Persistent Müllerian duct syndrome
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Persistent Müllerian duct syndrome (PMDS) is the presence of
Müllerian duct Paramesonephric ducts (or Müllerian ducts) are paired ducts of the embryo that run down the lateral sides of the genital ridge and terminate at the sinus tubercle in the primitive urogenital sinus. In the female, they will develop to form the fal ...
derivatives (
fallopian tube The fallopian tubes, also known as uterine tubes, oviducts or salpinges (singular salpinx), are paired tubes in the human female that stretch from the uterus to the ovaries. The fallopian tubes are part of the female reproductive system. In ot ...
s,
uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
, and/or the upper part of the
vagina In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hymen ...
) in what would be considered a genetically and otherwise physically normal
male Male (symbol: ♂) is the sex of an organism that produces the gamete (sex cell) known as sperm, which fuses with the larger female gamete, or ovum, in the process of fertilization. A male organism cannot reproduce sexually without access to ...
animal by typical human based standards. In humans, PMDS typically is due to an
autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...
recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
congenital disorder A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...
and is considered by some to be a form of
pseudohermaphroditism Pseudohermaphroditism is a condition in which an individual has a matching chromosomal and gonadal tissue (ovary or testis) sex, but mismatching external genitalia. Female pseudohermaphroditism refers to an individual with ovaries and external gen ...
due to the presence of Müllerian derivatives. Typical features include undescended testes (
cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...
) 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 Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differen ...
(AMH) effect due to
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s of the
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
for AMH or the anti-Müllerian hormone receptor, but may also be as a result of insensitivity to AMH of the target organ. PMDS can also present in non-human animals.


Presentation

The first visible signs of PMDS after birth is cryptorchidism (undescended testes) either unilaterally or bilaterally. Along with cryptorchidism, is also
inguinal hernia An inguinal hernia is a hernia (protrusion) of abdominal-cavity contents through the inguinal canal. Symptoms, which may include pain or discomfort especially with or following coughing, exercise, or bowel movements, are absent in about a third ...
s which may be presented unilaterally (affects one testicle) or bilaterally (affects both testicles). Adults who have been oblivious to this condition may be presented with
haematuria Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. “Gross hematuria” occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable w ...
, 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. The descended testes, fallopian tube and uterus all fall in the same inguinal canal, causing an inguinal hernia. Altogether when the aforementioned conditions occur, it is called transverse testicular ectopia. Under the microscope, some samples taken for biopsies displayed results where testicular tissue was at a stage of immaturity, and showed dysplasia.


Genetics

Mutation in AMH gene (PMDS Type 1) or AMHR2 gene (PMDS Type 2) are the primary causes of PMDS. AMH, or sometimes referred to as Müllerian inhibiting substance (MIS), is secreted by Sertoli cells during an individual's whole life. 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. The Sertoli cells in males secrete AMH, through the presence of a
Y chromosome The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abse ...
. The role of the ''AMH'' gene in reproductive development, is the production of a protein that contributes to male
sex differentiation Sexual differentiation is the process of development of the sex differences between males and females from an undifferentiated zygote. Sex-determination system, Sex determination is often distinct from sex differentiation; sex determination is the ...
. 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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
of the Müllerian duct cells, thus the regression of the Müllerian duct within males. 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. With the AMH gene mutation (PMDS Type 1), the AMH is either not produced, produced in deficient amounts, defective, secreted at the wrong critical period for male differentiation or the Müllerian ducts manifested a resistance to AMH. AMHR2 contains the instructions for generating the receptors that AMH binds to. If there if 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. PMDS is inherited in an autosomal recessive manner. The male individuals inherit mutated copies of the
X chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
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 The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
with the karyotype (46, XY) and
phenotypically In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
.


Mechanism


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. 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 The mesonephric duct (also known as the Wolffian duct, archinephric duct, Leydig's duct or nephric duct) is a paired Organ (anatomy), organ that forms during the embryonic development of humans and other mammals and gives rise to male Sex organ, r ...
s and the (Müllerian)
paramesonephric duct Paramesonephric ducts (or Müllerian ducts) are paired ducts of the embryo that run down the lateral sides of the genital ridge and terminate at the sinus tubercle in the primitive urogenital sinus. In the female, they will develop to form the fal ...
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 Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differen ...
signalling pathway causes the in-males-redundant Müllerian duct to persist and give rise to variously developed female reproductive organs. 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. 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. The AMH molecules bind to AMHRII (anti-Müllerian hormone receptor type II) regressing the Müllerian duct. The
Leydig cell Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral ...
s secrete
testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
to aid the male differentiation process by inducing structures such as the
epididymis The epididymis (; plural: epididymides or ) is a tube that connects a testicle to a vas deferens in the male reproductive system. It is a single, narrow, tightly-coiled tube in adult humans, in length. It serves as an interconnection between the ...
,
vas deferens The vas deferens or ductus deferens is part of the male reproductive system of many vertebrates. The ducts transport sperm from the epididymis to the ejaculatory ducts in anticipation of ejaculation. The vas deferens is a partially coiled tube ...
and
seminal vesicles The seminal vesicles (also called vesicular glands, or seminal glands) are a pair of two convoluted tubular glands that lie behind the urinary bladder of some male mammals. They secrete fluid that partly composes the semen. The vesicles are 5 ...
. 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). PMDS is usually coincidentally found during surgery for inguinal hernia, or when searching for adult male infertility causes.


Other diagnostic tests


Genetic

Another method for the confirmation of PMDS is genetic testing. It is not usually preferred because of its processing period and cost. With image screenings such as
ultrasound Ultrasound is sound waves with frequency, frequencies higher than the upper audible limit of human hearing range, hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hea ...
and
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
, 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. 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.


ELISA

An
ELISA The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presence ...
test is a form of
immunoassay An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoass ...
, 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, but this is only effective before the individual reaches puberty as it normally increases during this period. PMDS patients display low levels of AMH within the serum, and low levels of testosterone.


Treatment

The main form of treatment is
laparotomy A laparotomy is a surgical procedure involving a surgical incision through the abdominal wall to gain access into the abdominal cavity. It is also known as a celiotomy. Origins and history The first successful laparotomy was performed without ane ...
, a modern and minimally invasive type of surgery. Laparotomy properly positions the testes within the scrotum ( orchidopexy) and remove Müllerian structures, the uterus and fallopian tubes. Occasionally they are unsalvageable if located high in the
retroperitoneum The retroperitoneal space (retroperitoneum) is the anatomical space (sometimes a potential space) behind (''retro'') the peritoneum. It has no specific delineating anatomical structures. Organs are retroperitoneal if they have peritoneum on their ...
. 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 Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
replacement will be usually necessary at
puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy. ...
should the affected individual choose to pursue medical attention. Recently,
laparoscopic Laparoscopy () is an operation performed in the abdomen or pelvis using small incisions (usually 0.5–1.5 cm) with the aid of a camera. The laparoscope aids diagnosis or therapeutic interventions with a few small cuts in the abdomen.Medli ...
hysterectomy Hysterectomy is the surgical removal of the uterus. It may also involve removal of the cervix, ovaries (oophorectomy), Fallopian tubes (salpingectomy), and other surrounding structures. Usually performed by a gynecologist, a hysterectomy may b ...
is offered to patients as a solution to both improve the chances of fertility and to prevent the occurrence of
neoplastic A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
tissue formation. The surgery is recommended to be performed when the individual is between one and two years old, but usually done when less than one year old. 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. Overall, the purpose of the treatment improves self-identification of an individual, reduces the increased risk of cancer and reduces the possibility of infertility, if not already present. 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). The Müllerian structures and cryptorchidism can also develop into cancer if ignored, or if there are pieces of Müllerian structures left from past surgery. 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.


Epidemiology

PMDS is a relatively rare congenital disease. 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). Approximately, 40% are AMHR2 mutations, on the AMH receptor type 2 gene, which is on chromosome 12 (Type 2 PMDS). The remaining unknown 15% are referred to as idiopathic PMDS.


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. Imaging revealed that the patient had three cystic masses, with structures similar to the uterus and ovaries, thus PMDS. During the operation, the surgeons found malignant degeneration of the Müllerian remnants which occurs if PMDS is unnoticed for a long period of time. 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". Overlooking the symptoms of PDMS can cause permanent negative effects such as infertility and future malignancies, as shown by this male patient. The malignant degeneration of the Müllerian structures is supportive evidence for the cause of the male patient's infertility.


See also

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Intersex Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical bina ...
*
Sexual differentiation Sexual differentiation is the process of development of the sex differences between males and females from an undifferentiated zygote. Sex determination is often distinct from sex differentiation; sex determination is the designation for the deve ...
*
Cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...
*
Anti-Müllerian hormone Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differen ...


References


Further reading

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External links

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