Persistent Müllerian Duct Syndrome with Supernumerary Testicles Due to a Novel Homozygous Variant in the AMHR2 Gene and Literature Review
Authors: Cima Luminita Nicoleta , Grosu Iustina , Draghici Isabela Magdalena , Enculescu Augustina Cornelia , Chirita-Emandi Adela , Andreescu Nicoleta , Puiu Maria , Barbu Carmen Gabriela , Fica Simona 
Published: November 2024

Introduction: Persistent Müllerian duct syndrome (PMDS) is a rare disorder of sex development (DSD) caused by mutations in the genes coding anti-Müllerian hormone (AMH) or the AMH receptor, characterized by the persistence of Müllerian derivatives, the uterus and/or fallopian tubes, in otherwise normally virilized boys. Testicular regression syndrome is common in PMDS, yet the association with supernumerary testis has been reported in only two patients where genetic testing was not performed. Method: Thus, we report an individual with this particular association caused by a previously unreported homozygous variant in the AMHR2 gene to enable future genotype–phenotype correlations in this rare disorder. In addition, a search of PMDS associated with congenital anomalies reported in the literature was performed to provide a comprehensive overview of this pathology. Results: We present the case of a 13-year-old boy with a history of bilateral cryptorchidism. Two attempts of right orchidopexy were performed at the age of 4 and 5 years. At that time, exploratory laparoscopy identified an intra-abdominal left testicle. In addition, a fibrous structure extending from the left intra-abdominal testicle to the deep inguinal ring (Müllerian duct remnants) and a medially located abdominal mass, bilaterally fixated to the parietal peritoneum (uterine remnant), were detected. The left testicular biopsy revealed immature prepubertal testicular tissue. The uterine remnant was dissected and removed and the left orchidopexy was performed. The karyotype was 46, XY without other numerical or structural chromosomal abnormalities. Reinterventions on the left testicle were performed at the age of 9 and 12 years when a testicular remnant was identified in the left inguinal canal and removed. Three months after left orchidectomy, ultrasound followed by abdominopelvic MRI identified a structure resembling a testis in the left inguinal area. Another surgical exploration was performed, and a mass located outside (lateral) the inguinal canal was found. A biopsy from the suspected mass was performed. The histopathologic examination showed characteristics of immature prepubertal testis. The patient was later referred to our clinic with the suspicion of DSD. Serum AMH and inhibin B were normal. Therefore, the diagnosis of PMDS was suspected. Genetic testing was performed using next-generation sequencing in a gene panel that included AMH and AMHR2 genes. A homozygous variant classified as likely pathogenic in the AMHR2 gene was identified but remains unreported in the literature (NC_000012.11:g.53823315T>C in exon 8 of the AMHR2 gene). Conclusions: A high degree of suspicion and awareness is needed to diagnose this condition in order to avoid iterative surgery. The coexistence of two extremely rare conditions (PMDS and supernumerary testes) has been reported previously in only two patients, yet the association could have a common pathophysiologic background. Our case, reporting a novel AMHR2 variant, highlights the importance of genetic testing in these individuals in order to elucidate a possible genotype–phenotype correlation.