Hormone Research in Paediatrics最新文献

Introduction: Prepubertal gynecomastia (PG) and juvenile macromastia (JM) are rare breast overgrowth phenotypes arising from hormonal or genetic abnormalities. While many cases reflect physiological or endocrine variation, a subset may involve increased peripheral aromatization driven by genomic factors. The molecular basis remains unknown in many idiopathic cases. We evaluated whether copy number variations (CNVs) in CYP19A1 and other estrogen-related genes are associated with PG or JM.

Methods: We performed a cross-sectional study of 17 patients suspected of aromatase excess syndrome: 10 boys with PG and 7 girls with JM. Clinical and hormonal data at diagnosis and follow-up were reviewed. After excluding numerical and structural chromosomal anomalies, genome-wide oligonucleotide array comparative genomic hybridization (aCGH) was analyzed in Agilent Genomics Workbench (GRCh37/hg19). CNVs were interrogated across estrogen-related genes, including CYP19A1. As comparators, 988 individuals evaluated by aCGH at the same center for unrelated indications and without breast overgrowth served as controls.

Results: No pathogenic CNVs were observed in CYP19A1 or the other estrogen-related genes. By contrast, a recurrent 65.2-kilobase (kb) deletion spanning the OR4P4-OR4S2-OR4C6 olfactory receptor cluster at 11q11 occurred in 40.0% (4/10) of PG and 57.1% (4/7) of JM cases, in this cohort, overall, versus 3.4% (34/988) of controls, suggesting a strong association. Estimated risk ratio was 11-fold higher in PG and 16-fold higher in JM.

Conclusion: Although estrogen-gene CNVs were not detected, the OR4P4-OR4S2-OR4C6 deletion may represent an under-recognized genomic contributor to idiopathic PG and JM. Prospective studies with tissue-level validation and functional assays are needed to confirm clinical significance and clarify mechanism.

Introduction: Loss-of-function mutations in MKRN3, a maternally imprinted gene, represent the most common genetic defects associated with familial central precocious puberty (CPP) in both sexes. In recent years, the number of affected females with CPP due to MKRN3 mutations has been greater than affected males, despite the evidence of a dominant inheritance and apparent complete penetrance of this genetic condition.

Case presentation: We described a Brazilian family with several members with CPP due to a recurrent loss-of-function mutation of MKRN3 (p.Ala162Glyfs*15). The index case was a 6-year-old-girl who had thelarche, pubarche, growth acceleration, and advanced Tanner staging (B3P3) and bone age (11 years), confirmed by pubertal basal LH concentrations. This mutation was also identified in her affected sister (menarche at 7 years), paternal aunt (menarche at 9 years), and a paternal cousin who had a history of treatment of CPP. Her apparently asymptomatic father carried the same mutation but had no memory of his puberty period. The paternal origin of the mutated allele in this father was indicated by the evidence of CPP in his sister, supporting that he had undiagnosed precocious puberty. In fact, he attained borderline adult short stature, suggesting a probable loss of his genetic height potential. In addition, we performed a literature review on male carriers of MKRN3 mutations and compared with data obtained with female cases.

Conclusion: We demonstrated a marked male phenotypic variability associated with MKRN3 mutations and suggested a large proportion of underdiagnosed male cases in previous descriptions. Additionally, incomplete penetrance involving males with paternally inherited MKRN3 mutations cannot be ruled out to date.

Introduction: Bone health screening is established in cystic fibrosis (CF). Given the unknown status of bone quality in primary ciliary dyskinesia (PCD), these recommendations have not been adopted. We aimed to evaluate the bone phenotype in PCD compared to healthy controls and CF.

Methods: In this exploratory cross-sectional study, we assessed bone mineral density (BMD) at the whole body and lumbar spine using dual-energy X-ray absorptiometry (DXA), and tibial bone microarchitecture using high-resolution peripheral quantitative computed tomography (HR-pQCT) in 15 individuals with PCD and 45 with CF, aged 12-20 years. Measures were compared to healthy controls matched one-to-one by pubertal stage and sex. Disease-to-healthy differences were compared between PCD and CF, and associations with body mass index (BMI), lean mass, and lung function were analysed.

Results: DXA-measured areal BMD and HR-pQCT-derived total volumetric BMD showed no differences between PCD and controls. HR-pQCT revealed reduced cortical thickness, area, and BMD at the ultra-distal tibia in PCD compared to controls. While PCD and CF did not differ, the PCD bone phenotype more closely resembled pancreatic-insufficient than pancreatic-sufficient CF. Dimensional cortical deficits were largely explained by BMI or lean mass, especially in CF, but remained reduced in PCD after adjustment, indicating potentially intrinsic disease-related alterations. Lung function did not clearly correlate with bone outcomes in PCD.

Conclusion: Skeletal health appears compromised in young people with PCD. Despite mostly normal densitometry, tibial bone microarchitecture was altered. This study positions bone health as a research priority in PCD and supports the need for larger confirmatory studies.

Introduction: Alcohol consumption is common among people with type 1 diabetes mellitus (PwT1D), with prevalence rates similar to the general population. However, it is associated with unique risks - increased risk of (delayed) hypoglycemia, diabetic ketoacidosis, and impaired ability to self-manage diabetes. In this study, we aimed to explore the knowledge and experiences of young (>16 years old) PwT1D concerning safe alcohol use.

Methods: We designed an anonymous survey informed by the clinical expertise of healthcare professionals, the lived experience of people with type 1 diabetes represented within our team, and the perspective of a patient organization, which was made available in 12 languages on a dedicated website and promoted via social media. We collected data on responders' background, self-perceived safety of alcohol use, experience about the impact of specific alcoholic drinks on one's glycemia, and safety management strategies. Data collection was open from October 2022 to November 2023.

Results: We analyzed complete responses from 216 PwT1D (63.4% females, 54.2% aged 16-21 years old, 29.3% with diabetes duration >15 years), who represented 23 countries (most often Italy, Poland, and the USA). Only 53.2% of PwT1Ds reported feeling safe while consuming alcohol, and 37% assessed their alcohol-related knowledge as average or lower. Only 45.8% reported that the issue of safe alcohol consumption was discussed as part of diabetes education. A total of 48.2% of participants experienced unpredictable effects of alcoholic drinks on blood glucose levels. Alcohol-related severe hypoglycemia episodes were significantly more frequent in those reporting frequent excessive drinking (≥6 drinks ≥1/month, OR 4.19, 95% CI: 1.37-12.75) and routinely consuming ≥2 alcoholic drinks per occasion (OR 4.20, 95% CI: 1.52-11.61).

Conclusions: The topic of safe alcohol consumption requires more attention in diabetes education. Developing evidence-based and easy-to-apply strategies tailored to alcohol type, amount, and technology use is essential for reducing acute diabetes-related complications.

Introduction: In children, papillary thyroid cancer (PTC) is generally sporadic and may, less frequently, be part of an undiagnosed hereditary tumor predisposition syndrome (HTPS). Somatic molecular testing is useful to understand tumor etiology and behavior, predict prognosis, and possibly guide development of novel treatment strategies. The aims of our study were to analyze the findings of a next-generation sequencing (NGS) panel in a cohort of pediatric PTC from Argentina according to age at presentation, recurrence risk, and response to treatment.

Methods: A retrospective descriptive study was conducted of 63 consecutive pediatric patients with PTC seen at a single center in whom a DNA-based NGS panel was performed. The patients were classified according to the ATA-2015 recurrence risk stratification into a low (n = 10), an intermediate (n = 13), and a high-risk group (n = 40). All patients were treated with total thyroidectomy and radioiodine. At the last follow-up, patients were classified as excellent response (ER) or having persistent disease (PD).

Results: In 70% (44/63) of the samples, a pathogenic somatic variant was detected; the most frequent alterations were RET fusions (20%). Fusions were more frequent in younger patients (median age 11.45 vs. 13.7 years; p = 0.048), in diffuse sclerosing subtype histology (p = 0.01) and in the high-recurrence risk group (p < 0.014). The risk of PD was higher in patients in the high-risk group (odds ratio, 9.2). When evaluating treatment response based on molecular findings, we found that among the 25 patients who achieved ER, 12 (48%) had fusions and 13 (52%) had point variants, with no statistically significant difference. However, among the 19 patients with PD, 12 (64%) had fusions and 7 (36%) had point variants, a difference that was statistically significant (p < 0.01). In 5/63 (8%), pathological germline mutations were observed in genes associated with HTPSs: DICER1 (n = 2), PTEN (n = 1), and MSH6 (n = 2).

Conclusions: Interestingly, in our PTC cohort, the NGS panel was highly specific to detect molecular alterations. Fusions were more frequent at a younger age and in the ATA-2015 high-recurrence-risk group; however, it was not a determining factor to predict PTC outcome. Finally, detection of pathological germline mutations in genes involved in HTPS was useful for genetic counseling.

Introduction: Pediatric thyroid nodules and cancer are uncommon but have significant challenges in clinical management due to potential malignancy. Understanding the genotype-phenotype correlation helps in enhancing patient care and personalized treatment strategies.

Methods: Our study aimed to determine the molecular characterization of thyroid nodules and cancer in childhood and investigate the genotype-phenotype relationship. The Bethesda category (BC) is a standardized framework for classifying thyroid fine-needle aspiration (FNA) results. We conducted a retrospective analysis of clinical data, including next-generation sequencing (NGS), from pediatric thyroid nodule and cancer patients. Analysis was conducted using samples from a pathology archive and follow-up clinical data from a tertiary care center.

Results: A cohort of 62 pediatric patients (50 female, 12 male) aged 2.67-19.61 years (mean 14.18 ± 3.45 years), evaluated over a mean follow-up period of 5.06 ± 3.99 years. NGS analysis of 34 genes for DNA variants and RNA sequencing for gene fusions in BC II-VI samples. Of 62 patients, 37 (59.7%) had differentiated thyroid cancer (DTC), 14 (22.6%) had benign findings, and 9 (14.5%) were categorized as other. Pathogenic variants were found in 80% of DTC patients, with BRAFV600E being the most common (37%). RET, NTRK, and ALK fusions were present in 32% of DTC patients. In the benign group, variants in DICER1, TSHR, and PTEN were noted. Pathogenic variants were also identified in BC-II to BC-IV patients that later developed DTC. High-risk DTC patients included those with BRAFV600E and NCOA4-RET fusions.

Conclusions: BRAFV600E and gene fusions involving RET, NTRK, and ALK were the most frequent pathogenic findings in pediatric DTC, with implications for risk stratification and tailored management. Early molecular analysis can guide prognosis and treatment in patients with initial benign or indeterminate diagnoses.

Introduction: Prospective data quantifying physical activity (PA) levels in Australian youth with type 1 diabetes (T1D) are lacking. Structured questionnaire instruments may provide useful information, but have not been evaluated in youth with T1D. The objective of this study was to evaluate the validity of three paediatric PA questionnaires in young people with T1D and their ability to differentiate those not meeting PA guidelines of 60 min of moderate-to-vigorous PA (MVPA) per day from those who do.

Methods: Eighty youth with T1D (42 boys, 38 girls; age: 13.1 ± 2.6 years; body mass index: 20.2 ± 3.9 kg·m-2; glycosylated haemoglobin: 58.5 ± 10.1 mmol/mol; T1D duration: 5.4 ± 3.1 years) wore an Actigraph GT3x accelerometer for 7 days and on day 8 completed three self-report PA instruments: (i) the Physical Activity Questionnaire (PAQ), (ii) Previous Day Physical Activity Recall (PDPAR), and (iii) a Single-Item Physical Activity Scale (SIPAS). Validity coefficients for each instrument using accelerometry-derived MVPA minutes were determined using Spearman's correlation coefficient. Receiver operator characteristic (ROC) curves were generated and optimal cut-points determined.

Results: Mean daily MVPA minutes were 46.6 ± 25.5 min; 21/80 participants (26%) achieved an average of ≥60 MVPA minutes per day. The PAQ had the highest validity coefficient (r = 0.53; p < 0.001), followed by the single-item tool (r = 0.39; p < 0.001) and PDPAR (r = 0.09; p = 0.4). Area under the ROC curve was 0.7, 0.5, and 0.7 for the PAQ, PDPAR, and single-item tools, respectively. Optimal cut-points for sensitivity and specificity were (i) a PAQ composite score of 2.8 (66.1% and 66.7%), (ii) 75 MVPA minutes on the PDPAR (59.3% and 47.6%), and (iii) 4.5 days on the SIPAS (71.2% and 38.1%).

Conclusion: The PAQ has moderate-to-high criterion validity and showed moderate ability to discriminate between T1D youth meeting PA guidelines from those who do not. The single-item question had low-to-moderate construct validity, while the PDPAR did not correlate with objectively measured PA levels. The feasibility of incorporating the PAQ into clinical care for youth with T1D warrants further evaluation.

Introduction: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare disorder characterized by respiratory failure, autonomic dysregulation, and endocrine abnormalities. Some of these patients may also develop neuroendocrine tumors (ROHHAD-NET). The aim of this study was to evaluate the clinical features, biochemical findings, treatments, and outcomes in a cohort of pediatric patients with ROHHAD-NET syndrome followed at a single tertiary center.

Methods: A retrospective review of 10 medical records of patients with ROHHAD-NET syndrome followed between 2007 and 2024 was conducted. Data analyzed included clinical, biochemical, therapeutic interventions and outcomes.

Results: Rapid-onset obesity, observed in all 10 patients, was the first clinical sign with a mean age at onset (MAO) of 5.1 ± 1.8 years. Neurobehavioral disorders were also an early manifestation, occurring in 5 cases with a MAO of 5 ± 1 years. All patients developed respiratory symptoms, with a MAO of 7.4 ± 3 years. Six patients were diagnosed with obstructive sleep apnea syndrome, including 2 with associated alveolar central hypoventilation. Seven patients required ventilatory support. All patients had hypothalamic dysfunction, MAO 6.6 ± 1.3 years. Disorders of water balance were the most frequent manifestation (n = 10), followed by hyperprolactinemia, central hypothyroidism, growth hormone deficiency, adrenal insufficiency, precocious puberty, and hypogonadotropic hypogonadism. Autonomic dysregulation was present in the entire cohort (MAO 6.7 ± 2.3 years), with strabismus as the most common clinical sign (n = 6). Neural crest tumors (ganglioneuromas) were identified in 5 patients, with a MAO of 5.4 ± 1.3 years. Tumor location included the adrenal gland (n = 2) and mediastinum (n = 3). Other clinical findings included thrombocytopenia, celiac disease, enuresis, type 1 and type 2 diabetes, seizures, hypo- and hypertension, and primary hypothyroidism. All patients received symptomatic treatment; 3 also received intravenous immunoglobulin as compassionate therapy, without significant benefit. Three patients died.

Conclusion: High clinical suspicion and early recognition are essential for a prompt diagnosis, timely initiation of respiratory support, and reduction of morbidity and mortality. Larger cohorts are needed for better characterization of this syndrome and to further elucidate its etiology.