LEYDIG CELL HYPERPLASIA PRESENTING AS PRIMARY AMENORRHEA IN A KIDNEY TRANSPLANT PATIENT WITH FRASIER SYNDROME

Frasier syndrome is a rare disorder caused by splice-site mutations in the Wilms tumor protein (WT1) gene, characterized by progressive glomerulopathy and gonadal dysgenesis in 46,XY individuals with phenotypic female presentation. It carries an inherent risk for gonadoblastoma and Sertoli cell tumors, while Leydig cell hyperplasia—though associated with shared gonadal developmental pathways—has not been documented in post-kidney transplant patients with this condition. Recognition of atypical gonadal pathology in transplant recipients with primary amenorrhea is vital for timely intervention and optimal endocrine and renal outcomes.

This is a descriptive single-patient case report based on retrospective review of clinical records, imaging, hormonal studies, histopathology, and genetic data. Relevant clinical and transplant information were obtained from institutional medical charts. Gonadal tissue obtained by laparoscopic gonadectomy underwent histopathologic examination using hematoxylin and eosin staining. Genetic confirmation was performed via whole-exome sequencing (xGen Exome Research Panel version 2, NovaSeq X platform, Illumina) with variant interpretation based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. Ethical clearance was obtained from the institutional review board, and written informed consent was secured from the patient for publication.

A 21-year-old phenotypic female with childhood-onset end-stage renal disease secondary to chronic glomerulonephritis underwent living donor kidney transplantation at age 14. Post-transplant, she was maintained on cyclosporine and azathioprine until acute T-cell-mediated rejection in 2023 prompted rituximab and switch to tacrolimus, mycophenolate, and prednisone. At age 19, primary amenorrhea prompted endocrine evaluation, which revealed hypergonadotropic hypogonadism with follicle-stimulating hormone (FSH) 142 mIU/mL, luteinizing hormone (LH) 39.86 mIU/mL, and a 46,XY karyotype.

Whole-exome sequencing identified a heterozygous pathogenic WT1 variant, confirming the diagnosis of Frasier syndrome. Pelvic ultrasound demonstrated a hypoplastic uterus and absent ovaries. Bilateral laparoscopic gonadectomy revealed streak gonads with nodular Leydig cell hyperplasia characterized by polygonal cells with granular eosinophilic cytoplasm and Reinke crystalloid precursors in a fibrovascular stroma, without ovarian tissue or malignancy. 

Following gonadectomy, estradiol therapy (2 mg daily) induced subtle pubertal changes and stable allograft function, with only minor tacrolimus dose adjustments required following initiation of hormone replacement therapy.

This is the first reported case of Leydig cell hyperplasia in a post-transplant patient with Frasier syndrome, underscoring compensatory Leydig proliferation secondary to gonadal dysgenesis and elevated luteinizing hormone levels. Early genetic and pathologic evaluation in transplant recipients presenting with primary amenorrhea is essential to guide prophylactic gonadectomy, optimize hormone replacement, and prevent gonadal malignancy while preserving graft function. Multidisciplinary management—including nephrology, endocrinology, genetics, and psychosocial support—remains critical for long-term outcomes in this rare but clinically significant entity.