Persistent Müllerian duct syndrome

Overview

Persistent Müllerian Duct Syndrome (PMDS) is a rare genetic disorder of sexual development that affects individuals who are genetically male (46,XY karyotype). In this condition, affected individuals have normal male external genitalia but also retain internal female reproductive structures such as a uterus, fallopian tubes, and the upper portion of the vagina. These structures result from the failure of the Müllerian ducts to regress during embryogenesis, which typically occurs in normal male fetal development due to the action of anti-Müllerian hormone (AMH). PMDS is usually discovered incidentally during surgery for cryptorchidism (undescended testes) or inguinal hernia.

Causes

Persistent Müllerian Duct Syndrome is primarily caused by mutations in one of the following genes:

• AMH gene: This gene codes for anti-Müllerian hormone, which is produced by Sertoli cells in the testes during fetal development. A mutation can lead to reduced or absent AMH production.

• AMHR2 gene: This gene encodes the AMH receptor. Mutations result in the body’s inability to respond to the hormone even if it is produced in normal amounts.

PMDS follows an autosomal recessive inheritance pattern, meaning that both copies of the causative gene must be mutated for the condition to manifest. Carriers (with only one mutated copy) do not show symptoms but can pass the gene to their offspring.

Symptoms

Most individuals with PMDS are externally male and are often diagnosed due to complications related to internal reproductive structures. Common features include:

Typical Presentations

• Bilateral cryptorchidism: Both testes may be undescended and found in an abnormal position during surgery.

• Unilateral cryptorchidism with inguinal hernia: In some cases, one testis is descended while the other is found in the abdomen or associated with a hernia sac.

• Transverse testicular ectopia: Both testes are located on the same side of the body, often discovered during hernia repair.

Internal Anomalies

• Presence of a uterus and fallopian tubes within the abdominal or pelvic cavity

• Presence of a partial or complete vagina that may be connected to the urogenital tract

Other Possible Issues

• Infertility: May occur due to abnormal testicular positioning or function

• Risk of malignancy: Especially if testes remain undescended (intra-abdominal), increasing the chance of testicular cancer

Diagnosis

Diagnosis of PMDS can be difficult and is often made incidentally during surgery for inguinal hernia or cryptorchidism. Diagnostic steps include:

• Physical examination: Normal male external genitalia with undescended testes or inguinal hernias

• Imaging studies:

  • Ultrasound or MRI can reveal the presence of a uterus or other Müllerian structures

• Surgical exploration: Direct observation of female reproductive organs during procedures like hernia repair

• Genetic testing:

  • Mutation analysis of the AMH and AMHR2 genes

• Hormonal assays: Measurement of AMH levels can help differentiate between hormone deficiency and receptor insensitivity

• Karyotyping: Confirms a 46,XY male chromosomal pattern

Treatment

Treatment of PMDS focuses on managing undescended testes and removing or managing Müllerian structures. Treatment goals include preserving fertility, reducing cancer risk, and avoiding complications from abnormal anatomy. Key interventions include:

Surgical Management

• Orchidopexy: Surgical repositioning of undescended testes into the scrotum to preserve function and reduce malignancy risk

• Removal of Müllerian structures: May be considered to prevent obstruction, torsion, or diagnostic confusion in the future

• Hernia repair: In cases associated with inguinal hernia

Fertility Considerations

• Fertility counseling: Needed due to potential risk of infertility from abnormal testicular development

• Semen analysis: To evaluate sperm production in adolescents or adults

Long-term Monitoring

• Surveillance for testicular cancer: Particularly if testes remain undescended or are located intra-abdominally

• Regular follow-ups: With a multidisciplinary team including endocrinologists, urologists, and genetic counselors

Prognosis

The prognosis for individuals with Persistent Müllerian Duct Syndrome is generally favorable, especially if early diagnosis and appropriate surgical treatment are provided. With timely orchidopexy, the risk of testicular malignancy and infertility can be reduced, though not entirely eliminated. Most individuals maintain a male gender identity and live normal lives.

However, undiagnosed or untreated PMDS can lead to complications such as infertility, hernia recurrence, or tumor formation. Lifelong monitoring of testicular health is recommended. Genetic counseling is also important for families to under