Objective: As life expectancy increases in patients with congenital heart disease (CHD), providing appropriate gynecological care has become more important. While the gynecologic and reproductive health concerns of adults with CHD are increasingly recognized, studies focusing on menstrual problems in adolescents with CHD are limited. The aim was to evaluate menstrual characteristics and related symptoms in adolescents with CHD. Methods: Adolescents aged 12-21 years who had experienced menarche at least two years earlier were included. The CHD group was classified as mild, moderate, or severe, based on the European Society of Cardiology guidelines, and healthy adolescents served as controls. Menstrual histories were obtained from all participants. In the CHD group, additional clinical data (diagnosis, surgery/interventions, and medication use) were collected. Menstrual parameters were compared between the CHD and control groups, as well as across CHD subgroups. Results: A total of 108 adolescents with CHD (41 mild, 42 moderate, 25 severe) and 76 healthy controls were enrolled. No significant differences were found between groups in terms of age at menarche, menstrual cycle length, period duration, or daily pad use (p>0.05). Dysmenorrhea severity and frequency were similar; however, school absenteeism due to dysmenorrhea was significantly higher in the control group (p=0.037). Physical premenstrual symptoms, particularly bloating, anxiety, and mood swings, were more frequent in controls (p<0.05). Menstrual education rates from healthcare professionals were low in both groups. Conclusion: Our findings indicate that adolescents with CHD have menstrual characteristics comparable to those of healthy controls. However, despite these similarities, they may differ in their perception and tolerance of menstrual symptoms.
Aromatase deficiency (AD) is a rare autosomal recessive disorder caused by pathogenic variants in the CYP19A1 gene, resulting in impaired conversion of androgens to estrogens. Clinical manifestations in 46, XX individuals include ambiguous genitalia, delayed puberty, and reproductive dysfunction. Both sexes may develop metabolic abnormalities, delayed epiphyseal closure, eunuchoid body proportions, and low bone mass. Because of its rarity and overlap with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), diagnosis may be delayed or missed. Gonadal tumors have not been reported in association with AD. We describe a 20-year-old female with ambiguous genitalia at birth who was diagnosed in infancy with 21OHD and treated with hydrocortisone and fludrocortisone. Despite poor treatment adherence, she never developed adrenal insufficiency. At 16 years of age, she was referred for evaluation of primary amenorrhea and absent puberty. Assessment revealed hypergonadotropic hypogonadism with markedly low estradiol levels, normal basal and ACTH-stimulated 17-hydroxyprogesterone levels (17-OHP), and a 46, XX karyotype, findings that were inconsistent with CAH. Additional features included metabolic abnormalities and low bone mass. Whole-genome sequencing identified a homozygous pathogenic CYP19A1 splice-site variant (c.1263+1G>T), confirming AD. Imaging and surgery demonstrated an enlarged right adnexal mass and a hypoplastic left ovary. Histopathology revealed bilateral gonadoblastoma with dysgerminoma arising in the right ovary. This case highlights the diagnostic challenges of AD and emphasizes the importance of reconsidering a diagnosis of CAH when biochemical findings are discordant with the clinical picture. To our knowledge, this is the first reported case of genetically confirmed aromatase deficiency with coexisting gonadoblastoma and dysgerminoma. Whether this coexistence represents a causal association or a coincidental finding remains uncertain.
Objective:Pubertal gynecomastia (PG) is a benign condition considered to be caused by imbalance between estrogen and testosterone, though this is not frequently evident from serum analysis. This study aimed to determine possible alteration in sex hormone levels, as well as to investigate the role of sex hormone-binding globulin (SHBG) and leptin in PG development and persistence. Methods:A total of 95 boys with PG were included. They were divided into 3 groups considering stage. Anthropometric measurements, hormonal investigations, SHBG and leptin were collected and compared group of 64 controls without PG matched in pubertal status and anthropometrics. Results:Investigations of patients with gonadal Tanner stage 2 proved statistically significant estradiol [120.0 pmol/l (73.4-240.0) vs.77.80 (23.2-120), p=0.023] and decrease in testosterone/estradiol ratio compared to control group. The same is not found in PG groups with Tanner stage 3, 4 5. Difference of the levels of testosterone and Free Androgen Index (FAI) were not found in Tanner stage 2, but significantly lower FAI was determined in mid-pubertal boys with gynecomastia compared to controls [36.0(6.8-197.0) vs.64.0(1.79-140.1), p=0.017]. Additionally, a lack of decrease of SHBG in the PG group with pubertal advancement was observed, which might explain the lower FAI in that cohort. No statistically significant difference leptin level was found. Conclusion:The early rise of estradiol at the beginning of puberty might be responsible for PG, while lack of SHBG reduction with advancement of puberty and lower FAI might have an impact on its development and/or persistence in mid-pubertal boys.
Niemann-Pick type C disease (NP-C) is a rare neurovisceral disorder caused by mutations in the NPC1 or NPC2 genes. Clinical symptoms of NP-C can appear at any age. Here we report a case of a girl diagnosed with NP-C who subsequently developed central precocious puberty (CPP). To our knowledge, this association has not been described in the literature till now. An 8 year old girl was referred to the pediatric metabolism outpatient clinic due to poor school performance, behavioral changes and periventricular white matter signal changes observed on cranial magnetic resonance imaging (MRI). The physical examination revealed vertical supranuclear gaze palsy (VSGP) and splenomegaly. The patient was diagnosed NP-C through genetic analysis and was started miglustat treatment. The patient was also referred to the pediatric endocrinology outpatient clinic due to breast development (Tanner stage 3) and pubic hair (Tanner stage 3). Laboratory work up revealed normal basal serum LH (0. 2 U/L) and the LHRH test showed a LH value of 8.48 U/L and a peak LH/ FSH ratio of 2. 8 (>0.66). Pelvic ultrasonography revealed an uterine length of 45 mm and mean ovarian volume of 5. 5 mL, Leuprolide acetate was started and at the first year of follow-up the patient's height velocity was 0.4 SDS and Tanner's pubertal staging was 3. This case report highlights a potential association of NP-C with CPP and confirms the need for careful assessment of pubertal development in patients with white matter disease.
This is a case report of neonatal cholestasis caused by Graves' disease, accompanied by a literature review of previously published cases. Neonatal/Infantile cholestasis (NIC) is defined as an impairment in bile formation and/or flow presenting by the first year of age, typically within the first three months. Hyperthyroidism has been less frequently associated with this condition. Here, we report a case of neonatal cholestasis caused by Graves' disease and review relevant literature to summarize its clinical characteristics, and to enhance prompt and accurate recognition and diagnosis of this disease. A 28-day-old female infant was admitted to our center, presenting with jaundice, diarrhea, poor weight gain, and tachycardia. Laboratory examinations showed cholestasis, hyperthyroidism, and positive for thyrotropin receptor antibody (TRAb), confirming the diagnosis of neonatal Graves' disease. After treatment with propranolol and intravenous immunoglobulin (IVIG), the jaundice subsided, and thyroid function returned to normal. Neonatal Graves' disease must be included in the differential diagnosis of cholestasis, particularly in infants whose mothers have Graves' disease or a history of thyroid dysfunction. Early detection of hyperthyroidism in neonates with cholestasis is crucial.
Noonan syndrome occurs in approximately 1/1,000-1/2,500 live births and is caused by defects in the Ras/mitogen-activated protein kinase pathway. Pubertal development includes syndrome-specific differences which may manifest as delayed puberty in both sexes, as well as cryptorchidism and impaired gonadal function, especially in the males. However gonadal dysgenesis and disorders of sex development have not been previously reported in the literature before. Our patient presented with ambiguous genitalia at two days of age. There was no consanguinity between the parents. On physical examination, the external masculinisation score was 4. Laboratory tests were compatible with gonadal dysgenesis. Echocardiography revealed pulmonary stenosis and a secundum atrial septal defect. Karyotype was 46 XY, SRY (+) and no pathogenic variant was detected in the targeted gene sequencing panel for disorders of sex development. A targeted next-generation seqeuencing (NGS) panel for Noonan syndrome was performed in the patient due to pulmonary stenosis and suggestive facial appearance, identifying a pathogenic c.136 T>G variant in the RIT1 gene. Noonan syndrome may cause gonadal dysfunction leading to delayed puberty and infertility; however, gonadal dysgenesis and ambiguous genitalia have not been previously reported. Noonan syndrome should be investigated in every patient with suggested clinical findings and affected gonadal functions.
Objective: Subclinical hypothyroidism (SH) in childhood is frequently idiopathic and usually follows a benign course. Heterozygous loss-of-function variants in the thyrotropin receptor (TSHR) gene have emerged as a genetic cause of isolated hyperthyrotropinemia but data regarding long-term outcomes and management are limited. Methods: We retrospectively evaluated children (aged 1-18 years) diagnosed with idiopathic SH. TSHR gene analysis was performed using targeted next-generation sequencing in patients selected based on neonatal TSH elevation, family history of SH, thyroid gland in situ, or persistence of SH after levothyroxine withdrawal. Clinical, biochemical, ultrasonographic, and treatment outcomes were compared between patients with and without TSHR variants. Results: The cohort consisted of 51 patients followed for a mean of 4.9±2.6 years. Heterozygous TSHR variants were identified in 18 (35.2%), including one novel missense variant. Variant-positive patients generally showed a stable, compensated thyroid phenotype without progression to overt hypothyroidism. Levothyroxine therapy was discontinued in 6 of 11 initially treated patients after genetic diagnosis, with sustained biochemical stability. However, five patients required re-initiation of therapy due to rising TSH levels (15.7-27.8 mIU/L) or clinical symptoms. Lower thyroid volume standard deviation scores and the presence of additional clinical risk factors, such as small-for-gestational-age birth or developmental delay, were associated with treatment requirement. No patient developed overt hypothyroidism. Conclusion: Heterozygous TSHR variants appear to contribute to the pathogenesis of pediatric idiopathic SH and are frequently associated with a stable, compensated thyroid phenotype. These findings support a conservative, individualized management strategy rather than routine levothyroxine therapy.
Objective: To evaluate longitudinal changes in body mass index-standard deviation score (BMI-SDS) in girls with central precocious puberty (CPP) treated with gonadotropin-releasing hormone analogues from treatment initiation to final adult height. Methods: This retrospective study included 150 girls with idiopathic CPP treated with leuprolide acetate and followed to final adult height. BMI-SDS was assessed at treatment initiation, at 1 year of therapy, at treatment completion, and at final adult height. Patients were categorized according to BMI-SDS at the time of diagnosis as underweight, normal weight, overweight (OW), or obese (OB). BMI-SDS was evaluated at predefined time points and examined within baseline weight groups, and transitions between BMI-SDS categories were analyzed across the follow-up period. In addition to baseline weight status, participants were categorized as small for gestational age (SGA) or appropriate for GA (AGA) based on birth weight for gestational age. Results: In normal-weight girls, BMI-SDS increased significantly during the first treatment year and then declined toward final height, with no difference between baseline and final height. BMI-SDS remained stable in those OW or OB at treatment initiation. BMI-category distribution changed over follow-up (overall p=0.014), OW+OB prevalence increased during treatment (48.6%→56.6%) and decreased by final height (45.3%) (baseline vs final p=0.533). By final height, OB increased (p=0.0076) and OW decreased (p=0.006), while normal-weight prevalence did not differ from baseline (p=0.098). BMI-SDS was lower in SGA than AGA at baseline, year 1, and treatment completion (p=0.04, p=0.04, and p=0.01, respectively), but not at final adult height (p=0.6). In multivariable analysis, baseline BMI-SDS was inversely related to ΔBMI-SDS (treatment end-baseline) (β=-0.174, 95% confidence interval -0.291 to -0.057; p=0.004). Conclusion: In this large cohort of girls with idiopathic CPP followed through final adult height, BMI-SDS showed no sustained increase at final height across baseline weight groups, and the SGA-AGA differences observed earlier were not maintained. Baseline BMI-SDS was the key independent determinant of ΔBMI-SDS (treatment end-baseline), with lower baseline values predicting greater increases.
Objective: To comparatively evaluate the reliability, quality, and readability of responses generated by widely used large language model (LLM)-based chatbots to congenital hypothyroidism (CH)-related patient questions. Methods: Forty frequently asked questions (FAQs) about CH, derived from clinician-reviewed patient education resources, were submitted under standardized conditions (December 2025) to Chat Generative Pre-Trained Transformer-4 (ChatGPT-4), ChatGPT-5.2, Gemini, and Copilot. The modified DISCERN (mDISCERN) instrument was used to assess reliability, whereas the Global Quality Score (GQS) was used to evaluate quality. Readability was evaluated using Flesch Reading Ease (FRE), Flesch-Kincaid Grade Level (FKGL), Gunning Fog Index (GFI), Coleman-Liau Index (CLI), and Simple Measure of Gobbledygook (SMOG). Scores were compared using Friedman tests with Bonferroni-corrected post-hoc analyses. Results: Median mDISCERN scores were 5.0 for ChatGPT-4, ChatGPT-5.2, and Gemini, and 4.0 for Copilot. Median GQS scores were 5.0 for ChatGPT-4, ChatGPT-5.2, and Gemini, and 4.0 for Copilot. Differences among models were significant for both mDISCERN and GQS (p<0.001), with ChatGPT-5.2 outperforming others in key pairwise comparisons. Readability differed significantly across all indices (all p<0.001). ChatGPT-5.2 demonstrated the highest FRE and lowest FKGL, whereas Gemini produced the most complex text. However, all models exceeded the recommended sixth-grade reading level. Conclusion: LLM-based chatbots produced generally moderate-to-high quality CH information, but readability remains suboptimal for patient education. ChatGPT-5.2 showed the best overall performance. LLM outputs may support patient information needs but should complement, not replace, clinician-provided counseling.
Congenital hyperinsulinism (HI) is the most prevalent cause of persistent hypoglycemia in infancy and childhood and comprises a heterogeneous group of genetic disorders affecting insulin secretion. The most common etiology involves inactivating mutations in the ABCC8 and KCNJ11 genes, which encode the SUR1 and Kir6.2 subunits of the pancreatic β-cell ATP-sensitive potassium (KATP) channel. Variants in these genes are associated with a broad phenotypic spectrum, ranging from asymptomatic macrosomia and mild diazoxide-responsive disease to severe, persistent hyperinsulinemic hypoglycemia unresponsive to medical therapy. In some individuals, the clinical course may evolve over time, with progression from early hyperinsulinism to impaired glucose regulation and eventual diabetes mellitus. We describe a 13-year-old girl with diazoxide-unresponsive congenital hyperinsulinism caused by a heterozygous de novo ABCC8 variant (c.2147G>A, p.Gly716Asp) who later developed insulin-deficient diabetes mellitus. She was treated with octreotide from 2 months until 7 years of age, when therapy was discontinued after gradual remission of hypoglycemia. At 11 years, evaluation revealed impaired fasting glucose and impaired glucose tolerance, and glibenclamide was initiated. After being lost to follow-up, she presented at 13 years with hyperglycemia and was diagnosed with antibody-negative, insulin-deficient diabetes mellitus. Basal insulin therapy led to progressive normalization of glycemic levels. To our knowledge, this is the first report linking the ABCC8 p.Gly716Asp variant to transition from congenital hyperinsulinism to adolescent-onset diabetes, underscoring the phenotypic continuum of ABCC8-related disorders and the necessity for lifelong metabolic surveillance.
Objective: Subclinical hypothyroidism (SH) is defined as elevated thyroid-stimulating hormone (TSH) with normal thyroid hormone levels and typically presents without specific symptoms in children. Although treatment criteria exist, predictors of progression and treatment need remain uncertain. Methods: To evaluate the natural course of mild SH, identify clinical conditions associated with elevated TSH, determine predictors of progression requiring levothyroxine, and assess growth outcomes. Records of children (3 months-18 years) with mild SH (TSH 5-10 mIU/L on ≥2 measurements) and ≥6 months of follow-up were retrospectively reviewed. Demographic, biochemical, anthropometric, etiological, and imaging data were analyzed. Children were categorized as idiopathic or as having associated clinical factors (autoimmune thyroiditis, iodine imbalance, obesity, or medication use). Outcomes were classified as euthyroid, persistent SH, or requiring treatment. Results: During follow-up, 45 of the study cohort of 111 children (40.5%) became euthyroid, 49 (44.2%) remained subclinically hypothyroid, and 17 (15.3%) required levothyroxine. Idiopathic cases showed the most favorable course, with only 8.6% requiring therapy. Hashimoto’s thyroiditis (HT) was the strongest predictor of progression (42.1% vs. 9.8% in non-HT). A baseline TSH>7.5 mIU/L increased treatment likelihood by ~3.5-fold. Growth parameters remained within normal limits, with no deterioration in untreated children. Conclusion: Mild pediatric SH is generally benign and self-limiting, particularly in idiopathic cases. HT and higher baseline TSH levels are key predictors of progression, while growth remains stable. Management should be individualized based on underlying conditions, TSH severity, and autoimmune status.
21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia (CAH). Salt-wasting CAH can present with life-threatening salt-wasting crises, underscoring the importance of universal newborn screening. We present a patient diagnosed with classical CAH despite four negative newborn screening (NBS). A male infant was born at 35 weeks gestation with birthweight 1470 grams following signs of placental insufficiency. While hospitalized in the neonatal intensive care unit (NICU), four NBS samples from days of life 2 to 38 were all within normal range, including on repeat analysis using fully integrated fluoroimmunoassay. After initially normal biochemical testing, hyponatremia and hyperkalemia developed by day of life (DOL) 26, responsive to sodium chloride supplementation. Following recurrent hyponatremia after a trial off supplementation after DOL 50, 17-hydroxyprogesterone measured by liquid chromatography-tandem mass spectrometry were reported by two different labs as 10,900 ng/dL and 11,200 ng/dL (normal range at DOL 50<2 ng/dL). Subsequent testing identified deletion of one CYP21A2 allele and a mutation, I172N, in the second. This report illustrates the importance of maintaining a high index of suspicion for classical forms of CAH in infants with persistent electrolyte disturbances despite negative NBS results.
Primary adrenal insufficiency (PAI) in childhood is a rare and potentially life-threatening condition that may arise from defects in adrenal steroidogenesis, adrenal dysgenesis, ACTH resistance, autoimmune mechanisms, or inherited metabolic disorders. Among the latter, peroxisomal dysfunctions represent a rare cause. Although X-linked adrenoleukodystrophy is a well-recognized etiology, adrenal involvement in other peroxisomal diseases, such as ACOX1 deficiency, remains poorly defined. We report a three-year-old girl with global developmental delay, epilepsy, bilateral sensorineural hearing loss, and progressive neurological regression. Biochemical analyses revealed abnormal plasma very-long-chain fatty acids profile, suggesting a peroxisomal disorder. Whole-exome sequencing identified a homozygous pathogenic variant (c.1478+2T>A) in ACOX1, confirming the diagnosis of pseudo-neonatal adrenoleukodystrophy. During hospitalization for a urinary tract infection, endocrine evaluation revealed markedly elevated plasma ACTH (529 pg/mL) and low serum cortisol (8.62 µg/dL), while Na, K, and PRA were within normal limits. Adrenal imaging was consistent with atrophy. Hydrocortisone replacement was initiated with good clinical response. Notably, the patient had no classical signs of adrenal failure such as hyperpigmentation or electrolyte imbalance. This case provides additional evidence that ACOX1-related Pseudo-neonatal adrenoleukodystrophy may be associated with variable adrenal involvement, expanding the phenotypic spectrum of the disorder. The absence of typical clinical manifestations highlights the importance of routine hormonal screening in children with peroxisomal diseases, even in the absence of overt adrenal symptoms. Early recognition of endocrine dysfunction can prevent life-threatening adrenal crises and offers valuable insight into the broader pathophysiology of peroxisomal β-oxidation disorders.
