Context: Delayed puberty is a frequent complaint in males. The differential diagnosis between self-limited delayed puberty (SLDP) and congenital hypogonadotropic hypogonadism (CHH) is challenging. Commonly used endocrine tests, focusing on stimulated levels of LH or testosterone, are not satisfactory in making a diagnosis. Because FSH action on Sertoli cells results in testis enlargement and anti-Müllerian hormone (AMH) and inhibin B increased secretion, and the FSH-Sertoli cell axis function is detectable during normal childhood and early puberty, we tested whether the assessment of serum FSH, AMH, and inhibin B would be informative to distinguish between SLDP and CHH. Design: We performed a prospective, nested case-control study in a cohort of male adolescents presenting with delayed puberty, comparing baseline serum reproductive hormone levels to identify predictive biomarkers of CHH, after having followed all participants prospectively until a final diagnosis was ascertained based on gold-standard criteria (age 18 years or ≥4 years after testis volume reached 4 mL). Results: Of 65 participants who completed follow-up, 33 had a final diagnosis of SLDP and 32 of CHH. Serum FSH, AMH, and inhibin B showed better diagnostic efficiency than LH and testosterone for these differential diagnoses. FSH (IU/L)×inhibin B (pg/mL) < 92 and FSH (IU/L)×AMH (pmol/L) < 537 showed high sensitivity (>93%), specificity (≥92%), predictive values (>92%), and positive likelihood ratio (>12) for CHH. The diagnostic performance remained 89.7% and 88.2% for FSH × inhibin B and FSH × AMH, respectively, when analyzed in patients without red flags (micropenis, cryptorchidism, and/or microorchidism). Conclusion: Serum FSH combined with inhibin B or AMH is highly predictive to accurately distinguish between SLDP and CHH in adolescent males.

In patients with 46,XY disorders of sex development (DSDs), next-generation sequencing (NGS) has high diagnostic efficiency. One contribution to this diagnostic approach is the possibility of applying reverse phenotyping when a variant in a gene associated with multiple organ hits is found. Our aim is to report a case of a patient with 46,XY DSDs in whom the identification of a novel variant in MYRF led to the detection of a clinically inapparent congenital heart defect. A full-term newborn presented with ambiguous genitalia, as follows: a 2 cm phallus, penoscrotal hypospadias, partially fused labioscrotal folds, an anogenital distance of 1.2 cm, and non-palpable gonads. The karyotype was 46,XY, serum testosterone and AMH were low, whereas LH and FSH were high, leading to the diagnosis of dysgenetic DSD. Whole exome sequencing identified a novel, heterozygous, nonsense variant in MYRF, classified as pathogenic according to the ACMG criteria. MYRF encodes a membrane-bound transcriptional factor expressed in several tissues associated with OCUGS syndrome (ophthalmic, cardiac, and urogenital anomalies). In the patient, oriented clinical assessment ruled out ophthalmic defects, but ultrasonography confirmed meso/dextrocardia. We report a novel MYRF variant in a patient with 46,XY DSDs, allowing us to identify a clinically inapparent congenital heart defect by reverse phenotyping.

Central precocious puberty (CPP) results from the abnormally early reactivation of the hypothalamic-pituitary-gonadal axis, leading to the appearance of seconda

Context: Survival after pediatric hematologic malignancies has improved substantially, increasing concern regarding endocrine sequelae. While gonadotoxic effects on germ cells are characterized in adult survivors, the early impact of cancer and chemotherapy on hypothalamic–pituitary–testicular axis during childhood and adolescence remains insufficiently studied. Design: We conducted a prospective longitudinal cohort study including 63 boys and adolescents with acute lymphoblastic leukemia, acute myeloid leukemia, or non-Hodgkin lymphoma treated at a tertiary pediatric center in Argentina between 2013 and 2019. Hormonal markers of Sertoli cell (AMH, inhibin B, FSH) and Leydig cell function (testosterone, LH) were serially assessed from diagnosis, throughout chemotherapy, and up to 3 years after treatment completion. Results: In prepubertal boys, Sertoli cell function was mildly impaired at diagnosis, with reduced AMH and FSH levels. AMH increased during induction chemotherapy, fluctuated during treatment, and normalized thereafter, remaining stable up to 3 years post-treatment. Transient FSH suppression coincided with exposure to high-dose corticosteroids. Boys entering puberty during follow-up showed persistently elevated AMH relative to pubertal stage, suggesting delayed Sertoli cell maturation. In pubertal patients, a transient seminiferous tubular dysfunction, reflected by increased FSH and decreased inhibin B occurred, with recovery by 3 years after treatment. Mild compensated Leydig cell dysfunction persisted, characterized by elevated LH despite normal testosterone concentrations. Conclusions: Testicular dysfunction associated with pediatric hematologic malignancies is mostly reversible. However, delayed Sertoli cell maturation and persistent compensated Leydig cell insufficiency indicate residual testicular vulnerability, underscoring the importance of long-term endocrine surveillance during and after the end of chemotherapy.

Introduction: Delayed puberty in males requires differentiation between self-limited delay and congenital hypogonadotropic hypogonadism (CHH), including Kallmann syndrome (KS). Case Presentation: We report an adolescent male presenting with delayed puberty and anosmia, consistent with KS. Hormonal evaluation confirmed CHH, and MRI demonstrated olfactory bulb agenesis. Targeted next-generation sequencing identified two heterozygous variants in functionally related genes: a pathogenic nonsense variant in PROK2 and a missense variant in PROKR2 classified as a variant of uncertain significance. Given their ligand-receptor relationship, oligogenic analysis was performed. The variant combination was prioritized as highly likely disease-causing by ORVAL/VarCoPP and further supported by OLIDA-based interpretation, providing objective evidence for digenic inheritance. Parental segregation confirmed trans inheritance. Conclusion: To our knowledge, this is the first report with objective support for the high likelihood of the existence of a digenic etiology in a patient with CHH, based on the use of OLIDA, which provides a standardized framework for the interpretation of oligogenic combinations. These findings highlight the contribution of multilocus variation to CHH and underscore the need for standardized approaches to interpret oligogenic mechanisms in clinical practice.