- Email: [email protected]
Persistent Mullerian Duct Syndrome: A rare clinical entity
MJAFI-949; No. of Pages 4 medical journal armed forces india xxx (2017) xxx–xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/mjafi
Case Report
Persistent Mullerian Duct Syndrome: A rare clinical entity Lt Col Santosh Kumar Dey a,*, Lt Col Karunesh Chand a, Maj Ankit Sharma b, Lt Col Subhash Chandra Shaw c a
Classified Specialist (Surgery and Pediatric Surgery), Command Hospital (Southern Command), Pune 411040, India Resident, Department of Surgery, Armed Forces Medical College, Pune 411040, India c Assistant Professor, Department of Pediatrics, Armed Forces Medical College, Pune 411040, India b
article info Article history: Received 18 October 2016 Accepted 19 December 2017 Available online xxx Keywords: Persistent Mullerian Duct Syndrome Disorder of sexual differentiation Intersex
Introduction Persistent Mullerian Duct Syndrome (PMDS) is an extremely rare entity with only about 300 cases reported worldwide so far.1 It is a type of disorders of sexual differentiation (DSD) complex or more commonly referred to as intersex. The patient of PMDS is a normally vilrilised male with bilateral undescended testis and retained mullerian structures due to defect in either gene coding for the mullerian inhibiting substance (MIS)/anti-mullerian hormone (AMH) or it's receptor, AMH receptor type II (AMHRII). PMDS is inherited as an autosomal recessive trait, with location of AMH gene on short arm of chromosome 19 and AMHRII gene on long arm of chromosome 12.1–4 It has also been referred to by various other names like hernia uteri inguinalis, internal male pseudoher-
maphroditism and persistent oviduct syndrome.5 The presence of uterus, fallopian tubes and testes that resembles ovaries in its location and appearance, in a normal male child, is extremely intriguing for the surgeon, not familiar with these disorders.
Case report One-and-a-half-year-old male child, only product of a nonconsanguineous marriage, presented to a tertiary care service hospital with complaints of bilateral absence of testis in scrotum (Fig. 1A), noticed since birth. There was no history of infertility or similar condition in family. On examination the phallus was normal in size without any hypospadias. Clinically the testes were not palpable. MRI of the abdomen revealed both testes to be intra-abdominal and lying behind
* Corresponding author. E-mail address: [email protected] (S.K. Dey). https://doi.org/10.1016/j.mjafi.2017.12.008 0377-1237/© 2018 Published by Elsevier B.V. on behalf of Director General, Armed Forces Medical Services.
Please cite this article in press as: Dey SK, et al. Persistent Mullerian Duct Syndrome: A rare clinical entity, Med J Armed Forces India. (2018), https://doi.org/10.1016/j.mjafi.2017.12.008
MJAFI-949; No. of Pages 4
2
medical journal armed forces india xxx (2017) xxx–xxx
Fig. 1 – (A) Normal phallus with bilateral undescended testes. (B) Right testes. (C) Left testes.
the urinary bladder. After necessary baseline investigations, this child was taken up for laparoscopic orchidopexy. Intraoperatively, a rudimentary uterus with Fallopian tube and two structures resembling ovaries were seen in the mesosalpinx. No other structure resembling testis was seen even after exploration of right retroperitoneum. The procedure was abandoned and the child was referred to the pediatric surgery center. Further evaluation revealed a normal XY karyotype. Serum testosterone, dihydrotestosterone (DHT) and antimullerian hormone (AMH) levels were normal. This child was diagnosed as a case of PMDS and was taken up for excision of mullerian structures with bilateral orchidopexy (Fig. 1B and C). Proximal salpingectomies were done in continuation with the uterus. The testicular vessels were mobilized as far as possible. The vas was mobilized by taking a sliver of the uterine wall on either side (Fig. 2A and B). This was done to prevent injury to the vas and to preserve its blood supply. The uterus was excised at the cervix (Fig. 3) to avoid damage to the terminal opening of the vas. The testes which were soft in feel were then placed in scrotum. Postoperative outcome was unremarkable. On follow up after 4 months, both testes were palpable in scrotum. Histopathology confirmed a rudimentary uterus with bilateral fallopian tubes and cervix.
Discussion The development of external genitalia in a male is based on the interplay of two major hormones, with DHT causing the appearance and development of male external genitalia and MIS or AMH which brings the regression of mullerian structures. The effects of DHT occur during 8–12 week period gestation and helps in the development of penis, penile urethra and scrotum. Internally the sertoli cells in the testis produce MIS or AMH which brings about regression of mullerian structures. However, this regression occurs only if AMH is secreted between 6 and 8 weeks of gestation, after which the mullerian structures become insensitive to AMH. PMDS results mainly due to three causes – failure of
AMH secretion, end organ resistance to AMH, and lastly if secretion occurs after 8–9 weeks. On the other hand, Wolffian structures develop normally due to normal androgen secretion from Leydig cells.6 Exact incidence of PMDS is not fully known because of its rarity and lack of awareness about this entity. These children have normally virilised external genitalia, occasional hypospadias and sometimes gynecomastia have also been associated. Internal genitalia resemble that of a female, with presence of uterus, fallopian tubes and testes with cystic changes lying in the mesosalpinx and hence often labeled as the ovaries as in our case. The cervix remains attached to the posterior urethra at the verumontanum. The vasa deferentia have a very short free segment which runs in the mesosalpinx and they remain embedded in the lateral wall of uterus and cervix. They finally open into the vaginal fornix. Most patients with PMDS are diagnosed incidentally during surgery for inguinal hernia or undescended testis as in this case. Once the hernia sac is opened, testis with uterus and fallopian tube may be seen and this is referred to as hernia uteri inguinalis. In transverse testicular ectopia (TTE), in which both the testes are located on one inguinal side, traction on the sac contents can deliver the contralateral testis.5 These patients have a normal male karyotype of 46XY. This helps in ruling out ovotesticular DSD and mixed gonadal dysgenesis, which can also have retained mullerian structures. Ultrasound of the abdomen and pelvis or trans rectal sonography help, but it is not considered a good imaging modality for intraabdominal testis. MRI is the best noninvasive modality to identify the various remnants of Mullerian structures and also in identifying the intra-abdominal testes.7 Serum testosterone and DHT remain within normal range in these cases. AMH levels may be low in AMH gene mutations and normal or high in AMH receptor mutations. The mullerian remnants and the undescended testes in PMDS both are at high risk for developing malignancy. As many as 3.1–8.4% of PMDS patients are likely to develop malignancy of mullerian remnants. Similarly 5–18% of PMDS patients may develop testicular malignancy in undescended testes.8 Teratoma, seminoma, yolk sac tumor and embryonal carcinoma have been reported in these intra-abdominal
Please cite this article in press as: Dey SK, et al. Persistent Mullerian Duct Syndrome: A rare clinical entity, Med J Armed Forces India. (2018), https://doi.org/10.1016/j.mjafi.2017.12.008
MJAFI-949; No. of Pages 4 medical journal armed forces india xxx (2017) xxx–xxx
3
Fig. 3 – Excised specimen – uterus, fallopian tube and cervix.
testicular vessels are clipped and in second stage, orchidopexy along with removal of mullerian structures is done. To conclude, we have reported a case of PMDS in a child, presenting with cryptorchidism. The aim of reporting this case is to sensitize the readers of an extremely rare condition and the need of orchidopexy and excision of the remnants of mullerian duct in such a case.
Conflicts of interest The authors have none to declare. Fig. 2 – (A) Uterus, fallopian tubes and testes. (B) Uterus and fallopian tube excised and vasa deferentia mobilized with sliver of uterine tissue.
testes. Therefore testes in PMDS should be brought to scrotum to facilitate early detection, should a tumor develop.9 Most of these patients will remain infertile. The testes in this condition is abnormally mobile due to lack of gubernaculum and there is a high likelihood of torsion and subsequent degeneration.
Surgical options Excision of mullerian structures with orchidopexy is the most preferred procedure whether done open or laparoscopically. Orchidopexy in these patients is often challenging technically, because of the free segment of vas being short and then the vas lies embedded in the lateral aspect of the body of uterus. Surgical procedure followed are as described by Loeff et al.10 In certain cases single stage orchidopexy is not possible, and hence a two staged procedure is done. In the first stage
references
1. Aw LD, Zain MM, Esteves SC, Humaidan P. Persistent Mullerian Duct Syndrome: a rare entity with a rare presentation in need of multidisciplinary management. Int Braz J Urol. 2016;42:1237–1243. 2. Al-Faris A, Jabari M, Al-Sayed M, Al-Shehri H. Bilateral Cryptorchidism, a rare presentation for persistent Müllerian duct syndrome. Electron Physician. 2016;8(12):3395–3397. http://dx.doi.org/10.19082/3395. 3. Farikullah J, Ehtisham S, Nappo S, Patel L, Hennayake S. Persistent Müllerian duct syndrome: lessons learned from managing a series of eight patients over a 10-year period and review of literature regarding malignant risk from the Müllerian remnants. BJU Int. 2012;110:E1084– E1089. 4. Picard JY, Cate RL, Racine C, Josso N. The Persistent Mullerian Duct Syndrome: an update based upon a personal experience of 157 cases. Sex Dev. 2017;11:109–125. http://dx. doi.org/10.1159/000475516. 5. Prakash N, Khurana A, Narula B. Persistent Mullerian duct syndrome. Indian J Pathol Microbiol. 2009;52:546–548. 6. Gujar NN, Choudhari RK, Choudhari GR, et al. Male form of persistent Mullerian duct syndrome type I (hernia uteri inguinalis) presenting as an obstructed inguinal hernia: a case report. J Med Case Rep. 2011;5:586.
Please cite this article in press as: Dey SK, et al. Persistent Mullerian Duct Syndrome: A rare clinical entity, Med J Armed Forces India. (2018), https://doi.org/10.1016/j.mjafi.2017.12.008
MJAFI-949; No. of Pages 4
4
medical journal armed forces india xxx (2017) xxx–xxx
7. Singh R, Kumar SD, Aggarwal N. MRI findings of Persistent Mullerian Duct Syndrome: a rare case report. J Clin Diagn Res. 2017;1(6):5–6. 8. Farikullah J, Ehtisham S, Nappo S, Patel L, Hennayake S. Persistent Mullerian Duct Syndrome: lessons learned from managing a series of eight patients over a 10-year period and review of literature regarding malignant risk from the Mullerian Remnants. BJU Int. 2012;110:E1084E1089. PMID:22540537.
9. Alharbi KN, Khushaim AO, Alrasheed M, Akhtar M, Neimatallah M. Radiological findings in Persistent Mullerian Duct Syndrome: case report and review of literature. Radiol Case. 2017;11(3):7–14. 10. Loeff DS, Imbeud S, Reyes HM, et al. Surgical and genetic aspects of persistence mullerian duct syndrome. J Pediatr Surg. 1994;29:61–65.
Please cite this article in press as: Dey SK, et al. Persistent Mullerian Duct Syndrome: A rare clinical entity, Med J Armed Forces India. (2018), https://doi.org/10.1016/j.mjafi.2017.12.008
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/mjafi
Case Report
Persistent Mullerian Duct Syndrome: A rare clinical entity Lt Col Santosh Kumar Dey a,*, Lt Col Karunesh Chand a, Maj Ankit Sharma b, Lt Col Subhash Chandra Shaw c a
Classified Specialist (Surgery and Pediatric Surgery), Command Hospital (Southern Command), Pune 411040, India Resident, Department of Surgery, Armed Forces Medical College, Pune 411040, India c Assistant Professor, Department of Pediatrics, Armed Forces Medical College, Pune 411040, India b
article info Article history: Received 18 October 2016 Accepted 19 December 2017 Available online xxx Keywords: Persistent Mullerian Duct Syndrome Disorder of sexual differentiation Intersex
Introduction Persistent Mullerian Duct Syndrome (PMDS) is an extremely rare entity with only about 300 cases reported worldwide so far.1 It is a type of disorders of sexual differentiation (DSD) complex or more commonly referred to as intersex. The patient of PMDS is a normally vilrilised male with bilateral undescended testis and retained mullerian structures due to defect in either gene coding for the mullerian inhibiting substance (MIS)/anti-mullerian hormone (AMH) or it's receptor, AMH receptor type II (AMHRII). PMDS is inherited as an autosomal recessive trait, with location of AMH gene on short arm of chromosome 19 and AMHRII gene on long arm of chromosome 12.1–4 It has also been referred to by various other names like hernia uteri inguinalis, internal male pseudoher-
maphroditism and persistent oviduct syndrome.5 The presence of uterus, fallopian tubes and testes that resembles ovaries in its location and appearance, in a normal male child, is extremely intriguing for the surgeon, not familiar with these disorders.
Case report One-and-a-half-year-old male child, only product of a nonconsanguineous marriage, presented to a tertiary care service hospital with complaints of bilateral absence of testis in scrotum (Fig. 1A), noticed since birth. There was no history of infertility or similar condition in family. On examination the phallus was normal in size without any hypospadias. Clinically the testes were not palpable. MRI of the abdomen revealed both testes to be intra-abdominal and lying behind
* Corresponding author. E-mail address: [email protected] (S.K. Dey). https://doi.org/10.1016/j.mjafi.2017.12.008 0377-1237/© 2018 Published by Elsevier B.V. on behalf of Director General, Armed Forces Medical Services.
Please cite this article in press as: Dey SK, et al. Persistent Mullerian Duct Syndrome: A rare clinical entity, Med J Armed Forces India. (2018), https://doi.org/10.1016/j.mjafi.2017.12.008
MJAFI-949; No. of Pages 4
2
medical journal armed forces india xxx (2017) xxx–xxx
Fig. 1 – (A) Normal phallus with bilateral undescended testes. (B) Right testes. (C) Left testes.
the urinary bladder. After necessary baseline investigations, this child was taken up for laparoscopic orchidopexy. Intraoperatively, a rudimentary uterus with Fallopian tube and two structures resembling ovaries were seen in the mesosalpinx. No other structure resembling testis was seen even after exploration of right retroperitoneum. The procedure was abandoned and the child was referred to the pediatric surgery center. Further evaluation revealed a normal XY karyotype. Serum testosterone, dihydrotestosterone (DHT) and antimullerian hormone (AMH) levels were normal. This child was diagnosed as a case of PMDS and was taken up for excision of mullerian structures with bilateral orchidopexy (Fig. 1B and C). Proximal salpingectomies were done in continuation with the uterus. The testicular vessels were mobilized as far as possible. The vas was mobilized by taking a sliver of the uterine wall on either side (Fig. 2A and B). This was done to prevent injury to the vas and to preserve its blood supply. The uterus was excised at the cervix (Fig. 3) to avoid damage to the terminal opening of the vas. The testes which were soft in feel were then placed in scrotum. Postoperative outcome was unremarkable. On follow up after 4 months, both testes were palpable in scrotum. Histopathology confirmed a rudimentary uterus with bilateral fallopian tubes and cervix.
Discussion The development of external genitalia in a male is based on the interplay of two major hormones, with DHT causing the appearance and development of male external genitalia and MIS or AMH which brings the regression of mullerian structures. The effects of DHT occur during 8–12 week period gestation and helps in the development of penis, penile urethra and scrotum. Internally the sertoli cells in the testis produce MIS or AMH which brings about regression of mullerian structures. However, this regression occurs only if AMH is secreted between 6 and 8 weeks of gestation, after which the mullerian structures become insensitive to AMH. PMDS results mainly due to three causes – failure of
AMH secretion, end organ resistance to AMH, and lastly if secretion occurs after 8–9 weeks. On the other hand, Wolffian structures develop normally due to normal androgen secretion from Leydig cells.6 Exact incidence of PMDS is not fully known because of its rarity and lack of awareness about this entity. These children have normally virilised external genitalia, occasional hypospadias and sometimes gynecomastia have also been associated. Internal genitalia resemble that of a female, with presence of uterus, fallopian tubes and testes with cystic changes lying in the mesosalpinx and hence often labeled as the ovaries as in our case. The cervix remains attached to the posterior urethra at the verumontanum. The vasa deferentia have a very short free segment which runs in the mesosalpinx and they remain embedded in the lateral wall of uterus and cervix. They finally open into the vaginal fornix. Most patients with PMDS are diagnosed incidentally during surgery for inguinal hernia or undescended testis as in this case. Once the hernia sac is opened, testis with uterus and fallopian tube may be seen and this is referred to as hernia uteri inguinalis. In transverse testicular ectopia (TTE), in which both the testes are located on one inguinal side, traction on the sac contents can deliver the contralateral testis.5 These patients have a normal male karyotype of 46XY. This helps in ruling out ovotesticular DSD and mixed gonadal dysgenesis, which can also have retained mullerian structures. Ultrasound of the abdomen and pelvis or trans rectal sonography help, but it is not considered a good imaging modality for intraabdominal testis. MRI is the best noninvasive modality to identify the various remnants of Mullerian structures and also in identifying the intra-abdominal testes.7 Serum testosterone and DHT remain within normal range in these cases. AMH levels may be low in AMH gene mutations and normal or high in AMH receptor mutations. The mullerian remnants and the undescended testes in PMDS both are at high risk for developing malignancy. As many as 3.1–8.4% of PMDS patients are likely to develop malignancy of mullerian remnants. Similarly 5–18% of PMDS patients may develop testicular malignancy in undescended testes.8 Teratoma, seminoma, yolk sac tumor and embryonal carcinoma have been reported in these intra-abdominal
Please cite this article in press as: Dey SK, et al. Persistent Mullerian Duct Syndrome: A rare clinical entity, Med J Armed Forces India. (2018), https://doi.org/10.1016/j.mjafi.2017.12.008
MJAFI-949; No. of Pages 4 medical journal armed forces india xxx (2017) xxx–xxx
3
Fig. 3 – Excised specimen – uterus, fallopian tube and cervix.
testicular vessels are clipped and in second stage, orchidopexy along with removal of mullerian structures is done. To conclude, we have reported a case of PMDS in a child, presenting with cryptorchidism. The aim of reporting this case is to sensitize the readers of an extremely rare condition and the need of orchidopexy and excision of the remnants of mullerian duct in such a case.
Conflicts of interest The authors have none to declare. Fig. 2 – (A) Uterus, fallopian tubes and testes. (B) Uterus and fallopian tube excised and vasa deferentia mobilized with sliver of uterine tissue.
testes. Therefore testes in PMDS should be brought to scrotum to facilitate early detection, should a tumor develop.9 Most of these patients will remain infertile. The testes in this condition is abnormally mobile due to lack of gubernaculum and there is a high likelihood of torsion and subsequent degeneration.
Surgical options Excision of mullerian structures with orchidopexy is the most preferred procedure whether done open or laparoscopically. Orchidopexy in these patients is often challenging technically, because of the free segment of vas being short and then the vas lies embedded in the lateral aspect of the body of uterus. Surgical procedure followed are as described by Loeff et al.10 In certain cases single stage orchidopexy is not possible, and hence a two staged procedure is done. In the first stage
references
1. Aw LD, Zain MM, Esteves SC, Humaidan P. Persistent Mullerian Duct Syndrome: a rare entity with a rare presentation in need of multidisciplinary management. Int Braz J Urol. 2016;42:1237–1243. 2. Al-Faris A, Jabari M, Al-Sayed M, Al-Shehri H. Bilateral Cryptorchidism, a rare presentation for persistent Müllerian duct syndrome. Electron Physician. 2016;8(12):3395–3397. http://dx.doi.org/10.19082/3395. 3. Farikullah J, Ehtisham S, Nappo S, Patel L, Hennayake S. Persistent Müllerian duct syndrome: lessons learned from managing a series of eight patients over a 10-year period and review of literature regarding malignant risk from the Müllerian remnants. BJU Int. 2012;110:E1084– E1089. 4. Picard JY, Cate RL, Racine C, Josso N. The Persistent Mullerian Duct Syndrome: an update based upon a personal experience of 157 cases. Sex Dev. 2017;11:109–125. http://dx. doi.org/10.1159/000475516. 5. Prakash N, Khurana A, Narula B. Persistent Mullerian duct syndrome. Indian J Pathol Microbiol. 2009;52:546–548. 6. Gujar NN, Choudhari RK, Choudhari GR, et al. Male form of persistent Mullerian duct syndrome type I (hernia uteri inguinalis) presenting as an obstructed inguinal hernia: a case report. J Med Case Rep. 2011;5:586.
Please cite this article in press as: Dey SK, et al. Persistent Mullerian Duct Syndrome: A rare clinical entity, Med J Armed Forces India. (2018), https://doi.org/10.1016/j.mjafi.2017.12.008
MJAFI-949; No. of Pages 4
4
medical journal armed forces india xxx (2017) xxx–xxx
7. Singh R, Kumar SD, Aggarwal N. MRI findings of Persistent Mullerian Duct Syndrome: a rare case report. J Clin Diagn Res. 2017;1(6):5–6. 8. Farikullah J, Ehtisham S, Nappo S, Patel L, Hennayake S. Persistent Mullerian Duct Syndrome: lessons learned from managing a series of eight patients over a 10-year period and review of literature regarding malignant risk from the Mullerian Remnants. BJU Int. 2012;110:E1084E1089. PMID:22540537.
9. Alharbi KN, Khushaim AO, Alrasheed M, Akhtar M, Neimatallah M. Radiological findings in Persistent Mullerian Duct Syndrome: case report and review of literature. Radiol Case. 2017;11(3):7–14. 10. Loeff DS, Imbeud S, Reyes HM, et al. Surgical and genetic aspects of persistence mullerian duct syndrome. J Pediatr Surg. 1994;29:61–65.
Please cite this article in press as: Dey SK, et al. Persistent Mullerian Duct Syndrome: A rare clinical entity, Med J Armed Forces India. (2018), https://doi.org/10.1016/j.mjafi.2017.12.008