend and absolute FT4 level. Moderate cases of NHT should be treated if age at confirmatory testing is >21 days or if there is no downward trend in TSH and FT4 level is in the lower half of age-specific reference range in the first 21 days. In in-between cases of moderate NHT, thyroid ultrasound may guide treatment decision by determining mild cases of thyroid dysgenesis that require life-long treatment. Otherwise, monitoring is a reasonable option. Infants with compensated hypothyroidism (venous TSH >30 mU/L and normal FT4) or persistent hyperthyrotropinemia (>6-10 mU/L after the neonatal period) should receive L-thyroxine treatment. However, all treated cases of isolated TSH elevation should be closely monitored to avoid overtreatment, and re-evaluated by a trial off therapy. This alternative approach will largely eliminate unnecessary treatment of infants with transient NHT, mostly caused by ID or excess in Türkiye, and will reduce workload and costs by preventing unwarranted investigation and long-term follow-up.

Objective: Heterozygous COL2A1 gene mutations are associated with type 2 collagenopathies, characterized by a wide, diverse, and overlapping clinical spectrum in related diseases. Our goal is to describe the clinical, radiological, and molecular findings of patients with COL2A1-related dysplasia and investigate the phenotype-genotype correlation. We also highlight the challenge of categorizing COL2A1-related diseases with similar clinical and radiological phenotypes.

Methods: Six patients from five unrelated families presented with disproportionate short stature.delayed motor milestones, waddling gait, normal intelligence, and similar radiological features, including delayed epiphyseal ossification, epimetaphyseal changes, scoliosis, lordosis, and platyspondyly. All underwent whole exome sequencing. Demographic, clinical, laboratory, and radiological data were retrospectively obtained from hospital records. Segregation analysis was conducted using Sanger sequencing in all patients.

Results: Based on clinical, radiological, and molecular results, the six patients were categorized into kniest dysplasia, spondyloepiphyseal dysplasia congenita, and spondyloepimetaphyseal dysplasia Strudwick type. Four novel variants (c.1023+2T>C, p.Gly465Asp, p.Gly855Asp, p.Gly669Ala) were identified in the COL2A1 gene.

Conclusion: Accurate classification of type 2 collagenopathies is vital to provide appropriate genetic counseling. Predicting extraskeletal manifestations and reducing morbidity through early diagnosis and treatment will significantly improve the quality of life for patients.

Objective: The honeymoon phase in type 1 diabetes (T1D) represents a temporary improvement in glycemic control but may complicate insulin management. The aim was to develop and validate a machine learning (ML)-driven method for accurately detecting this phase to optimize insulin therapy and prevent adverse outcomes.

Methods: Data from pediatric T1D patients aged 6-17 years, including continuous glucose monitoring data, glucose management indicator (GMI) reports, hemoglobin A1c (HbA1c) values, and patient medical history, were used to train ML models including long short-term memory (LSTM) networks, transformer models, random forest, and gradient boosting machines (GBMs). These were designed to analyze glucose trends and identify the honeymoon phase in T1D patients.

Results: The transformer model achieved the highest accuracy at 91%, followed by GBMs at 89%, LSTM at 88%, and random forest at 87%. Key features, such as glucose variability, insulin adjustments, GMI values, and HbA1c levels were critical to model performance. Accurate identification of the honeymoon phase enabled optimized insulin adjustments, enhancing glucose control and reducing hypoglycemia risk.

Conclusion: The ML-driven approach provides a robust method for detecting the honeymoon phase in T1D patients, demonstrating potential for improved personalized insulin management. The findings suggest significant benefits in patient outcomes, with future research focused on further validation and clinical integration.