So, what is PMDS? An unconventional form of internal pseudohermaphroditism in a genetically and normally virilized male depicted by the presence of Mullerian duct derivatives such as the uterus, fallopian tubes, cervix, vagina is known as PMDS. In other words, this is a rare variety of DSD. Clinically these patients present with normal external genitalia, however have ambiguous genitalia/secondary sexual characteristics [1].
Looking into genetics of PMDS, it is usually inherited in an autosomal recessive manner. Around 85% of the patients have mutation of the MIS gene on chromosome 19p13 or MISR-II gene on chromosome 12q13, while the cause is unknown in 15% of them [2].The main etiology underlying this disorder is the lack of Mullerian inhibiting substance (MIS)/ AMH in the body [3].It is caused either due to a lack in production of Anti Mullerian Hormone[AMH] from immature sertoli cells in newly developed testis (PMDS type I) or resistance to AMH receptor (AMHR2 gene), (PMDS type II) [4].
In the embryogenesis period, that is during early development, the embryonal reproductive tract in either sex consists of both the Mullerian duct and Wolffian ducts. In a male fetus at the 8th week of gestation, testosterone and Mullerian Inhibiting Substance (MIS) are produced from leydig cells and sertoli cells from the recently formed testes. This testosterone helps in differentiation of the Wolffian duct into various structures like epididymis, seminal vesicles and vas deferens. On the other hand, MIS, commonly known as AMH is a glycoprotein homodimer which plays an important role in testicular descent as well in Mullerian duct regression. On the contrary, in females this testosterone absence causes degeneration of the Wolffian duct. With the lack of MIS, Mullerian duct differentiation into female reproductive organs like uterus, fallopian tubes and ovaries occurs [5,6,7].
How can we classify types of PMDS? PMDS can be broadly divided into two types (Fig. 5), a male form and a female form based on anatomical structure. Male form being the more common one (80–90% of cases), is characterized clinically by unilateral cryptorchidism and contralateral inguinal hernia with usually the ipsilateral testis as its content. In case the uterus was also dragged along with it, it would be known as hernia uteri inguinalis. Another variant of this male form is when both the testes are spotted inside the same hernial sac along with the uterus and fallopian tubes, it is known as transverse testicular ectopia which accounts for ~ 10% of the cases. Female form is characterized by bilateral cryptorchidism and uterus fixed to the pelvis with bilateral testes attached to the round ligaments on either side in ovarian positions. Inguinal hernia is not seen in this type. On a side note, mobility of the Mullerian duct derivatives plays an important role, as presence of mobility causes the uterus and fallopian tube to be drawn into the inguinal canal and absence of mobility may block testicular descent [8].
In the respective cases discussed above in our article, Case 1 was female form and Case 2 was male form.
How important is the role of radiological scans in recognizing patients with PMDS? Diagnosis of this uncommon entity is usually incidental, as structures derived from Mullerian duct are routinely undetectable in abdominal or scrotal examination, hence radiological investigations like USG, CT, and magnetic resonance imaging (MRI) play an important role in identifying this clinical condition. Patients who present with bilateral undescended testis or unilateral inguinal hernia accompanied by a contralateral cryptorchid testis or unilateral inguinal hernia along with a palpable mass above the normally descended testis must undergo USG, CT or MRI and chromosomal analysis suspecting the presence of Mullerian duct structures. In our case, the first patient had already developed an endodermal sinus tumor. Hence chemotherapy and debulking laparotomy were performed on this patient. In patients with PMDS the risk of malignant transformation into germ cell tumours such as gonadoblastoma is high of 15–40% according to the available current literature [9], hence immediate surgical removal of these structures and the undescended testis (orchidopexy) should be performed to eliminate the risk [10].On the other hand, there is a patient to patient variation regarding fertility in PMDS patients. Even though infertility seems to be a complication in PMDS patients, according to a study by Josso et al. [11], fertility is preserved if the gonads descend into the scrotum.
Looking at the importance of lab value parameters, determination of AMH levels in the serum using a specific test like ELISA can be used as a screening tool in the approach and confirmation of the diagnosis. In patients with PMDS, sexual function is routinely normal, but fertility is a bit compromised, even in treated patients. Discussing further about Case 1 in our article, after using karyotyping and histopathological reports to confirm PMDS, in this patient, EST was observed. The characteristic increase in Alpha feto protein was observed as these are secreted from the malignant endodermal cells. Along with this, Schiller duval bodies were confirmatory of EST in pathological slides. LDH which is expressed on chromosome 12p, linked to the testes as mentioned above, increases in testicular malignancies, hence the spike in our Case1.
A common differential to cryptorchidism in these patients is anorchia, for which AMH serum assay is recommended, however, only this test is not entirely specific in patients with AMH mutations, hence in such cases testosterone assay and thorough ultrasound examination will help in diagnosis. Mixed gonadal dysgenesis is another common differential, where biopsy is necessary to confirm the sex and rule this out. Diagnosing PMDS is challenging as it is complex and anatomically variable.
Management of PMDS includes removal of the Mullerian duct structures as they could hypertrophy and accumulate blood causing pain and discomfort to the patient. They obstruct the prostatic utricle causing recurrent urinary tract infection, stones and voiding disturbances. Removal also reduces the risk of malignancy in these patients from the MDS structures. Subtotal hysterectomies (in order to avoid hormonal problems) and salpingectomies are performed.
Regarding the Wolffian duct structures, orchidopexy to place the testes in the scrotal sac is the main treatment of choice along with preservation of vas to maintain fertility. In case streak gonads are present, or of the testes aren’t mobile, then orchidectomy is treatment of choice. In our patient (Case 1), malignant transformation of the testes was noted, hence we proceeded with debulking laparotomy and chemotherapy.