View source for Persistent Müllerian duct syndrome

{{More medical citations needed|date=May 2018}}
{{Infobox medical condition (new)
| synonyms        = Persistent Müllerian derivatives
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| caption         = Persistent Müllerian duct syndrome has an autosomal recessive pattern of [[inheritance]].
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'''Persistent Müllerian duct syndrome''' ('''PMDS''') is the presence of [[Müllerian duct]] derivatives ([[fallopian tube]]s, [[uterus]], and/or the upper part of the [[vagina]])<ref name="Renu">{{Cite journal |vauthors=Renu D, Rao BG, Ranganath K |date=February 2010 |title=Persistent mullerian duct syndrome |department=primary |journal=The Indian Journal of Radiology & Imaging |volume=20 |issue=1 |pages=72–4 |doi=10.4103/0971-3026.59761 |pmc=2844757 |pmid=20352001 |doi-access=free}}</ref>  in what would be considered a genetically and otherwise physically normal [[male]] animal by typical human based standards.<ref>{{Cite book |last=Carlson |first=Neil R. |url=https://archive.org/details/physiologybehavi00carl_811 |title=Physiology of behavior |date=2013 |publisher=Pearson |isbn=978-0205239399 |edition=11th |location=Boston |page=[https://archive.org/details/physiologybehavi00carl_811/page/n348 328] |url-access=limited |name-list-style=vanc |department=review}}</ref>  In humans, PMDS typically is due to an [[autosomal]] [[recessive]]<ref name="Imbeaud_1996">{{Cite journal |vauthors=Imbeaud S, Belville C, Messika-Zeitoun L, Rey R, di Clemente N, Josso N, Picard JY |date=September 1996 |title=A 27 base-pair deletion of the anti-müllerian type II receptor gene is the most common cause of the persistent müllerian duct syndrome |department=primary |journal=Human Molecular Genetics |volume=5 |issue=9 |pages=1269–77 |doi=10.1093/hmg/5.9.1269 |pmid=8872466 |doi-access=free}}</ref> [[congenital disorder]] and is considered by some to be a form of [[pseudohermaphroditism]] due to the presence of Müllerian derivatives.<ref name="Renu" /><ref name="laphysto">{{Cite journal |vauthors=Colacurci N, Cardone A, De Franciscis P, Landolfi E, Venditto T, Sinisi AA |date=February 1997 |title=Laparoscopic hysterectomy in a case of male pseudohermaphroditism with persistent Müllerian duct derivatives |department=primary |journal=Human Reproduction |volume=12 |issue=2 |pages=272–4 |doi=10.1093/humrep/12.2.272 |pmid=9070709 |doi-access=free}}</ref> PMDS can also present in non-human animals.<ref>{{Cite journal |last=Cinti |first=F |last2=Sainato |first2=D |last3=Charlesworth |first3=T |date=April 2021 |title=A case of persistent Mullerian duct syndrome in a dog. |url=https://pubmed.ncbi.nlm.nih.gov/33034383/ |journal=The Journal of Small Animal Practice |volume=62 |issue=4 |pages=311 |doi=10.1111/jsap.13225 |pmid=33034383 |s2cid=222235106 |access-date=19 May 2022}}</ref><ref>{{Cite web |date=12 April 2016 |title=Persistent Müllerian Duct Syndrome |url=https://vetmed.umn.edu/research/labs/canine-genetics-lab/genetic-testing/persistent-müllerian-duct-syndrome |access-date=19 May 2022 |website=College of Veterinary Medicine - University of Minnesota |language=en}}</ref>

Typical features include undescended testes ([[cryptorchidism]]) and the presence of a small, underdeveloped uterus in an XY infant or adult. This condition is usually caused by deficiency of fetal [[anti-Müllerian hormone]] (AMH) effect due to [[mutation]]s of the [[gene]] for AMH or the [[anti-Müllerian hormone receptor]], but may also be as a result of insensitivity to AMH of the target organ.<ref name="Renu" />

==Presentation==
The first visible signs of PMDS after birth is cryptorchidism (undescended testes) either unilaterally or bilaterally,<ref name="Vanikar_2016">{{Cite journal |vauthors=Vanikar AV, Nigam LA, Patel RD, Kanodia KV, Suthar KS, Thakkar UG |date=June 2016 |title=Persistent mullerian duct syndrome presenting as retractile testis with hypospadias: A rare entity |department=primary |journal=World Journal of Clinical Cases |volume=4 |issue=6 |pages=151–4 |doi=10.12998/wjcc.v4.i6.151 |pmc=4909461 |pmid=27326401 |doi-access=free}}</ref> as well as [[inguinal hernia]]s. Adults who have been oblivious to this condition may present with [[Hematuria|haematuria]], which is when blood appears in urine because of hormonal imbalances. PMDS Type I is also referred to as '''hernia uteri inguinalis''', which exhibits one descended testis that has also pulled the fallopian tube, and sometimes uterus, through the inguinal canal.<ref name="Josso_2005" /> The descended testes, fallopian tube and uterus all fall in the same inguinal canal, causing an inguinal hernia.<ref name="Josso_2005" />  When the aforementioned conditions occur together, it is called '''transverse testicular ectopia'''.<ref name="Josso_2005" />

Under the microscope, some samples taken for biopsies displayed results where testicular tissue was at a stage of immaturity and showed dysplasia.<ref name="Pappis _1979" />

==Genetics==
Mutation in AMH gene (PMDS Type 1) or AMHR2 gene (PMDS Type 2) are the primary causes of PMDS.<ref name="Fernandes_1990" /> AMH, or sometimes referred to as Müllerian inhibiting substance (MIS), is secreted by Sertoli cells during an individual's whole life.<ref name="Josso_2005" /> It is essential during the foetal period as it functions to regress the Müllerian ducts. However, AMH also functions in the last trimester of pregnancy, after birth, and even during adulthood in minimal amounts.<ref name="Josso_2005" /> The Sertoli cells in males secrete AMH, through the presence of a [[Y chromosome]].<ref name="Josso_2005" />

The role of the ''AMH'' gene in reproductive development, is the production of a protein that contributes to male [[sex differentiation]]. During development of male foetuses, the AMH protein is secreted by cells within the testes. AMHs bind to the AMH Type 2 Receptors, which are present on cells on the surface of the Müllerian duct. The binding of AMH to its receptors on the Müllerian duct induces the [[apoptosis]] of the Müllerian duct cells, thus the regression of the Müllerian duct within males.<ref name="Agrawal_2015" /> However, for females who originally do not produce AMH proteins during foetal development, the Müllerian duct eventually becomes the uterus and fallopian tubes as normal.<ref name="Agrawal_2015" /> With the AMH gene mutation (PMDS Type 1), the AMH is either not produced, produced in deficient amounts, defective, or secreted at the wrong critical period for male differentiation.<ref name="Agrawal_2015" />

AMHR2 contains the instructions for generating the receptors that AMH binds to. If there is a mutation in the AMHR2 gene, the response to AMH molecules binding to the receptor cannot be properly reciprocated. Other possibilities include an absence of the receptors, such that the AMH molecules cannot induce differentiation. Mutation in the AMHR2 is critical to proper male sex differentiation. The genetic mutational cause of PMDS, is a 27 base-pair deletion of the Anti-Müllerian Type 2 Receptor gene. The 27-base-pair deletion that occurs PMDS is in exon 10 on one allele.<ref name="Pappis _1979">{{Cite journal |vauthors=Pappis C, Constantinides C, Chiotis D, Dacou-Voutetakis C |date=April 1979 |title=Persistent Müllerian duct structures in cryptorchid male infants: surgical dilemmas |department=primary |journal=Journal of Pediatric Surgery |volume=14 |issue=2 |pages=128–31 |doi=10.1016/0022-3468(79)90002-2 |pmid=37292}}</ref> With the AMHR2 gene mutation (PMDS Type 2), the AMHR2 is either not produced, produced in deficient amounts, defective, or the Müllerian ducts manifested a resistance to AMH.<ref name="Agrawal_2015" />

PMDS is inherited in an autosomal recessive manner.<ref name="Fernandes_1990" /> The male individuals inherit mutated copies of the [[X chromosome]]s from the maternal and paternal genes, implying the parents are carriers and do not show symptoms. Females inheriting two mutated genes do not display symptoms of PMDS, though remain as carriers. Males are affected [[genotypically]] with the karyotype (46, XY) and [[phenotypically]].<ref name="Sekhon_2017" />

==Diagnosis==
Persistent Müllerian duct syndrome (PMDS), also known as persistent oviduct syndrome, is a congenital disorder related to male sexual development. PMDS usually affects phenotypically normal male individuals with the karyotype (46, XY) and is a form of pseudohermaphroditism.<ref name="Fernandes_1990">{{Cite journal |vauthors=Fernandes ET, Hollabaugh RS, Young JA, Wilroy SR, Schriock EA |date=December 1990 |title=Persistent müllerian duct syndrome |department=primary |journal=Urology |volume=36 |issue=6 |pages=516–8 |doi=10.1016/0090-4295(90)80191-O |pmid=1978951}}</ref><ref name="Agrawal_2015">{{Cite journal |vauthors=Agrawal AS, Kataria R |date=June 2015 |title=Persistent Müllerian Duct Syndrome (PMDS): a Rare Anomaly the General Surgeon Must Know About |department=review |journal=The Indian Journal of Surgery |volume=77 |issue=3 |pages=217–21 |doi=10.1007/s12262-013-1029-7 |pmc=4522266 |pmid=26246705}}</ref>

The condition occurs in males and consists of normal-functioning reproductive organs and gonads, but also female reproductive organs such as the uterus and the fallopian tubes. The fetus has two sets of tubes which give rise to accessory reproductive organs - the (Wolffian) [[mesonephric duct]]s and the (Müllerian) [[paramesonephric duct]]s. Usually, the Wolffian duct gives rise to male reproductive organs (specifically the testicle, epididymis and vas deferens) while the Müllerian to female (the fallopian tubes, the uterus and the vagina), while the other duct regresses. In PMDS, an abnormality in the [[anti-Müllerian hormone]] signaling pathway causes the in-males-redundant Müllerian duct to persist and give rise to variously developed female reproductive organs.{{citation needed|date=October 2021}}

PMDS has various causes related to AMH or receptor abnormalities. For example, AMH has failed to synthesize, failed to release or was secreted at the wrong time.<ref name="Prakash_2009">{{Cite journal |vauthors=Prakash N, Khurana A, Narula B |date=2009-10-01 |title=Persistent Müllerian duct syndrome |department=primary |journal=Indian Journal of Pathology & Microbiology |volume=52 |issue=4 |pages=546–8 |doi=10.4103/0377-4929.56160 |pmid=19805969 |doi-access=free}}</ref> Normally, both the Müllerian and Wolffian ducts are present during the 7th week of gestation. At approximately the end of the 7th and the beginning of the 8th week of gestation, the Sertoli cell's secretion of AMH occurs, causing male sex differentiation during fetal development.<ref name="Agrawal_2015" /> The AMH molecules bind to AMHRII (anti-Müllerian hormone receptor type II) regressing the Müllerian duct. The [[Leydig cell]]s secrete [[testosterone]] to aid the male differentiation process by inducing structures such as the [[epididymis]], [[vas deferens]] and [[seminal vesicles]]. However, with PMDS individuals, the Müllerian duct persists instead of regressing, either due to AMH secretion (PMDS Type I) or AMH receptors (PMDS Type II).<ref name="Al-Salem_2017">{{Cite book |title=An Illustrated Guide to Pediatric Urology |vauthors=Al-Salem AH |publisher=Springer International Publishing Springer |year=2017 |isbn=978-3-319-44181-8 |location=Cham |pages=287–293 |chapter=Persistent Müllerian Duct Syndrome (PMDS) |doi=10.1007/978-3-319-44182-5_10 |department=review}}</ref> PMDS is usually coincidentally found during surgery for inguinal hernia, or when searching for adult male infertility causes.<ref name="Sekhon_2017">{{Cite journal |vauthors=Sekhon V, Luthra M, Jevalikar G |date=January 2017 |title=Persistent Mullerian Duct Syndrome presenting as irreducible inguinal hernia – A surprise surgical finding! |department=primary |journal=Journal of Pediatric Surgery Case Reports |volume=16 |pages=34–36 |doi=10.1016/j.epsc.2016.11.002 |doi-access=free}}</ref>

=== Other diagnostic tests ===

==== Genetic ====
Another method for the confirmation of PMDS is [[genetic testing]].<ref name="Imbeaud_1996" /> It is not usually preferred because of its processing period and cost. With image screenings such as [[Ultrasound computer tomography|ultrasound]] and [[MRI]], the condition can be efficiently confirmed. Genetic tests can identify those who hold the mutated gene, identify the family member's chances and risks, and advise those who are trying to get pregnant.<ref name="Imbeaud_1996" /> Genetic counseling and further genetic testing is offered to confirm the chances and risks of an individual's offspring obtaining the pair of mutated genes. Further research into the family tree and inheritance is possible as well.{{citation needed|date=October 2021}}

==== ELISA ====
An [[ELISA]] test is a form of [[immunoassay]], a technique which uses an antibody or antigen to identify the presence of particular substances. For PMDS, ELISA tests can be used to determine the levels of AMH within the male individual's [[Serum (blood)|serum]], but this is only effective before the individual reaches puberty as it normally increases during this period.<ref name="Josso_2005">{{Cite journal |vauthors=Josso N, Belville C, di Clemente N, Picard JY |date=2005-05-05 |title=AMH and AMH receptor defects in persistent Müllerian duct syndrome |department=review |journal=Human Reproduction Update |volume=11 |issue=4 |pages=351–6 |doi=10.1093/humupd/dmi014 |pmid=15878900 |doi-access=free}}</ref> PMDS patients display low levels of AMH within the serum, and low levels of testosterone.<ref name="Josso_2005" />

==Treatment==
{{Intersex sidebar}}

Persistent Müllerian duct syndrome does not cause any [[physical complication]]s, and does not pose any danger to a newborn child. Surgeries on newborn infants have a high rate of failure, and uterine tissue tends to be healthy.<ref name="ghattas">{{Cite book |last=Ghattas |first=Dan Christian |author-link=Dan Christian Ghattas |url=http://www.boell.de/sites/default/files/endf_human_rights_between_the_sexes.pdf |title=Human Rights between the Sexes A preliminary study on the life situations of inter*individuals |last2=Heinrich-Böll-Stiftung |author-link2=Heinrich Böll Foundation |date=2013 |publisher=Heinrich-Böll-Stiftung |isbn=978-3-86928-107-0 |location=Berlin |archive-url=https://web.archive.org/web/20150923223221/http://www.boell.de/sites/default/files/endf_human_rights_between_the_sexes.pdf |archive-date=23 September 2015 |url-status=live |df=dmy-all}}</ref><ref>{{Cite web |date=21 April 2004 |title="Intersex", Radio Netherlands Archives, April 21, 2004 |url=http://www.radionetherlandsarchives.org/intersex/ |url-status=live |archive-url=https://web.archive.org/web/20200829030112/http://www.radionetherlandsarchives.org/intersex/ |archive-date=29 August 2020 |access-date=16 April 2019}}</ref> [[The World Health Organization]] (WHO) standard of care is to delay surgery until the child is old enough to participate in informed consent; performing [[intersex genital surgeries]] on newborn infants is considered a [[human rights violation]], including by the WHO.<ref>{{Cite journal |last=Carpenter |first=Morgan |date=December 2018 |title=Intersex Variations, Human Rights, and the International Classification of Diseases |journal=Health and Human Rights |volume=20 |issue=2 |pages=205–214 |pmc=6293350 |pmid=30568414}}</ref><ref>{{Cite journal |last=Greenberg |first=Julie A. |date=June 2017 |title=Legal, ethical, and human rights considerations for physicians treating children with atypical or ambiguous genitalia |journal=Seminars in Perinatology |volume=41 |issue=4 |pages=252–255 |doi=10.1053/j.semperi.2017.03.012 |pmid=28478089}}</ref>

The main form of treatment is [[laparotomy]], a modern and minimally invasive type of surgery. Laparotomy properly positions the testes within the scrotum ([[Orchiopexy|orchidopexy]]) and removes Müllerian structures, the uterus, and fallopian tubes.<ref name="Fernandes_1990" /> Occasionally they are unsalvageable if located high in the [[retroperitoneum]]. During this surgery, the uterus is usually removed and attempts made to dissect away Müllerian tissue from the vas deferens and epididymis to improve the chance of fertility. If the person has male gender identity and the testes cannot be retrieved, [[testosterone (medication)|testosterone]] replacement will usually be necessary at [[puberty]] should the affected individual choose to pursue medical attention. Recently, [[Laparoscopy|laparoscopic]] [[hysterectomy]] is offered to patients as a solution to both improve the chances of fertility and to prevent the occurrence of [[neoplastic]] tissue formation.<ref name="laphysto" /> Having a target age for surgery reduces the risks of damaging the vas deferens. The vas deferens is in close proximity to the Müllerian structures, and is sometimes lodged in the uterine wall.<ref name="Sekhon_2017" /><ref name="Fernandes_1990" />

PMDS patients have a possibility of infertility in the future if not promptly operated on. When the affected males are adults, those who are not aware of the condition may find the presence of blood in their semen (hematospermia).<ref name="Gujar_2011">{{Cite journal |vauthors=Gujar NN, Choudhari RK, Choudhari GR, Bagali NM, Mane HS, Awati JS, Balachandran V |date=December 2011 |title=Male form of persistent Mullerian duct syndrome type I (hernia uteri inguinalis) presenting as an obstructed inguinal hernia: a case report |department=primary |journal=Journal of Medical Case Reports |volume=5 |issue=1 |pages=586 |doi=10.1186/1752-1947-5-586 |pmc=3259122 |pmid=22185203 |doi-access=free}}</ref> The Müllerian structures and cryptorchidism can also develop into cancer, although this is incredibly rare. If PMDS is found during adulthood, or if Müllerian structures had to be left behind due to risks in surgery, biopsies of the remaining Müllerian structures can be performed. Upon pathohistological observation, the endometrial tissues appear atrophied, and the fallopian tubes have begun to congest showing signs of fibrosis.<ref name="Gujar_2011" />

== Epidemiology ==
PMDS is a relatively rare congenital condition. From current data, approximately 45% of the known cases are caused by mutations in the AMH gene, being a mutation on chromosome 19 (Type I PMDS).<ref name="Sekhon_2017" /> Approximately, 40% are AMHR2 mutations, on the AMH receptor type 2 gene, which is on chromosome 12 (Type 2 PMDS).<ref name="Sekhon_2017" /> The remaining unknown 15% are referred to as '''idiopathic PMDS'''.<ref name="Sekhon_2017" />

== Case studies ==
Especially before the 21st century, these conditions were hard to diagnose due to the lack of modern imaging capabilities. For this reason, the older population, or those in poorer countries found out later. PMDS was usually overlooked because the external symptoms, such as the cryptorchidism and inguinal hernias, were assumed to be the only complication.

A case reported in 2013, involves a 50-year-old male with a history of low testosterone levels, high cholesterol and the congenital absence of his right testis.<ref name="Prakash_2009" /> Imaging revealed that the patient had three cystic masses, with structures similar to the uterus and ovaries, thus PMDS.<ref name="Prakash_2009" /> During the operation, the surgeons found malignant degeneration of the Müllerian remnants which occurs if PMDS is unnoticed for a long period of time.<ref name="Prakash_2009" /> The cause of the complications presented in the male patient was due to the unidentified bilateral cryptorchidism since birth, as doctors at that time assumed the complication was just the "congenital absence of his right testis".<ref name="Prakash_2009" /> Overlooking the symptoms of PDMS can cause permanent negative effects such as infertility and future malignancies, as shown by this male patient.<ref name="Prakash_2009" /> The malignant degeneration of the Müllerian structures is supportive evidence for the cause of the male patient's infertility.

== See also ==
* [[Intersex]]
* [[Sexual differentiation]]
* [[Cryptorchidism]]
* [[Anti-Müllerian hormone]]

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{Cite journal |vauthors=Picard JY, Cate RL, Racine C, Josso N |date=2017 |title=The Persistent Müllerian Duct Syndrome: An Update Based Upon a Personal Experience of 157 Cases |department=review |journal=Sexual Development |volume=11 |issue=3 |pages=109–125 |doi=10.1159/000475516 |pmid=28528332 |doi-access=free}}
* {{Cite journal |vauthors=Da Aw L, Zain MM, Esteves SC, Humaidan P |date=2016 |title=Persistent Mullerian Duct Syndrome: a rare entity with a rare presentation in need of multidisciplinary management |department=review |journal=International Brazilian Journal of Urology |volume=42 |issue=6 |pages=1237–1243 |doi=10.1590/S1677-5538.IBJU.2016.0225 |pmc=5117982 |pmid=27532119}}
* {{Cite journal |vauthors=Elias-Assad G, Elias M, Kanety H, Pressman A, Tenenbaum-Rakover Y |date=June 2016 |title=Persistent Müllerian Duct Syndrome Caused by a Novel Mutation of an Anti-MüIlerian Hormone Receptor Gene: Case Presentation and Literature Review |department=review |journal=Pediatric Endocrinology Reviews |volume=13 |issue=4 |pages=731–40 |pmid=27464416}}
{{refend}}

== External links ==
{{Medical resources
| DiseasesDB      = 33868
| ICD10           = {{ICD10|Q|55|8|q|55}}
| ICD9            =
| ICDO            =
| OMIM            = 261550
| MedlinePlus     =
| eMedicineSubj   =
| eMedicineTopic  =
| MeshID          = C536665
| Orphanet        = 2856
| SNOMED CT       = 702358005
}}
{{Male congenital malformations of genital organs, indeterminate sex and pseudohermaphroditism}}
{{Receptor deficiencies}}

<references group="References" />

{{DEFAULTSORT:Persistent Mullerian duct syndrome}}
[[Category:Congenital disorders of male genital organs]]
[[Category:Autosomal recessive disorders]]
[[Category:Rare syndromes]]
[[Category:Cell surface receptor deficiencies]]
[[Category:Intersex variations]]