Carney Complex (CNC) is a rare genetic disorder characterized by multiple endocrine and nonendocrine neoplasms, primarily driven by mutations in the PRKAR1A gene. This study explores the clinical heterogeneity in CNC patients, with a focus on adrenal and extra adrenal involvement and its impact on patient outcomes. We present three pediatric cases with unique clinical manifestations. Case 1: A 12-year-old female with ACTH-independent cyclic Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). The patient's condition progressed, leading to complications such as obesity, depression, and short stature, ultimately requiring bilateral adrenalectomy. Case 2: A 9-year-old male presented with an intranasal osteochondromyxoma and a large cell calcifying sertoli cell tumor. In the followup he developed hypocortisolism secondary to ACTH deficiency, with further complications including central precocious puberty and a growth hormone-secreting pituitary adenoma. Case 3: A 12-year-old female with adrenal insufficiency due to ACTH deficiency, complicated by a pituitary adenoma and a recurrent cardiac myxoma. Over time, the patient developed ACTH-independent Cushing syndrome secondary to PPNAD, necessitating bilateral adrenalectomy. Multiple fusiform aneurysms were also discovered after the recurrence of atrial myxoma. All cases highlight the absence of a consistent genotype-phenotype correlation in CNC, emphasizing the need for individualized management strategies. The findings underscore the complexity of diagnosing and treating CNC, particularly in pediatric populations, and call for further research into the underlying molecular mechanisms to develop more targeted therapies.

Precocious puberty (PP) refers to the early onset of secondary sexual characteristics, occurring before 8 years of age in females and 9 in males. This condition commonly results from a premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, a phenomenon identified as central precocious puberty (CPP). Central precocious puberty (CPP) in females is predominantly idiopathic, whereas in males, it is mostly caused by hypothalamic-pituitary lesions. Diagnosis is established through comprehensive clinical assessment, encompassing a thorough anamnesis from both the patient and their caregivers, detailed physical examination, and Tanner staging conducted by a pediatric endocrinologist. Neuroimaging, particularly brain MRI, is employed to detect intracranial anomalies or pituitary pathology, with pituitary microadenomas being a commonly observed finding. This report presents the case of a 5-year-old male who exhibited signs of secondary sexual development, with testicular volume consistent with Tanner stage 5 based on laboratory evaluation. Assessment of skeletal maturation revealed a significantly advanced bone age, approximating that of a 11-year-old child. The patient underwent an ultrasound examination by the results of testicular volume greater than the normal value of his age. Due to the results of the examination, the patient underwent an MRI examination of the head to find the cause by the conclusion on MRI, namely pituitary microadenoma. Although generally considered a testicular neoplasm, with the vast majority occurring in men, Leydig cell tumors may occur in both sexes. In men, Leydig cell tumors initially appear as testicular neoplasms. While accounting for a relatively small proportion of all cancer diagnoses in men, testicular neoplasms are the most common malignancy in men aged 15 to 44. Testicular neoplasms are broadly categorized into germ cell tumors, which comprise approximately 95% of all testis cancers, and sex cord–stromal tumors, accounting for 2% to 5% in adults but 25% in children due to the lower incidence of germ cell tumors in the pediatric population. Among sex cord–stromal tumors, Leydig cell tumors are the most common subtype (75%), originating from the specialized Leydig cells within the testicular interstitium between the seminiferous tubules. These tumors were first described by German zoologist and anatomist Franz von Leydig in 1870. Leydig cell tumors are relatively rare, but they represent the most common type of nongerm cell testicular tumors. Leydig cells are essential for testosterone production, which is stimulated by luteinizing hormone, and are critical to the development of the male reproductive organs, such as the prostate and testes. Testosterone is responsible for the secondary male sexual characteristics, as well as increased muscle and bone mass, maintenance of libido, stimulation of erythropoiesis, and promotion of spermatogenesis. Furthermore, Leydig cell tumors are typically benign, and malignancy is rare in children. In adults, older estimates reported malignancy rates of 5% to 10%; recent large-scale study results report a considerably lower rate of approximately 2.5%. However, other results indicate a malignancy rate of around 10% during follow-up.  These tumors exhibit a bimodal age distribution, with incidence peaks in prepubertal boys (5 to 10 years) and adults (30 to 60 years). Their inherent hormonal activity can lead to diverse clinical manifestations, including precocious puberty (62%), gynecomastia in adults (20%), or infertility (17% to 18%). However, many Leydig cell tumors are discovered incidentally, such as during an infertility evaluation in men, in otherwise asymptomatic individuals. In women, Leydig cell tumors constitute less than 0.5% of all ovarian neoplasms. Most occur around the time of menopause (70% to 85%), accompanied by increased androgen levels, causing hirsutism and virilization. High serum testosterone levels (more than 3 times the reference range for age) cause an increase in masculinization symptoms. Other sources of hyperandrogenism should be excluded, such as endocrinopathies, other hormonally active ovarian tumors, iatrogenic factors, and idiopathic causes. Diagnostic imaging in women may include transvaginal ultrasonography of the ovaries, pelvic MRI, and abdominal CT scans to evaluate the adrenal glands. Fluorodeoxyglucose positron emission tomography can identify smaller foci of Leydig cell tumors. Negative imaging results indicate that diagnostic laparoscopy is necessary. In the absence of any apparent ovarian lesions, if no clear etiology is determined and adrenal causes of hyperandrogenism have been excluded, bilateral oophorectomy should be considered. Treatment is surgical resection of the affected ovaries and fallopian tubes, and possible hysterectomy. Leydig cell malignancies in women are rare, with a poor prognosis due to the aggressive nature of these neoplasms.

Precocious puberty (PP) is the early onset of secondary sexual characteristics before the typical age of puberty, which can be caused by hormonal imbalances or external factors, such as medications. Drug-induced precocious puberty (DIPP) has become a growing concern, particularly in pediatric populations. However, the impact of gender differences on DIPP risk and the challenges in drug safety assessments have not been fully explored. To investigate gender-specific differences in the occurrence of drug-induced precocious puberty (DIPP) and identify potential risk signals related to medication use, utilizing data from the U.S. FDA Adverse Event Reporting System (FAERS). Data from the FAERS database (2004-2024) were used to identify adverse event reports related to drug-induced precocious puberty. Disproportionality analysis (DPA) was applied to detect potential signals of DIPP. The analysis considered demographic variables, including drug, age, gender, weight, indications, and reporting country. Only the most recent report for each unique "caseid" was retained. A total of 529 reports of DIPP were identified, with a significant increase in reports from 2004 to 2024. The number of reports rose from 9 in 2004 to 53 in 2024, with an average of 40 reports per year from 2018 to 2024. The most frequently implicated drugs were testosterone (N = 88), somatropin (N = 52), and methylphenidate (N = 49). Drugs with the highest Reporting Odds Ratios (RORs) included mitotane (ROR = 220.35), mecasermin (ROR = 145.42), and clomifene (ROR = 141.35). Gender differences were observed, with 56.9% of reports from females and 36.3% from males. The majority of reports came from developed countries, with the U.S. contributing 50.47% of cases. The median time to adverse event occurrence was 238 days, with males showing a median induction time of 192.5 days and females at 242 days, though no statistically significant difference in induction time between males and females was found (p > 0.05). Drug-induced precocious puberty presents a significant clinical concern, particularly in pediatric populations. Gender-specific differences in drugs associated with precocious puberty highlight the need for personalized drug safety assessments. Key drugs associated with DIPP, but not listed as risk factors in labeling, underscore the importance of long-term monitoring. Further research is necessary to explore the mechanisms behind gender differences and enhance drug safety strategies, particularly for children and adolescents.

Many primary and secondary disorders in childhood may cause tall stature (height of +2 standard deviations above the mean height for age and sex). Growth-monitoring programs are aimed at early detection of such disorders to avoid permanent health consequences and support children's wellbeing. However, age- and sex-specific data on the incidence of disorders associated with tall stature are scarce. This retrospective population-based cohort study aims to specify the epidemiological data that are needed to develop better diagnostic practices. The study population included 1 144 503 children (51% boys) born in Finland between 1998 and 2017 with 16.5 million register notifications including medical diagnoses. The first occurrences of several primary or secondary disorders associated with tall stature were identified from multiple registers. The age- and sex-specific cumulative incidences (CMIs) from birth until 18 years of age and the median age at diagnosis were determined. A total of 1641 children (0.14% of the whole birth cohort, 44% boys) had a primary or secondary disorder associated with tall stature. Klinefelter syndrome (47,XXY karyotype) was the most common primary disorder (median age at diagnosis: 8.4 years, CMI at 18 years: 1/2146 boys). Marfan syndrome (5.9 years, 1/4307 girls; 7.1 years, 1/5202 boys) and congenital overgrowth syndromes (1.7 years, 1/4717 girls; 1.8 years; 1/4925 boys) did not have a predilection for either sex. Secondary conditions such as central precocious puberty (1/894 girls at 8 years, and 1/4856 boys at 9 years) and hyperthyroidism (15.1 years, 1/936 girls; 14.4 years, 1/5675 boys) were more common among girls. Disorders associated with tall stature are rare and are frequently underdiagnosed in childhood. We suggest that during early childhood, the focus of growth screening should be particularly on Marfan syndrome and congenital overgrowth syndromes, with the addition of Klinefelter syndrome and central precocious puberty thereafter.

Central precocious puberty (CPP) was an unexplored issue during COVID-19 pandemic and an important disease in the adolescence life. Our aim was to evaluate the incidence of the new cases of CPP during COVID-19 pandemic, comparing these results with the data for the same period over the previous three years. The secondary objective was to analyze the rate of pubertal progression in children during COVID-19 outbreak. We performed a retrospective study of all children presented at our hospital for suspected CPP during COVID-19 outbreak, comparing their clinical and endocrinological data to the same over the previous three years. Secondary, endocrinological data of some patients in follow-up, with at least two visits 6 months apart during the COVID-19 period, are compared to evaluate the rate of pubertal progression. We enrolled 90 suspected enrolled CPP cases, 26 (28.9%) referred to our hospital during the COVID-19 outbreak and 64 (71.1%) in the previous 3 years. During COVID-19 outbreak 12 girls (42.9%) were at stage T3 compared to 14 (23%) of the 3 previous years (P=0.01). New CPP diagnosis were found in 11 (39.3%) children during pandemic, while 15 (24.2%) in the previous 3 years. A accelerated pubertal progression rate was observed in 22/45 (48.9%) patients, with a greater number of children at stages T3 and T4-5. Our data showed a progressive increase of newly diagnosed CPP and a significantly accelerated rate of pubertal progression in children during COVID-19 outbreak. We hypothesize that the increase in the weight and BMI during the lockdown and the psychological effects of the COVID-19 outbreak were involved in triggering and progression of puberty.