A Novel Anti-Mullerian Hormone (AMH) Gene Mutation in a Patient with Persistent Müllerian Duct Syndrome (PMDS) type 1

Abstract

PMDS is an autosomic recessive disorder of sexual development caused by inactivating mutations in the AMH or the AMH receptor gene (PMDS type I and II respectively). This condition leads to the persistence of Müllerian duct derivatives in otherwise normally virilized 46,XY individuals. This clinical picture coexists with several degrees of testicular descent abnormalities and defects in male excretory ducts. Cryptorchidism is a usual presenting symptom. We report the clinical, biochemical, anatomical, and molecular features of a patient with PMDS type I. A 4.9-year-old boy was referred to us because of the incidental finding of Müllerian structures during laparoscopic assessment for bilateral non-palpable gonads. A rudimentary uterus with symmetrical fallopian tubes, and testis-appearing gonads in an ovarian-like position were found. Physical examination was unremarkable except for the absence of palpable gonads. Serum gonadotropins and testosterone levels were within the normal reference range for age and sex. Serum AMH level was undetectable (<1.0 pmol/L). Karyotype analysis was 46, XY. Molecular study of the AMH gene revealed that the patient is compound heterozygous for a previously reported p.Arg123Trp (c.367C>T) substitution in exon 1 (paternal allele), and a novel frameshift mutation p.Leu301ArgfsTer18 (c.902_929del) in exon 5 predicted to result in a premature stop codon 18 residues downstream the deletion (maternal all ele). This mutation is classified as pathogenic according to ACMG. A complex and two-staged bilateral orchidopexy was performed. The uterus fundus was partially sectioned in the midline in order to allow testicular descent into the scrotum trying to minimize the risk to the vasculature. Histological examination of both gonads revealed the presence of ectopic seminiferous tubules within the tunica albuginea in an otherwise normal prepubertal testicular tissue. Negative OCT3/4 immunoexpression in germ cells. Conclusion: We report a novel pathogenic frameshift mutation in exon 5 (c.902_929del) in a boy with PMDS type I classically presenting with bilateral cryptorchidism. Even though testicular biopsy is unnecessary, histological testicular features in this case showed signs of testicular dysgenesis. Close follow-up is mandatory to attempt to evaluate postsurgical testicular endocrine function as well as the possible long-term complications regarding malignancy and esterility/infertility.