Persistent Müllerian Duct Syndrome

Anti-Müllerian hormone (AMH) is a protein produced by Sertoli cells in the testis in intrauterine life. In persons with karyotype 46,XY, AMH is responsible for the regression of the Müllerian ducts, i.e., embryonic structures from which the tubes, uterus and upper third of the vagina originate. The inability to produce AMH, or alterations in the receptor of this hormone, lead to the development of female internal genitalia in a person with the 46,XY karyotype.
Individuals with this Variation of Sex Characteristic (VSC)/Difference of Sex Development (DSD) have a typically male phenotype at birth, often associated with bilateral cryptorchidism (testicles that fail to fall into the scrotum) and inguinal hernia; in the presence of a uterus, there will also be fallopian tubes and the upper third of the vagina. Testosterone production is maintained. A common trait is azoospermia (absence of sperm in the ejaculate), due to malformation of the vas deferens or absence of the epididymis. The prevalence of this condition is unknown.

Genetic traits
The persistence of Müllerian derivatives may be due to mutations in the AMH gene located on chromosome 19p.13.3, or to mutations in the gene encoding for the AMH receptor, located on chromosome 12q13. Variants of these two genes can be found in about 85% of cases. The cause of the syndrome in the remaining 25% is still unknown. The inheritance of this condition is autosomal recessive. This means that for the gene variation to occur, it must be inherited from both parents. Individuals who have inherited the gene variation from only one parent will not exhibit it in any way, but they may still pass it on to their offspring.

Identification
The diagnostic suspicion can be formulated in consideration of clinical and biochemical evidence, supported by imaging investigations to visualize the gonads and Müllerian derivatives. Normally, AMH levels are measurable in childhood and decrease during puberty. People with variants in the AMH gene have low AMH levels since birth, while those with variants in the AMH receptor gene have high AMH levels.
In any case, diagnostic confirmation is molecular, and based on the identification of variants in the genes involved.

Medical options
Persons with this VSC/DSD may choose from several surgical options. In accordance with the most recent international recommendations, we must stress that all partially reversible or irreversible interventions should be postponed until the person can express their informed consent on the matter. The gender identity expressed by the individual should always be taken into account.
Since cryptorchid testicles lead to an increased risk of testicular cancer – although there is no scientific evidence specifically pointing to people with this VSC/DSD – preventive strategies must be implemented. These include annual monitoring with ultrasound / MRI, orchidopexy (repositioning of the testicles in the scrotal bursa) and orchidectomy (removal of the testicles), according to the person’s gender identity.
If the person with this VSC/DSD has a male gender identity, surgical options may include salpingectomy (excision of the fallopian tubes) and hysterectomy (removal of the uterus). Since testosterone production is preserved, hormone replacement therapy is not needed in this case.

Bibliography
Imbeaud S et al. Molecular genetics of the persistent mullerian duct syndrome: a study of 19 families [Abstract]. Human Molecular Genetics. 1994;3(1):125-131
Saleem M et al. Persistent mullerian duct syndrome: A 24-year experience [Abstract]. Journal of Pediatric Surgery. 2016;51(10):1721-1724

Further Links
Orphnet. Testicular regression syndrome
MedlinePlus (NLM). Persistent Müllerian duct syndrome
Online Mendelian Inheritance in Man (OMIM). PERSISTENT MULLERIAN DUCT SYNDROME, TYPES I AND II; PMDS