AMH – Persistent Mullerian Duct Syndrome

Persistent Mullerian duct syndrome (PMDS) is a rare autosomal recessive 46,XY disorder of sex development characterized by the persistence of Müllerian duct derivatives in otherwise normally masculinized males. Pathogenic variants in the anti-Müllerian hormone gene (AMH) underlie the failure of Müllerian duct regression.

Genetic evidence supports a definitive association between AMH and PMDS. Recessive inheritance of AMH loss-of-function alleles—frameshift, nonsense, splice-site and missense mutations—has been documented in over 17 unrelated probands from at least six independent families, with segregation of compound heterozygous or homozygous variants ([PMID:1483695], [PMID:23611722], [PMID:26181047], [PMID:28742509], [PMID:31238341], [PMID:23295284]).

Case reports have identified diverse variant types: a 14-bp deletion in exon 2 (c.472_485del (p.Pro158fs)) disrupting the open reading frame, a splice donor site mutation c.555+1G>T, a nonsense variant c.571C>T (p.Arg191Ter), missense substitutions c.1591T>C (p.Tyr531His) and c.1577G>T (p.Cys526Phe), and a regulatory promoter deletion at –225 bp reducing SF1 binding.

Functional assays demonstrate that the promoter deletion significantly decreases SF1-mediated transactivation of AMH, and affected individuals have undetectable serum AMH, consistent with haploinsufficiency and loss of hormone bioactivity. Murine promoter studies further corroborate the quantitative regulation of AMH by SF1.

Few conflicting data exist, limited to non-human models where AMH sequence variants were not causal in feline PMDS, underscoring species specificity of AMH regulation.

Integration of genetic and experimental findings confirms that biallelic AMH variants cause PMDS via impaired hormone synthesis or receptor activation. Early molecular diagnosis facilitates surgical planning for Müllerian remnant excision and orchidopexy. Key take-home: AMH mutation analysis is essential in 46,XY individuals with cryptorchidism or hernia to confirm PMDS and guide management.

References

• Human genetics | 1992 | Variants of the anti-Müllerian hormone gene in a compound heterozygote with the persistent Müllerian duct syndrome and his family PMID:1483695
• Journal of pediatric urology | 2013 | A novel mutation of anti-Mullerian hormone gene in Persistent Mullerian Duct Syndrome presented with bilateral cryptorchidism: a case report. PMID:23611722
• Journal of pediatric endocrinology & metabolism | 2015 | A novel mutation of AMH in three siblings with persistent Mullerian duct syndrome. PMID:26181047
• Hormones (Athens, Greece) | 2017 | Persistent Müllerian duct syndrome: A novel mutation in the Anti-Müllerian Hormone gene PMID:28742509
• Human molecular genetics | 2019 | A mutation inactivating the distal SF1 binding site on the human anti-Müllerian hormone promoter causes persistent Müllerian duct syndrome PMID:31238341
• Arquivos brasileiros de endocrinologia e metabologia | 2012 | Analysis of anti-Müllerian hormone (AMH) and its receptor (AMHR2) genes in patients with persistent Müllerian duct syndrome PMID:23295284

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