AMHR2 – Persistent Mullerian Duct Syndrome

Persistent Mullerian duct syndrome (PMDS) is an autosomal recessive disorder in which 46,XY males retain Müllerian structures despite normal virilization. The syndrome arises from loss of function in the anti-Müllerian hormone receptor type II (AMHR2), a transmembrane serine/threonine kinase that mediates regression of the Müllerian ducts. Affected individuals present classically with cryptorchidism and inguinal hernia due to the presence of uterus and fallopian tubes in otherwise male patients.

Genetic evidence stems from several independent reports. The first PMDS patient was a compound heterozygote with a 27-bp deletion in exon 10 and a novel intron 5 splice mutation causing frameshift and premature termination (PMID:14745940). An adult Colombian man with bilateral cryptorchidism and seminoma harbored a homozygous frameshift p.Leu306CysfsTer29 due to c.916delC in AMHR2 (PMID:31184456). Two unrelated 46,XY males were reported with homozygous microdeletions encompassing five exons or the entire AMHR2 locus; the latter also carried a stop variant on the remaining allele (PMID:32187366). More recently, monozygotic twins were found to carry two novel missense variants in AMHR2; c.118G>C (p.Gly40Arg) significantly impaired AMH binding and downstream TGFβ/BMP signaling in luciferase assays (PMID:35655435).

Across four unrelated families, at least six probands have been identified with biallelic AMHR2 lesions. Segregation is consistent with autosomal recessive inheritance, though few extended pedigrees are available. The variant spectrum includes small deletions leading to frameshifts, multi-exon microdeletions, and missense substitutions disrupting ligand binding or kinase function.

Functional studies corroborate the pathogenicity of AMHR2 defects. Missense variants such as p.Gly40Arg reduce receptor–AMH affinity and abolish SMAD1/5/8 phosphorylation in vitro. Gene dosage studies of microdeletions confirm complete loss of receptor expression, phenocopying human PMDS. Dominant-negative splice isoforms of AMHR2 also inhibit AMH signaling, underscoring the receptor’s critical role in Müllerian regression.

No conflicting human data have been reported; variants in other genes (e.g., AMH) cause phenotypically similar PMDS, supporting the specific contribution of AMHR2. Further large-scale screening may delineate additional alleles and clarify genotype–phenotype correlations.

In summary, biallelic AMHR2 mutations cause autosomal recessive PMDS via loss of receptor function. Clinical sequencing of AMHR2 is recommended in 46,XY individuals with unexplained cryptorchidism or inguinal hernia to confirm diagnosis and guide management.

References

• Birth defects research. Part A, Clinical and molecular teratology | 2003 | Persistent Mullerian duct syndrome caused by both a 27-bp deletion and a novel splice mutation in the MIS type II receptor gene. PMID:14745940
• International braz j urol : official journal of the Brazilian Society of Urology | 2019 | Novel homozygous mutation in a colombian patient with persistent müllerian duct syndrome: expanded phenotype PMID:31184456
• Human reproduction (Oxford, England) | 2020 | Persistent Müllerian duct syndrome due to anti-Müllerian hormone receptor 2 microdeletions: a diagnostic challenge PMID:32187366
• Molecular genetics & genomic medicine | 2022 | Two novel AMHR2 gene variants in monozygotic twins with persistent Müllerian duct syndrome: A case report and functional study PMID:35655435

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