Final Diagnosis -- Persistent Müllerian Duct Syndrome

FINAL DIAGNOSIS  

Persistent Müllerian Duct Syndrome

DISCUSSION

Persistent Müllerian Duct Syndrome (PMDS) is a rare type of pseudohermaphroditism found in phenotypically normal appearing males. It occurs when anti-müllerian hormone (AMH) (also müllerian inhibitory substance) is not able to cause regression of the Müllerian ducts in fetal male development either because of a mutation in the AMH gene or in the AMH receptor gene (chromosomes 19 and 12, respectively). Patients with PMDS always have a normal male karyotype of 46, XY. Since the SRY gene on the Y chromosome is normal in these patients, they develop testes and have normal androgenic production during development with near normal development of the Wolffian derivatives, and normal male external genitalia. However, patients often present with unilateral or bilateral cryptorchidism, sometimes with an inguinal hernia as a direct result of the close structural relationship between the gonad and the retained Müllerian duct structures. The Müllerian duct derivatives of fallopian tubes, uterus and cervix are often discovered during orchidopexy or herniorrhaphy, usually as contents of the hernia sac. Males with PMDS may be fertile if Müllerian-derived structures have not compromised the integrity of the vasa deferentia and correction of the cryptorchid testis is done in a timely matter (typically less than one year of age) without significant germ cell hypoplasia. The syndrome can be sporadic or inherited in an autosomal recessive or X-linked fashion.

As with other males with cryptorchidism, malignant germ cell tumors are a concern in patients with PMDS, but they are not generally considered to be at further increased risk. However, case reports have shown the development of malignant tumors in Müllerian structures. The histologic features of the testicular biopsy in this case is consistent with cryptorchidism, including a variable decrease in the fertility index for age, decreased mean tubular diameter, and numerous microliths. While there is generally no dysgenetic features, if the condition goes undetected until adulthood the testes can develop changes reminiscent of testicular dysgenesis with a variably collagenized tunica albuginea with a cellular connective tissue resembling ovarian stroma, as anti-müllerian hormone is also responsible for the collagenization of the tunica. The seminiferous tubules in the adult male may also show atrophic changes with a thick, hyalinized tubular basement membrane and reduced spermatogenesis.

Differential diagnosis of PMDS most notably includes those disorders of sexual differentiation with defective regression of the Müllerian derivatives including mixed gonadal dysgenesis (MGD) which accounts for approximately 15% of all disorders of sexual differentiation, and its variant, dysgenetic male pseudohermaphroditism.

Features of MGD include:

• Ambiguous external genitalia (variable depending on degree of testosterone and AMH expressed by dysgenetic testis) and may present with Turner syndrome stigmata.
• Asymmetric gonadal differentiation with dysgenetic gonads: Testicular differentiation (dysgenetic testis or streak testis) present on one side and streak gonad (classic streak or streak testis) on the contralateral side
• Testicular morphology is abnormal with histologic features of testicular dysgenesis (poorly collagenized tunica albuginea with a cellular stroma or penetrating malformed cords along the surface, and abnormal immature Sertoli only cords) or streak testis formation (steak gonad: flat ovoid structure with ovarian stroma devoid of ovocytes plus dysgenetic testicular features)Combination of Müllerian and Wolffian-derived structures, typically Müllerian derivatives often associated with contralateral streak gonad, but can be associated with testicular tissue.
• Hypoplastic uterus and poorly developed vagina are common
• Karyotype is 46,X0/46,XY mosaic in 50% of cases; can also be 46,XY or 46,X0/47,XXYHighest risk of gonadoblastoma and subsequent germ cell neoplasia

Features of dysgenetic male pseudohermaphroditism

• Ambiguous external genitalia.
• Bilateral dysgenetic testis or streak testis
• Karyotype is 46,XY or 46,X0/46,XY mosaic
• Combination of Müllerian and Wolffian-derived structures
• Hypoplastic uterus and poorly developed vagina are common
• Risk of gonadoblastoma and subsequent germ cell neoplasia

REFERENCES

1. Bostwick, David G., and Liang Cheng. Urologic Surgical Pathology. 2nd ed. N.p.: Mosby Elsevier, 2008. Print.
2. Zhou, Ming, and Cristina Magi-Galluzzi. Genitourinary Pathology. Philadelphia: Churchill Livingstone Elsevier, 2007. Print. Foundations in Diagnostic Pathology.
3. Boyd, T. Disorders of Sexual Differentiation, Surgical Pathology Clinics, Volume 3, Issue 3, September 2010, Pages 553-601.
4. Nistal, M., et al., Bilateral prepubertal testicular biopsies predict significance of cryptorchidism-associated mixed testicular atrophy, and allow assessment of fertility. Am J Surg Pathol, 2007. 31(8): p. 1269-76.

Contributed by Jennifer Harness, BS and Jennifer Picarsic, MD