For infants with suspected  congenital  Zika virus disease, the CDC recommends testing with both serologic and molecular assays such as RT-PCR, IgM  ELISA  and  plaque reduction neutralization test  (PRNT). [ 62 ]  RT-PCR of the infants serum and urine should be performed in the first two days of life. [ 62 ]  Newborns with a mother who was potentially exposed and who have positive blood tests, microcephaly or intracranial calcifications  [ 63 ]  should have further testing including a thorough physical investigation for neurologic abnormalities, dysmorphic features, splenomegaly, hepatomegaly, and rash or other skin lesions. [ 62 ]  Other recommended tests are cranial ultrasound, hearing evaluation, [ 64 ]  and eye examination. [ 62 ]  Testing should be done for any abnormalities encountered as well as for other congenital infections such as  syphilis ,  toxoplasmosis , rubella,  cytomegalovirus  infection,  lymphocytic choriomeningitis  virus infection, and  herpes simplex virus . [ 62 ]  Some tests should be repeated up to 6 months later as there can be delayed effects, particularly with hearing. [ 62 ]


In response to the widespread transmission of Zika virus during the 2016 outbreak and concerns of viral genetic material detected in breast milk the  World Health Organization  (WHO) released a Guideline of infant feeding in areas of Zika virus transmission, first in 2016 and updated in 2021, where the evidence showed that despite the detection of Zika virus in breast milk, there is unclear evidence of transmission to the infant, and considering that Zika virus infection among infants is mild, the balance between desirable and undesirable effects favours breastfeeding versus not breastfeeding. [ 65 ]  According to the 2021WHO guidelines: [ 65 ]


The virus is spread by mosquitoes, making mosquito avoidance an important element to disease control. The CDC recommends that individuals: [ 66 ]


The CDC also recommends strategies for controlling mosquitoes such as eliminating standing water, repairing  septic tanks  and using screens on doors and windows. [ 69 ] [ 70 ]  Spraying  insecticide  is used to kill flying mosquitoes and  larvicide  can be used in water containers. [ 1 ]


Because Zika virus can be sexually transmitted, men who have gone to an area where Zika fever is occurring should be counseled to either abstain from sex or use  condoms  for 6 months after travel if their partner is pregnant or could potentially become pregnant. [ 19 ] [ 39 ] [ 48 ]   Breastfeeding  is still recommended by the WHO, even by women who have had Zika fever. There have been no recorded cases of Zika transmission to infants through breastfeeding, though the  replicative virus  has been detected in breast milk. [ 49 ] [ 71 ]


When returning from travel, with or without symptoms, it is suggested that prevention of mosquito bites continue for 3 weeks in order reduce the risk of virus transmission to uninfected mosquitos. [ 66 ]


Because of the "growing evidence of a link between Zika and microcephaly", in January 2016, the CDC issued a  travel alert  advising pregnant women to consider postponing travel to countries and territories with ongoing local transmission of Zika virus. [ 72 ]  Later, the advice was updated to caution pregnant women to avoid these areas entirely if possible and, if travel is unavoidable, to protect themselves from mosquito bites. [ 73 ]  Male partners of pregnant women and couples contemplating pregnancy who must travel to areas where Zika is active are advised to use condoms or abstain from sex. [ 73 ]  The agency also suggested that women thinking about becoming pregnant should consult with their physicians before traveling. [ 72 ] [ 74 ]


In September 2016, the CDC travel advisories included: [ 75 ]


In December 2020, no active Zika outbreaks were reported by the CDC. [ 76 ]


Both the regional  Pan American Health Organization  (PAHO) as well as the WHO have issued statements of concern about the widespread public health impact of the Zika virus and its links to GBS and microcephaly. [ 77 ] [ 78 ]  The WHO Director-General,  Margaret Chan , issued a statement in February 2016 "declaring that the recent cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes a Public Health Emergency of International Concern." [ 13 ]  The declaration allowed the WHO to coordinate international response to the virus as well as gave its guidance the force of  international law  under the  International Health Regulations . [ 79 ] [ 80 ]  The declaration was ended in November 2016. [ 81 ]


As of 2016 there was no available vaccine. Development was a priority of the US  National Institutes of Health  (NIH), but officials stated that development of a vaccine could take years. [ 4 ] [ 19 ] [ 54 ] [ 82 ]  To speed new  drug development  regulatory strategies were proposed by the WHO and NIH. [ 83 ] [ 84 ]  Animal and early human studies were underway as of September 2016. [ 85 ] [ 86 ]  As of December 2019, there were several vaccine candidates in various stages of development. [ 87 ]


Disease control in the affected countries currently centres around mosquito control. Several approaches are available for the management of  Aedes aegypti  mosquito populations, including the destruction of larval breeding sites (the aquatic pools in which eggs are laid and larvae hatch prior to mosquito development into flying adults); and, insecticides targeting either the larval stages, adult mosquitoes or both. Additionally, a whole host of novel technologies are under current development for mosquito control and the World Health Organization has recently lent its support for the accelerated development of modern methods for mosquito control such as the use of  Wolbachia  bacteria to render mosquitoes resistant to the virus, and, the release of sterilized male mosquitoes that breed with wild female mosquitoes to give rise to non-viable offspring (offspring that do not survive to the biting, adult stage). [ 88 ]


Oxitec 's genetically modified OX513A mosquito was approved by Brazil's National Biosecurity Technical Commission (CTNBio) in April 2014 [ 89 ]  and it was being used to try to combat mosquitoes carrying the  Zika virus  in the town of  Piracicaba , São Paulo in 2016. [ 90 ]


In the 1940s and 1950s, the  Aedes aegypti  mosquito was eradicated on some Caribbean islands and in at least eighteen Latin American countries.  Decreasing political will and presumably available money, mosquito resistance to insecticide, and a pace of urbanization which exceeded eradication efforts led to this mosquito's comeback. [ 91 ]


There is currently no specific treatment for Zika virus infection. Care is supportive with treatment of pain, fever, and itching. [ 38 ]  Some authorities have recommended against using  aspirin  and other  NSAIDs  as these have been associated with hemorrhagic syndrome when used for other flaviviruses. [ 4 ] [ 19 ]  Additionally, aspirin use is generally avoided in children when possible due to the risk of  Reye syndrome . [ 92 ]


Zika virus had been relatively little studied until the major outbreak in 2015, and no specific antiviral treatments are available as yet. [ 19 ]  Advice to pregnant women is to avoid any risk of infection so far as possible, as once infected there is little that can be done beyond supportive treatment. [ 93 ]


Most of the time, Zika fever resolves on its own in two to seven days, but rarely, some people develop  Guillain–Barré syndrome . [ 4 ] [ 94 ]    The fetus of a pregnant woman who has Zika fever may die or be born with congenital central nervous system malformations, like  microcephaly . [ 4 ]


In April 1947, as part of studies sponsored by the  Rockefeller Foundation  into  yellow fever , 6 caged rhesus monkeys were placed in the canopy of the Zika Forest of Uganda. [ 95 ]  On April 18 one of the monkeys (no. 776) developed a fever and blood samples revealed the first known case of Zika fever. [ 33 ] [ 95 ]  Population surveys at the time in Uganda found 6.1% of individuals to be seropositive for Zika. [ 47 ]  The first human cases were reported in Nigeria in 1954. [ 96 ]  A few outbreaks have been reported in tropical Africa and in some areas in Southeast Asia. [ 97 ]  Until recently there were no documented cases of Zika virus in the  Indian subcontinent , [ 98 ]  however, the first cases were reported in 2017 from Gujarat state and Tamil Nadu, [ 99 ]   more cases were reported in Rajasthan state involving an outbreak of 153 reported cases [ 100 ]  and in a pregnant women living in Kerala state. [ 101 ]  A 1954 study assessing blood samples from several people from different states found  antibodies  to Zika in healthy people in India which could indicate past exposure, though it could also be due to  cross-reaction  with other flaviviruses. [ 98 ]


By using  phylogenetic  analysis of Asian strains, it was estimated that Zika virus had moved to Southeast Asia by 1945. [ 47 ]  In 1977–1978, Zika virus infection was described as a cause of fever in Indonesia. [ 102 ]  Before 2007, there were only 13 reported natural infections with Zika virus, all with a mild, self-limited febrile illness. [ 33 ] [ 103 ]  As of July 2019, evidence of local transmission from mosquitoes to humans has been reported in a total of 87 countries from four of six  WHO Regions ; African, Americas, South-East Asia and Western Pacific. [ 104 ]


The first major outbreak, with 185 confirmed cases,  was reported in 2007  in the  Yap  Islands of the Federated States of Micronesia. [ 105 ]  A total of 108 cases were confirmed by PCR or serology and 72 additional cases were suspected. The most common symptoms were rash, fever, arthralgia, and conjunctivitis, and no deaths were reported. The mosquito  Aedes hensilli , which was the predominant species identified in Yap during the outbreak, was probably the main vector of transmission. While the way of introduction of the virus on Yap Island remains uncertain, it is likely to have happened through introduction of infected mosquitoes or a human infected with a strain related to those in Southeast Asia. [ 47 ] [ 105 ]  This was also the first time Zika fever had been reported outside Africa and Asia. [ 3 ]  Before the Yap Island outbreak, only 14 human cases had ever been reported. [ 106 ]


In 2013–2014, several outbreaks of Zika were reported in  French Polynesia ,  New Caledonia ,  Easter Island  and the  Cook Islands . The source of the virus was thought to be an independent introduction of the virus from  Southeast Asia , unrelated to the Yap Islands outbreak. [ 47 ]


Genetic analyses of Zika virus strains suggest that Zika first entered the Americas between May and December 2013. [ 107 ]  It was first detected in the  Western Hemisphere  in February 2014, and rapidly spread throughout  South  and Central America, reaching Mexico in November 2015. [ 19 ] [ 47 ] [ 108 ]  In 2016 it established local transmission in Florida and Texas. [ 109 ] [ 110 ]  The first death in the United States due to Zika occurred in February 2016. [ 111 ]


In May 2015, Brazil officially reported its first 16 cases of the illness. [ 112 ]  Although, a case of illness was reported in March 2015 in a returning traveller. [ 113 ]  According to the Brazilian Health Ministry, as of November 2015 there was no official count of the number of people infected with the virus in Brazil, since the disease is not subject to compulsory notification. Even so, cases were reported in 14 states of the country. Mosquito-borne Zika virus is suspected to be the cause of 2,400 possible cases of microcephaly and 29 infant deaths in Brazil in 2015 (of the 2400 or so notified cases in 2015, 2165 were under investigation in December 2015, 134 were confirmed and 102 were ruled out for microcephaly). [ 114 ]


The Brazilian Health Ministry has reported at least 2,400 suspected cases of microcephaly in the country in 2015 as of 12 December, and 29 fatalities. [ 114 ] [ 115 ] [ 116 ] [ 117 ]  Before the Zika outbreak, only an average of 150 to 200 cases per year were reported in Brazil. [ 118 ]  In the state of  Pernambuco  the reported rates of microcephaly in 2015 are 77 times higher than in the previous 5 years. [ 118 ]  A model using data from a Zika outbreak in French Polynesia estimated the risk of microcephaly in children born to mothers who acquired Zika virus in the first trimester to be 1%. [ 119 ]


On 24 January 2016, the WHO warned that the virus is likely to spread to nearly all countries of the Americas, since its vector, the mosquito  Aedes aegypti , is found in all countries in the region, except for  Canada  and  continental   Chile . [ 120 ] [ 121 ]  The mosquito and dengue fever have been detected in Chile's Easter Island, some 3,500 km (2,200 mi) away from its closest point in mainland Chile, since 2002. [ 122 ]


In February 2016, WHO declared the outbreak a  Public Health Emergency of International Concern  as evidence grew that Zika is a cause of birth defects and neurological problems. [ 19 ] [ 123 ] [ 124 ] [ 125 ]  In April 2016, WHO stated there is a scientific consensus, based on preliminary evidence, that Zika is a cause of  microcephaly  in infants and  Guillain–Barré syndrome  in adults. [ 10 ]  Studies of this and prior outbreaks have found Zika infection during pregnancy to be associated with early pregnancy loss and other pregnancy problems. [ 126 ] [ 127 ]  In the Americas the number of cases peaked during the first half of 2016 and declined through 2017–2018, with a total of 31,587 suspected, probable, and confirmed cases of ZIKV disease were reported in the Region of the Americas. Of these, 3,473 (11%) were laboratory confirmed. In general, transmission persists at low levels in some areas and is not uniformly distributed within countries. [ 104 ]


In 2016 imported or locally transmitted Zika was reported in all the countries of Asia except Brunei, Hong Kong, Myanmar and Nepal. [ 128 ]   Serological surveys  have indicated that Zika virus is  endemic  in most areas of Asia, though at a low level. [ 128 ]  While there was a sharp rise in the number of cases of Zika detected in Singapore after the  2016 Summer Olympics  in Brazil, genetic analysis revealed that the strains were more closely related to strains from Thailand than from those causing the epidemic in the Americas. [ 129 ] [ 130 ] [ 131 ]


It is named after the  Zika Forest  near  Entebbe ,  Uganda , where the Zika virus was first identified. [ 132 ]


Zika virus was first identified in the late 1940s in Kampala, Uganda, Africa but was first confirmed in Brazil. Since it was first identified, Zika has been found in more than 27 countries and territories. [ 133 ]  Following the initial Zika outbreak in Northeastern Brazil in May 2015, physicians observed a very large surge of reports of infants born with  microcephaly , with 20 times the number of expected cases. [ 134 ] [ 135 ]  Many of these cases have since been confirmed, leading WHO officials to project that approximately 2,500 infants will be found to have born in Brazil with Zika-related microcephaly. [ 136 ] [ 137 ]


Proving that Zika causes these effects was difficult and complex for several reasons. [ 138 ] [ 139 ]  For example, the effects on an infant might not be seen until months after the mother's initial infection, long after the time when Zika is easily detected in the body. [ 138 ]  In addition, research was needed to determine the mechanism by which Zika produced these effects. [ 140 ]


Since the initial outbreak, studies that use several different methods found evidence of a link, leading public health officials to conclude that it appears increasingly likely the virus is linked to microcephaly and miscarriage. [ 140 ] [ 141 ]  On 1 February 2016, the  World Health Organization  declared recently reported clusters of microcephaly and other neurological disorders a  Public Health Emergency of International Concern  (PHEIC). [ 142 ]  On 8 March 2016, the WHO Committee reconfirmed that the association between Zika and neurological disorders is of global concern. [ 140 ]


The Zika virus was first linked with newborn microcephaly during the Brazil Zika virus outbreak. In 2015, there were 2,782 suspected cases of microcephaly compared with 147 in 2014 and 167 in 2013. [ 134 ]  Confirmation of many of the recent cases is pending, [ 143 ]  and it is difficult to estimate how many cases went unreported before the recent awareness of the risk of virus infections. [ 144 ]


In November 2015, the Zika virus was isolated in a newborn baby from the northeastern  state  of  Ceará , Brazil, with microcephaly and other  congenital disorders .  The Lancet  medical journal reported in January 2016 that the  Brazilian Ministry of Health  had confirmed 134 cases of microcephaly "believed to be associated with Zika virus infection" with an additional 2,165 cases in 549  counties  in 20 states remaining under investigation. [ 19 ] [ 145 ]  An analysis of 574 cases of microcephaly in Brazil during 2015 and the first week of 2016, reported in March 2016, found an association with maternal illness involving rash and fever during the first trimester of pregnancy. [ 146 ]  During this period, 12 Brazilian states reported increases of at least 3  standard deviations  (SDs) in cases of microcephaly compared with 2000–14, with the northeastern states of Bahia,  Paraíba  and  Pernambuco  reporting increases of more than 20 SDs. [ 146 ]


In January 2016, a baby in  Oahu , Hawaii, was born with microcephaly, the first case in the United States of brain damage linked to the virus. The baby and mother tested positive for a past Zika virus infection. The mother, who had probably acquired the virus while traveling in Brazil in May 2015 during the early stages of her pregnancy, had reported her bout of Zika. She recovered before relocating to Hawaii. Her pregnancy had progressed normally, and the baby's condition was not known until birth. [ 147 ]


In February 2016, ocular disorders in newborns have been linked to Zika virus infection. [ 148 ]  In one study in Pernambuco state in Brazil, about 40 percent of babies with Zika-related microcephaly also had  scarring of the retina with spots, or pigment alteration . [ 149 ]  On 20 February 2016, Brazilian scientists announced that they had successfully sequenced the Zika virus genome and expressed hope that this would help in both developing a vaccine and in determining the nature of any link to birth defects. [ 150 ]


Also in February 2016,  rumors  that microcephaly is caused by the use of the larvicide  pyriproxyfen  in  drinking water  were refuted by scientists. [ 151 ] [ 152 ] [ 153 ]  "It's important to state that some localities that do not use pyriproxyfen also had reported cases of microcephaly", read a Brazilian government statement. [ 154 ]  The Brazilian government also refuted  conspiracy theories  that chickenpox and rubella vaccinations or genetically modified mosquitoes were causing increases in microcephaly. [ 153 ]


Researchers also suspected that Zika virus could be transmitted by a pregnant woman to her baby (" vertical transmission "). This remained unproven until February 2016, when a paper by Calvet et al. was published, showing not only was the Zika virus genome found in the amniotic fluid but also IgM antibodies against the virus. [ 155 ]  This means that not only can the virus cross the placental barrier, but also the antibodies produced by the mother can reach the fetus, which suggests that vertical transmission is plausible in these cases. One other study published in March 2016 by Mlakar and colleagues analyzed autopsy tissues from a fetus with microcephaly that was probably related to Zika virus; researchers found ZIKV in the brain tissue and suggested that the brain injuries were probably associated with the virus, which also shed a light on the vertical transmission theory. [ 156 ]  Also in March 2016, first solid evidence was reported on how the virus affects the development of the brain, indicating that it appears to preferentially kill developing brain cells. [ 157 ]


The first cases of birth defects linked to Zika in Colombia [ 158 ]  and in Panama were reported in March 2016. [ 159 ]  In the same month, researchers published a prospective cohort study that found profound impacts in 29 percent of infants of mothers infected with Zika, some of whom were infected late in pregnancy. [ 25 ]  This study did not suffer from some of the difficulties of studying Zika: the study followed women who presented to a Rio de Janeiro clinic with fever and rash within the last five days. The women were then tested for Zika using PCR, then the progress of the pregnancies were followed using ultrasound. [ 25 ] [ 160 ]


A high rate of the autoimmune disease  Guillain–Barré syndrome  (GBS), noted in the French Polynesia outbreak, has also been found in the outbreak that began in Brazil. [ 145 ]  Laboratory analysis found Zika infections in some patients with GBS in Brazil, El Salvador, Suriname and Venezuela, [ 161 ]  and the WHO declared on 22 March 2016 that Zika appeared to be "implicated" in GBS infection and that if the pattern was confirmed it would represent a global public health crisis. [ 162 ]


Early in the  2015–16 Zika virus epidemic , research was begun to better understand how Zika virus causes microcephaly and other neurological disorders. [ 163 ]   However, with the 2019 election of  Jair Bolsonaro  in Brazil, who cut funding for research, and the emergence of the  COVID-19 pandemic  in early 2020, most Zika-related research projects were abandoned or reduced. [ 164 ]


It may involve infection of the primary neural  stem cells  of the fetal brain, known as neural progenitor cells. [ 165 ] [ 29 ]  The main roles of brain stem cells are to proliferate until the correct number is achieved, and then to produce  neurons  through the process of  neurogenesis . [ 166 ]   Zika proteins NS4A and NS4B have also been shown to directly suppress neurogenesis. [ 29 ]  Infection of brain stem cells can cause cell death, which reduces the production of future neurons and leads to a smaller brain. [ 165 ]  Zika also appears to have an equal  tropism  for cells of the developing eye, leading to high rates of eye abnormalities as well. [ 29 ]


In addition to inducing cell death, infection of neural progenitor cells may alter the process of cell proliferation, causing a depletion in the pool of progenitor cells. [ 167 ]  A large number of cases of  microcephaly  have been associated with inherited gene mutations, and specifically with mutations that lead to dysfunction of the  mitotic spindle . There is some evidence that Zika virus may directly or indirectly interfere with  mitotic  function, this may play a role in altering cell proliferation. [ 168 ]


Another line of research considers that Zika, unlike other flaviviruses, may target developing brain cells after it crosses the placenta, and considers the resulting damage likely to be the result of  inflammation  as a byproduct of the  immune response  to the infection of those cells. [ 169 ]


Some experimental methods of prevention include breeding and releasing mosquitoes that have been genetically modified to prevent them from transmitting pathogens, or have been infected with the  Wolbachia  bacterium, believed to inhibit the spread of viruses. [ 19 ] [ 170 ]  A  strain of  Wolbachia  helped to reduce the vector competence of the Zika virus in infected  Aedes aegypti  released in Medellin, Colombia. [ 171 ]


Gene drive  is a technique for changing wild populations, for instance to combat insects so they cannot transmit diseases (in particular mosquitoes in the cases of malaria and Zika). [ 172 ]  Another method which been researched aims to  render male mosquitoes infertile  by nuclear radiation in the hope to reduce populations; this is done with a  cobalt-60  gamma cell irradiator. [ 173 ]  In 2016 the  World Health Organization  encouraged field trials of transgenic male  Aedes aegypti  mosquitoes developed by  Oxitec  to try to halt the spread of the Zika virus. [ 174 ]


Caudal duplication , (or caudal duplication syndrome) is a rare  congenital disorder  in which various structures of the caudal region,  embryonic cloaca , and  neural tube  exhibit a spectrum of abnormalities such as duplication and malformations. [ 2 ]  The exact causes of the condition is unknown, [ 2 ]  though there are several theories implicating abnormal embryological development as a cause for the condition. [ 3 ]  Diagnosis is often made during prenatal development of the second trimester through anomaly scans or immediately after birth. [ 4 ]  However, rare cases of adulthood diagnosis has also been observed. Treatment is often required to correct such abnormalities according to the range of symptoms present, [ 4 ]  whilst treatment options vary from conservative expectant management to resection of caudal tissue to restore normal function or appearance. [ 5 ]  As a rare congenital disorder, the prevalence at birth is less than 1 per 100,000  [ 3 ]  with less than 100 cases reported worldwide. [ 6 ]


The term "caudal duplication syndrome" has been coined since 1993 [ 2 ]  to describe caudal abnormalities and conditions. However, there has been recent debate into the appropriateness of the term being "caudal split syndrome" instead of caudal duplication due to the "splitting" nature of the abnormalities, rather than "duplication". [ 5 ]


The condition’s symptoms vary greatly due to the diverse spectrum of gastrointestinal (GI), urogenital (genitourinary, GU), spinal, and limb anomalies possible. [ 7 ]  Common forms include anorectal malformation and duplication of the external genitalia, [ 7 ]  while less common forms may include incomplete duplication of the lower spine and spinal cord, ( diastematomyelia )  [ 8 ]  and partial fusion to complete duplication of the uterus, vagina, colon, and bladder. [ 9 ]


Malformations of the spine are indicated to cause varying levels of neurological impairment. [ 8 ]  Although the level of neurological impairment is dependent upon the severity and type of spinal abnormality, most reported cases of spinal cord duplication exhibit severe neurological impairment, [ 8 ]  though cases of mild or absent neurological impairment has also been observed. [ 8 ]


Though patients often present a diverse variety of symptoms, a case was observed in which a female adult with duplication of the colon, rectum, anus, urinary bladder, urethra, uterus, cervix, vagina, and external genitalia exhibited no detrimental effects. [ 4 ]  This suggests that rarely seen cases of complete duplication of the urogenital and gastrointestinal tract are often  asymptomatic . [ 10 ]


As patients often present a multitude of differing symptoms within the caudal region, each patient exhibits a unique, characterised symptom which may or may not be cosmetically or physiologically detrimental to the individual. [ 2 ]


The exact cause of the condition is unknown. [ 2 ]  Although various theories indicate incomplete separation of monozygotic twins as an etiological factor, [ 3 ]  abnormal adherence between the  ectoderm  and  endoderm  during  gastrulation , [ 7 ]  polytopic primary developmental field defects, [ 11 ]   somatic  and  germ line mutations  in  developmental genes , [ 3 ]  and damage to the caudal cell mass and posterior gut have also been linked to cause structural anomalies in the caudal region. [ 7 ]


It is speculated that the condition is related to the  HOX gene , [ 3 ]  namely HOX10 and HOX11. Normally coding for the mammalian appendicular and axial skeleton, misexpression of the genetic factors could lead to abnormal proliferation of the caudal  mesenchyme . [ 3 ]


Embryology is suggested to have an intimate association with the development of caudal duplication syndrome. [ 2 ]  At day 15 after fertilisation, the  notochord  grows from the  primitive knot , in which it invaginates and forms the notochord canal within. [ 2 ]  Progressively, on day 20, the ventral wall of the notochord dissolves, while communications are formed between the amniotic and yolk sac. [ 2 ]  One such connection is the Kovalevsky’s canal. From the 23rd to 25th day of gestation, the spinal cord develops except for its distal-most aspect where the notochord and neural tube are joined to form the caudal cell mass. [ 2 ]  The canal of Kovalevsky crosses the caudal cell mass, while endoderm located anteriorly to the cell mass develops into the  hindgut , various insults towards the cell mass and hindgut during the stage of development may lead to the development of caudal anomalies, one of which is caudal duplication syndrome. [ 2 ]


The incomplete regression of Kovalevsky’s canal may also lead to formations of fibrous bands joining the hindgut to the  spinal canal , [ 5 ]  possibly leading to the onset of diastemetaomyelia. [ 4 ]  These bands may divide the notochord, developing into duplications of the lower spine and spinal cord, the adjacent mesoderm is also divided, resulting in duplicates of GI and GU tracts. [ 4 ]  Subsequently, the duplications can also lead to the presence of a range of anomalies including  dorsal enteric fistulas , enteric cysts,  spina bifida , malformed or duplicated colon, bladder, sacrum, and lower spinal cord. [ 2 ] [ 12 ]


Moreover, a midline pelvic mass defect during gestation could be an obstacle to caudal migration of paramesonephric structures ( Müllerian duct ), which could lead to duplication of the genital tract. [ 2 ]  Whilst failures of migration or fusion of those structures is one of the more prevalent embryological theories for duplication of lower genitourinary organs such as the bladder. [ 2 ]  Intestinal duplications extending into the rectum or anus is often rare. [ 2 ] [ 6 ]  However, if the caudal cell mass is divided early, duplications of the distal bowel may still occur. [ 2 ]


In gastrointestinal abnormalities, a mechanism known as “caudal twinning” [ 3 ]   is proposed in which during the 23rd to 25th day of gestation, the intestinal tract is filled by rapid proliferation of endothelial cells, as the gut increases in size, vacuoles appear within the cell masses to constitute a single lumen. [ 2 ] [ 4 ]  However, in abnormal cases where a vacuole is pinched off, a second lumen is created. [ 4 ]  The second lumen is then proposed to magnify in size in proportion to the growth of the colon, effectively duplicating all caudal structures distal from the point of separation. [ 2 ] [ 10 ]


The condition can often be seen as malformations that can be diagnosed by a prenatal anomaly scan in the second trimester, while progressively detailed examinations can be conducted after the first day of life of the baby. [ 3 ]  If an abnormality is detected early on, psychological and surgical preparation may be required to resort to a  cesarean section  to prevent obstructed labour, in which medical paediatric and surgical care soon follows after delivery. [ 13 ] [ 14 ] [ 15 ]


Diagnosis during adulthood is extremely rare [ 2 ]  in cases where abnormalities are  asymptomatic  or are not visible upon physical inspection upon prenatal or birth inspections. [ 6 ]  Similarly to paediatric and prenatal diagnosis, an adulthood diagnosis can be made through various imaging modalities [ 4 ]  such as computed tomography (CT) scans to explicitly define the range of symptoms present in caudal duplication. [ 13 ]


Dipygus deformity is a severe and extreme type of caudal duplication that occurs at the caudal end of the body axis, where it duplicates completely. [ 16 ]


The rare, complex syndrome includes a wide spectrum of malformations ranging from partial or isolated to complete duplication of caudal organs in GI, GU, and neural systems. [ 13 ]  The syndrome may cause functional impairments such as an  imperforate anus  and hernia which may lead to death due to shock and organ failure and require prompt surgical intervention, [ 17 ]  but most presented symptoms are not life-threatening and duplicated organs are in fact functional in many cases. [ 2 ] [ 6 ]  For instance, patients with genital duplication are mostly expected to have normal menstruation, sexual intercourse, and even pregnancy, [ 18 ]  although their self-esteem and quality of life may be influenced. [ 5 ]  Since the clinical presentation of each patient and its complexity vary greatly, the management which usually includes surgery are carefully planned and individualised based on the extent of duplication and functionality of the involved organs. [ 4 ]


An extensive medical work-up is required primarily before prognosis to understand the anatomy of patients and to decide appropriate treatment. Imaging modalities such as  echocardiography ,  conventional X-ray ,  magnetic resonance imaging  (MRI),  ultrasonography ,  barium enema ,  computed tomography  (CT) scan, and  voiding cystourethrography  (VCU) can be used to examine anomalies in detail. [ 3 ] [ 4 ] [ 13 ]   Exploratory laparotomy  can also be conducted when needed. [ 7 ]  In most cases, surgical approach is utilised to excise or fuse the duplicated organs; [ 3 ] [ 7 ] [ 19 ]  however, surgical intervention is not a compulsory procedure for patients that do not exhibit functional deterioration and symptoms. [ 4 ]  Based on the work-up results, a multidisciplinary team consisting of a (paediatric) surgeon, a urologist, and a neurosurgeon plans individualised, staged correction. [ 20 ]


If a prenatal or after birth diagnosis is made, medical paediatric and surgery care are organised soon after delivery. [ 15 ]  Adults with the syndrome, however, usually do not require surgical treatment unless accompanied by symptoms or psychological issues. [ 4 ] [ 6 ]  Reconstructive surgeries are performed to resolve the issue of functional impairments such as obstruction of colon, anatomic anomalies that hinder movement or cause infertility, and to improve cosmetic appearances in the case of genital duplication. [ 4 ]


Treatments for colonic duplication varies from conservative management for asymptomatic cases to excision of duplicated colon to avoid potential issues such as colon structure and obstruction. [ 4 ] [ 7 ]  Resection is possible when each duplicated colon has a complete blood supply. If the duplicated colons share a wall, a septotomy can be performed to create a small hole to connect two colons. [ 4 ] [ 7 ]  In cases where rectum is also duplicated, either the rectums should be converted into one reservoir through septotomy followed by anorectoplasty or the duplicated colon and rectum should be removed and colostomies should be constructed. [ 4 ]  For patients with poor prognosis for bowel control, a  Malone procedure  can be utilised during the colostomy. [ 4 ]  Alternatively, in cases of renal duplication, the  Mitrofanoff procedure  is performed instead. [ 4 ]


Duplication of genital tract that does not involve functional impairment does not require surgical intervention; however, plastic surgery can be carried out to improve patients’ self-esteem and social status. [ 19 ]  For duplication of female genital tract, the septum between duplicated organs such as vagina, cervix, and vulva are resected to combine two duplicated organs into one or one duplicated organ could be detached and excised. [ 19 ]  For male patients, one duplicated genitalia can be removed, and duplicated scrotum and testis can be either combined or excised. [ 15 ]  The external genitalia of both male and female can be reconstructed by midline apposition of tissues. [ 19 ]  For duplication of urinary tract, bladders can be combined to form a single larger bladder without altering the duplicated ureters. [ 19 ]


In cases of spine duplication,  prophylactic  surgery can be done to remove one duplicated spine, although it depends on the severity of duplication. [ 21 ]  In cases of malformation of the neural cord such as  myelomeningocele  and tethered cord which accompanies severe symptoms, preserving neurological function is the utmost importance by closing myelomeningocele and detethering the neural cord. [ 4 ]  This is a highly complex procedure that requires extreme caution not to injure the rectum in which case can cause a cerebrospinal fluid infection. [ 4 ]  For duplication of lower limb which not only hinders patients’ gait but also is highly visible and may affect patients’ self-esteem, excision of the supernumerary, non-functional pair of limb is often carried out. [ 15 ]


Due to the spectrum of symptoms present within caudal duplication, there is no uniform surgical treatment in relieving symptoms. [ 20 ]  The type and severity of surgical intervention is often dependent upon the type and complexity of symptoms presented. [ 20 ]  Thus, the primary goal of surgical treatment for the syndrome is to relieve symptoms, not to restore normal anatomy, and hence, potentially life-threatening malformations are addressed first and often followed by other anatomic or aesthetic reconstructions in later stages. [ 4 ] [ 6 ]  After the medical treatment, the patients are periodically monitored. [ 19 ] [ 15 ]


Caudal duplication syndrome is a rare condition with only less than 100 patients in literature worldwide as of 2014 with only 2 patients diagnosed in adulthood. [ 6 ]  The prevalence of the syndrome is less than one per 100,000 births. [ 5 ]  The sex ratio of male to female patients is about 1:2, with no familial or racial predisposition being found. [ 20 ]


The first systematic review for caudal duplication symptoms was done and the term "caudal duplication syndrome" was first proposed in 1993. [ 2 ]  The term was coined to describe rare anomalies associated with complete or partial duplication of caudal structures resulted from insults during embryogenesis to distinguish symptoms of spinal duplication syndrome which only involves spinal duplicity, only when there is associated complete or partial duplicity of vascular structures and/or organs such as bladder and distal gastrointestinal tract the term caudal duplication syndrome can be used. [ 12 ]


However, recently in 2013, it was suggested that “duplication” is a misnomer based on an analysis of two cases and literature review in which researchers found “hemi” organs was “split” not duplicated, proposing caudal “split” syndrome may be a more appropriate title. [ 5 ]


The  cloacal membrane  is the membrane that covers the  embryonic cloaca  during the  development of the urinary and reproductive organs .


It is formed by  ectoderm  and  endoderm  coming into contact with each other. [ 1 ]  As the human embryo grows and  caudal folding  continues, the  urorectal septum  divides the cloaca into a ventral  urogenital sinus  and dorsal  anorectal canal . Before the urorectal septum has an opportunity to fuse with the cloacal membrane, the membrane ruptures, exposing the urogenital sinus and dorsal anorectal canal to the exterior. Later on, an ectodermal plug, the  anal membrane , forms to create the lower third of the rectum. It ruptures in the seventh week of gestation.


This article incorporates text in the  public domain  from  page 47  of the 20th edition of   Gray's Anatomy   (1918)


This  developmental biology  article is a  stub . You can help Wikipedia by  expanding it .


The  development of the gonads  is part of the  prenatal   development of the reproductive system  and ultimately forms the  testicles  in males and the  ovaries  in females. The  immature ova  originate from cells from the dorsal  endoderm  of the  yolk sac . Once they have reached the  gonadal ridge  they are called  oogonia . Development proceeds and the oogonia become fully surrounded by a layer of  connective tissue  cells (pre-granulosa cells). In this way, the rudiments of the  ovarian follicles  are formed.


In the testicle, a  network  of tubules fuse to create the  seminiferous tubules . Via the  rete testis , the seminiferous tubules become connected with outgrowths from the  mesonephros , which form the  efferent ducts  of the testicle. The descent of the testicles consists of the opening of a connection from the testis to its final location at the anterior abdominal wall, followed by the development of the  gubernaculum , which subsequently pulls and translocates the testicle down into the developing  scrotum . Ultimately, the passageway closes behind the testicle. A failure in this process causes an  indirect inguinal hernia .


Germ cells  migrate from near the  allantois  and colonize the primordial gonads. In the female, the germ cells colonise the cortex and become oogonia. In the male, the germ cells colonise the seminiferous cords of the medulla, becoming  spermatogonia .


The first appearance of the  gonad  is essentially the same in the two sexes, and consists in a thickening of the  mesothelial  layer of the  peritoneum . The thick plate of epithelium extends deeply, pushing before it the mesoderm and forming a distinct projection. This is termed the  gonadal ridge . The gonadal ridge, in turn, develops into a gonad. This is a  testis  in the male and an  ovary  in the female.


At first, the  mesonephros  and gonadal ridge are continuous, but as the embryo grows the gonadal ridge gradually becomes pinched off from the mesonephros. However, some cells of mesonephric origin join the gonadal ridge. Furthermore, the gonadal ridge still remains connected to the remnant of that body by a fold of peritoneum, namely the  mesorchium  or  mesovarium . About the seventh week the distinction of sex in the gonadal ridge begins to be perceptible.


The  ovary  is thus formed mainly from the genital ridge and partly from the mesonephros. Later the mass is differentiated into a central part, the  medulla of ovary , covered by a surface layer, the  germinal epithelium . Between the cells of the germinal epithelium a number of larger cells, the  immature ova , are found. The immature ova, in turn, are carried into the  stroma  beneath by bud-like ingrowths ( genital cords of the germinal epithelium ). The surface germinal epithelium ultimately forms the permanent epithelial covering of this organ. Furthermore, it soon loses its connection with the central mass. Instead, the  tunica albuginea of the ovaries  develops between them.


During early embryonic development, cells from the dorsal  endoderm  of the  yolk sac  migrate along the hindgut to the gonadal ridge. These  primordial germ cells  (PGCs) multiply by mitosis and once they have reached the gonadal ridge they are called  oogonia  (diploid stem cells of the ovary).


Once oogonia enter this area they attempt to associate with the other somatic cells, derived from both the peritoneum and mesonephros. Development proceeds and the oogonia become fully surrounded by a layer of connective tissue cells (pre- granulosa cells ) in an irregular manner. In this way, the rudiments of the  ovarian follicles  are formed.


During oogenesis, the oogonia become primary oocytes.   Oocytes  (immature ova) residing in the  primordial follicle  of the ovary are in a non-growing  prophase  arrested state, but have the capacity to undergo highly efficient  homologous recombinational  repair of  DNA damages  including double-strand breaks. [ 1 ]   This ability to repair DNA damage allows  genome  integrity to be maintained and offspring health to be protected. [ 1 ]


The embryological origin of  granulosa cells  remains controversial. In the 1970s, evidence emerged that the first cells to make contact with the oogonia were of mesonephric origin. It was suggested that mesonephric cells already closely associated with the oogonia proliferated throughout development to form the granulosa cell layer. [ 2 ] [ 3 ] [ 4 ]


Recently this hypothesis has been challenged with some thorough histology. Sawyer et al. hypothesized that in sheep most of the granulosa cells develop from cells of the  mesothelium  (i.e., epithelial cells from the presumptive surface epithelium of the ovary). [ 5 ]


Just as in the male, there is a  gubernaculum  in the female, which effects a considerable change in the position of the ovary. The gubernaculum in the female lies in contact with the  fundus of the uterus  and adheres to this organ, and thus the ovary can only descend as far as to this level. The part of the gubernaculum between the ovary and the uterus ultimately becomes the proper  ovarian ligament , while the part between the uterus and the labium majus forms the  round ligament of the uterus . A pouch of peritoneum analogous to the  vaginal process  in the male accompanies it along the inguinal canal: it is called the  canal of Nuck .


In rare cases, the gubernaculum may fail to contract adhesions to the uterus, and then the ovary descends through the inguinal canal into the  labium majus ; under these circumstances, its position resembles that of the testis.


The  testicle  is developed in much the same way as the ovary, originating from mesothelium as well as mesonephros. Like the ovary, in its earliest stages it consists of a central mass covered by a surface epithelium. In the central mass a series of cords appear, and the periphery of the mass is converted into the  tunica albuginea , thus excluding the surface epithelium from any part in the formation of the tissue of the testis. The cords of the central mass run together toward the future  hilum  and form a network which ultimately becomes the  rete testis . On the other hand, the  seminiferous tubules  are developed from the cords distal to the hilum, and between them connective-tissue septa extend. Via the rete testis, the seminiferous tubules become connected with outgrowths from the mesonephros, which form the efferent ducts of the testicle.


The descent of the testicles consists of the opening of a connection from the testis to its final location at the anterior abdominal wall, followed by the development of the gubernaculum, which subsequently pulls and translocates the testicle down into the developing scrotum. Ultimately, the passageway closes behind the testis. Such descent is ancestral in  placental mammals  with a derived condition of non-descent with testes remaining near the kidneys occurring in  Afrotheria  such as  elephants . [ 6 ]


At an early period of fetal life the testicles are placed at the back part of abdominal cavity, behind the peritoneum, and each is attached by a peritoneal fold, the  mesorchium , to the mesonephros. From the front of the mesonephros a fold of peritoneum termed the inguinal fold grows forward to meet and fuse with a peritoneal fold, the  inguinal crest , which grows backward from the antero-lateral abdominal wall. The testis thus acquires an indirect connection with the anterior abdominal wall. At the same time, a portion of the peritoneal cavity lateral to these fused folds is marked off as the future  vaginal process .


Also, in the inguinal crest a structure, the  gubernaculum testis , makes its appearance. This is at first a slender band, extending from that part of the skin of the  groin  which afterward forms the  scrotum  through the  inguinal canal  to the body and epididymis of the testicle. As  and contains the upper part of the gubernaculum, and ultimately also the internal spermatic vessels; the one below, the  plica gubernatrix , contains the lower part of the gubernaculum.


The gubernaculum grows into a thick cord. It ends below at the abdominal inguinal ring in a tube of peritoneum, the vaginal process, which protrudes itself down the inguinal canal. By the fifth month the lower part of the gubernaculum still is a thick cord, while the upper part has disappeared. The lower part now consists of a central core of  smooth muscle fibers , surrounded by a firm layer of  striated muscle  elements, connected, behind the peritoneum, with the abdominal wall.


As the testicles develop, the main portion of the lower end of the gubernaculum is carried, following the skin to which it is attached, to the bottom of this pouch. Other bands are carried to the medial side of the thigh and to the perineum. The tube of peritoneum constituting the vaginal process projects itself downward into the inguinal canal, and emerges at the  external inguinal ring , pushing before it a part of the  obliquus internus  and the  aponeurosis  of the  obliquus externus , which form respectively the  cremaster muscle  and the  external spermatic fascia . The vaginal process forms a gradually elongating pouch, which eventually reaches the bottom of the scrotum, and behind this pouch, the testicle is drawn by the growth of the body of the fetus, for the gubernaculum does not grow proportionately with the growth of other parts, and therefore the testicle, being attached by the gubernaculum to the bottom of the scrotum, is prevented from rising as the body grows, and is instead drawn first into the inguinal canal and eventually into the scrotum. It seems certain also that the gubernacular cord becomes shortened as development proceeds, and this assists in causing the testis to reach the bottom of the scrotum.


By the end of the eighth month, the testicle has reached the scrotum, preceded by the vaginal process, which communicates by its upper extremity with the peritoneal cavity. Just before birth, the upper part of the vaginal process, at the internal inguinal ring, usually becomes closed, and this obliteration extends gradually downward to within a short distance of the testicle. The process of peritoneum surrounding the testis is now entirely cut off from the general peritoneal cavity and constitutes the tunica vaginalis.


Male  germ cells  produced in the testicles can carry out special  DNA repair  processes that act during meiosis to repair DNA damages and to maintain the integrity of the  genomes  that are to be transmitted to progeny. [ 7 ]   These DNA repair processes include  homologous recombinational  repair and  non-homologous end joining . [ 7 ]


If the internal inguinal ring does not close properly, then there is a risk that other contents of the abdominal cavity protrudes through the passageway and cause  indirect inguinal hernia .


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The  development of the reproductive system  is the part of  embryonic growth  that results in the  sex organs  and contributes to  sexual differentiation . Due to its large overlap with  development of the urinary system , the two systems are typically described together as the  genitourinary system .


The reproductive organs develop from the  intermediate mesoderm  and are preceded by more primitive structures that are superseded before birth. These embryonic structures are the  mesonephric ducts  (also known as  Wolffian ducts ) and the  paramesonephric ducts , (also known as  Müllerian ducts ). The mesonephric duct gives rise to the male  seminal vesicles ,  epididymides  and  vasa deferentia . The paramesonephric duct gives rise to the female  fallopian tubes ,  uterus ,  cervix , and upper part of the  vagina . [ 1 ]


The mesonephric duct originates from a part of the  pronephric duct .


In the outer part of the  intermediate mesoderm , immediately under the  ectoderm , in the region from the fifth  cervical segment  to the third  thoracic segment , a series of short  evaginations  from each segment grows  dorsally  and extends  caudally , fusing successively from before backward to form the  pronephric duct . This continues to grow caudally until it opens into the ventral part of the  cloaca ; beyond the  pronephros  it is termed the mesonephric duct. Thus, the mesonephric duct remains after the atrophy of the pronephros duct.


In the male, the duct persists, and forms the tube of the  epididymis , the  vas deferens  and the  ejaculatory duct , while the  seminal vesicle  arises during the third month as a lateral diverticulum from its hinder end. A large part of the head end of the mesonephros atrophies and disappears; of the remainder the anterior tubules form the efferent ducts of the  testicle ; while the  posterior  tubules are represented by the  ductuli aberrantes , and by the  paradidymis , which is sometimes found in front of the  spermatic cord  above the head of the epididymis.


In the female, the mesonephric bodies and ducts atrophy. The nonfunctional remains of the  mesonephric tubules  are represented by the  epoophoron , and the  paroöphoron , two small collections of  rudimentary  blind tubules which are situated in the  mesosalpinx .


The lower part of the mesonephric duct disappears, while the upper part persists as the longitudinal duct of the  epoöphoron , called  Gartner's duct .


There are also developments of other tissues from the mesonephric duct that persist, e.g. the  development of the suspensory ligament of the ovary .


Shortly after the formation of the mesonephric ducts, a second pair of ducts is developed; these are the  paramesonephric ducts . Each arises on the lateral aspect of the corresponding mesonephric duct as a tubular invagination of the cells lining the abdominal cavity. The orifice of the invagination remains open, and undergoes enlargement and modification to form the  distal tubal opening  (abdominal ostium) of the  fallopian tube . The ducts pass backward lateral to the mesonephric ducts, but toward the posterior end of the embryo they cross to the medial side of these ducts, and thus come to lie side by side between and behind the latter—the four ducts forming what is termed the  common genital cord [ citation needed ] , to distinguish it from the  genital cords of the germinal epithelium [ citation needed ]  seen later in this article. The mesonephric ducts end in an epithelial elevation, the  sinus tubercle , on the ventral part of the cloaca between the orifices of the mesonephric ducts. At a later stage the sinus tubercle  opens in the middle, connecting the paramesonephric ducts with the cloaca.


In the male, the paramesonephric ducts atrophy (but traces of their anterior ends are represented by the  appendix of testis  of the male), while their terminal fused portions form the  prostatic utricle  in the floor of the  prostatic urethra . This is due to the production of  anti-Müllerian hormone  by the  Sertoli cells  of the  testes .


In the female, the paramesonephric ducts persist and undergo further development. The portions which lie in the  genital cord [ citation needed ]  fuse to form the  uterus   and  vagina . This fusion of the paramesonephric ducts begins in the third month, and the septum formed by their fused medial walls disappears from below upward.


The parts outside this cord remain separate, and each forms the corresponding  fallopian tube . The  ostium of the fallopian tube  remains from the anterior extremity of the original tubular invagination from the abdominal cavity.


About the fifth month a ring-like constriction marks the position of the  cervix  of the uterus, and after the sixth month the walls of the uterus begin to thicken. For a time the vagina is represented by a solid rod of epithelial cells. A ring-like outgrowth of this epithelium occurs at the lower end of the uterus and marks the future  vaginal fornix . At about the fifth or sixth month the  lumen  of the vagina is produced by the breaking down of the central cells of the epithelium. The  hymen  represents the remains of the sinus tubercle . [ 2 ]


The gonads are the precursors of the  testicles  in males and  ovaries  in females. They initially develop from the mesothelial layer of the peritoneum.


The ovary is differentiated into a central part, the medulla of ovary, covered by a surface layer, the  germinal epithelium . The  immature ova  originate from cells from the dorsal  endoderm  of the  yolk sac . Once they have reached the gonadal ridge they are called  oogonia . Development proceeds and the oogonia become fully surrounded by a layer of connective tissue cells (pre-granulosa cells). In this way, the rudiments of the ovarian follicles are formed. The embryological origin of  granulosa cells , on the other hand, remains controversial. Just as in the male, there is a  gubernaculum  in the female, which pulls it downward, albeit not as much as in males. The gubernaculum later becomes the proper  ovarian ligament  and the  round ligament of the uterus .


The periphery of the testicles are converted into the  tunica albuginea . Cords of the central mass run together and form a network which becomes the  rete testis , and another network, which develops the  seminiferous tubules . Via the rete testis, the seminiferous tubules become connected with outgrowths from the mesonephros, which form the efferent ducts of the testicle.


In short, the descent of the testicles consists of the opening of a connection from the testicle to its final location at the anterior abdominal wall, followed by the development of the gubernaculum, which subsequently pulls and translocates the testicle down into the developing scrotum. Ultimately, the passageway closes behind the testicle. A failure in this process can cause  indirect inguinal hernia  or an infantile hydrocoele.


After the separation of the rectum from the dorsal part of the cloaca, the ventral part becomes the primary  urogenital sinus . [ 3 ]  The urogenital sinus, in turn, divides into the superficial definitive urogenital sinus and the deeper anterior vesico-urethral portion.


The definitive urogenital sinus consists of a caudal cephalic portion and an intermediate narrow channel, the pelvic portion.


The vesico-urethral portion is the deepest portion, continuous with the allantois. It absorbs the ends of the mesonephric ducts and the associated ends of the renal diverticula, and these give rise to the  trigone of urinary bladder  and part of the  prostatic urethra . The remainder of the vesico-urethral portion forms the body of the bladder and part of the prostatic urethra; its apex is prolonged to the umbilicus as a narrow canal, the  urachus , which later is obliterated and becomes the  median umbilical ligament  of the adult.


The  prostate  originally consists of two separate portions, each of which arises as a series of diverticular buds from the epithelial lining of the urogenital sinus and vesico-urethral part of the cloaca, between the third and fourth months. These buds become tubular, and form the glandular substance of the two lobes, which ultimately meet and fuse behind the urethra and also extend on to its ventral aspect. The median  lobe of the prostate  is formed as an extension of the lateral lobes between the common ejaculatory ducts and the bladder.


Skene's glands  in the female urethra are regarded as the homologues of the prostatic glands.


The  bulbourethral glands  in the male, and  Bartholin's gland  in the female, also arise as diverticula from the epithelial lining of the urogenital sinus.


Until about the ninth week of gestational age, [ 4 ]  the external genitalia of human males and females look the same, and follow a common development. This includes the development of a genital tubercle and a membrane dorsally to it, covering the developing  urogenital opening , and the development of the  labioscrotal fold .


In  placental mammals , the urogenital folds become the ventral aspect of the penis in the male and the  labia minora  ( primates  including humans)/ labia vulvae  (non-primates) in the female. [ 5 ] [ 6 ] [ 7 ]


Even after differentiation can be seen between the sexes, some stages are common, e.g. the disappearing of the membrane. On the other hand, sex-dependent development include further protrusion of the genital tubercle in the male to form the  glans  and  shaft  of the penis and in the female, the  glans  and  body  of the clitoris. [ 8 ] [ 9 ]  The labioscrotal swellings evolve into the  scrotum  in males, and into the  labia majora   (dissipated in non-primates) in females. [ 8 ] [ 10 ]


There is initially a  cloacal membrane , composed of ectoderm and endoderm, reaching from the  umbilical cord  to the tail, separating the cloaca from the exterior. After the separation of the rectum from the dorsal part of the cloaca, the ventral part of the cloacal membrane becomes the  urogenital membrane .


Mesoderm extends to the  midventral line  for some distance behind the umbilical cord, and forms the lower part of the abdominal wall; it ends below in a prominent swelling, the cloacal tubercle, which after the separation of the rectum becomes the  genital tubercle . Dorsally, to this tubercle the sides are not really fused. Rather, the urogenital part of the cloacal membrane separates the ingrowing sheets of mesoderm.


The genital tubercle develops into the  primordial phallus , the first rudiment of the  penis  or  clitoris . [ 8 ]


The terminal part of the phallus, representing the future glans becomes solid. The remainder of the phallus, which remains hollow, is converted into a longitudinal groove by the absorption of the urogenital membrane.


The term genital tubercle still remains but only refers to the future glans  [ 4 ]


In both sexes, the phallic portion of the  urogenital sinus  extends on to the under surface of the cloacal tubercle as far forward as the apex. At the apex, the walls of the phallic portion come together and fuse, obliterating the  urogenital opening . Instead, a solid plate, the urethral plate, is formed. The remainder of the phallic portion is for a time tubular, and then, by the absorption of the urogenital membrane, it establishes a communication with the exterior. This opening is for a while the primitive urogenital opening, and it extends forward to the corona glandis.


The following developments occur in both males and females, although a difference in the development between the sexes already can be seen:


In the female, a deep groove forms around the phallus. The sides of it grow dorsalward as the  labioscrotal folds , which ultimately form the labia majora in females. The labia minora, in contrast, arise by the continued growth of the lips of the groove on the under surface of the phallus; the remainder of the phallus forms the  clitoral glans . [ 8 ]


The labioscrotal folds extend around between the pelvic portion and the anus, and form a  scrotal  area. During the changes associated with the descent of the testes, this scrotal area is drawn out to form the scrotal sacs. The penis is developed from the phallus.


As in the female, the urogenital membrane undergoes absorption, forming a channel on the under surface of the phallus; this channel extends only as far forward as the  corona glandis .


Later, this opening, which is located on the dorsal side of the penis, [ 11 ]  closes from behind forward. Meanwhile, the urethral plate of the glans breaks down centrally to form a median groove continuous with the primitive ostium. This groove also closes from behind forward, leaving only a small pipe running in the middle of the penis. Thus, the urogenital opening is shifted forward to the end of the glans.


A.—Diagram of the primitive urogenital organs in the embryo previous to sexual distinction.


B.—Diagram of the female type of sexual organs.


C.—Diagram of the male type of sexual organs.


The  development of the urinary system  begins during  prenatal development , and relates to the development of the  urogenital system  – both the organs of the  urinary system  and the  sex organs  of the  reproductive system . The development continues as a part of  sexual differentiation .


The urinary and reproductive organs are developed from the  intermediate mesoderm . The permanent organs of the adult are preceded by a set of structures which are purely embryonic, and which with the exception of the ducts disappear almost entirely before birth. These embryonic structures are on either side; the  pronephros , the  mesonephros  and the  metanephros  of the  kidney , and the  Wolffian  and  Müllerian ducts  of the  sex organ . The pronephros disappears very early; the structural elements of the mesonephros mostly degenerate, but the  gonad  is developed in their place, with which the Wolffian duct remains as the duct in males, and the Müllerian as that of the female. Some of the tubules of the mesonephros form part of the permanent kidney.


In the outer part of the  intermediate mesoderm , immediately under the ectoderm, in the region from the fifth  cervical segment  to the third  thoracic segment , a series of short  evaginations  from each segment grows  dorsally  and extends  caudally , fusing successively from before backward to form the  pronephric duct . This continues to grow caudally until it opens into the ventral part of the  cloaca ; beyond the  pronephros  it is termed the  Wolffian duct . Thus, the Wolffian duct is what remains of the pronephric duct after the atrophy of the pronephros.


The original evaginations form a series of transverse tubules each of which communicates by means of a funnel-shaped ciliated opening with the  abdominal cavity , and in the course of each duct a glomerulus also is developed. A secondary glomerulus is formed ventral to each of these, and the complete group constitutes the pronephros. In humans, the pronephros is just rudimentary, and undergoes rapid atrophy and disappears.


On the medial side of the Wolffian duct, from the sixth cervical to the third lumbar segments, a series of tubules, the  Wolffian tubules , develops. They increase in number by outgrowths from the original tubules. They change from solid masses of cells to instead become hollowed in the center. One end grows toward and finally opens into the Wolffian duct, the other dilates and is invaginated by a tuft of capillary bloodvessels to form a glomerulus. The tubules collectively constitute the  mesonephros .


The mesonephros persists and form the permanent kidneys in fish and amphibians, but in reptiles, birds, and mammals, it atrophies and for the most part disappears rapidly as the permanent kidney ( metanephros ) develops beginning during the sixth or seventh week, so that by the beginning of the fifth month only the ducts and a few of the tubules of the mesonephros remain.


In the male, the  Wolffian duct  persists, and forms for example the  epididymis , the  ductus deferens , the  ejaculatory duct ,  seminal vesicle  and efferent ducts.


In the female, on the other hand, the Wolffian bodies and ducts atrophy, leaving behind only remnants in the adult, involving e.g. the  development of the suspensory ligament of the ovary .


Shortly after the formation of the Wolffian ducts, a second pair of ducts is developed; these are the  Müllerian ducts . Each arises on the lateral aspect of the corresponding Wolffian duct as a tubular invagination of the cells lining the abdominal cavity. The orifice of the invagination remains open, and undergoes enlargement and modification to form the abdominal  ostium of the fallopian tube . The ducts pass backward lateral to the Wolffian ducts, but toward the posterior end of the embryo they cross to the medial side of these ducts, and thus come to lie side by side between and behind the latter—the four ducts forming what is termed the  common genital cord , to distinguish it from the  genital cords of the germinal epithelium  seen later in this article. The Müllerian ducts end in an epithelial elevation, the  Müllerian eminence , on the ventral part of the cloaca between the orifices of the Wolffian ducts. At a later stage, the eminence opens in the middle, connecting the Müllerian ducts with the cloaca.


In the male, the Müllerian ducts atrophy, but traces of their anterior ends are represented by the  appendices testis  ( hydatids of Morgagni  of the male), while their terminal fused portions form the  utriculus  in the floor of the  prostatic urethra .


In the female, the Müllerian ducts persist and undergo further development. The portions which lie in the  genital cord  fuse to form the  uterus  and  vagina . This fusion of the Müllerian ducts begins in the third month, and the septum formed by their fused medial walls disappears from below upward.


Around the fifth month, a ring-like constriction marks the position of the  cervix  of the uterus, and after the sixth month, the walls of the uterus begin to thicken. For some time, the vagina is represented by a solid rod of epithelial cells. A ring-like outgrowth of this epithelium occurs at the lower end of the uterus and marks the future  vaginal fornix . At about the fifth or sixth month, the  lumen  of the vagina is produced by the breaking down of the central cells of the epithelium. The  hymen  represents the remains of the Müllerian eminence. [ 1 ]


The metanephros is the definite, permanent, but yet immature kidney. It arises from two directions. On one hand, the precursor of the ureter buds from the Wolffian duct, while on the other hand, the precursor of the renal tubules develop from the metanephrogenic blastema. The ureteric bud subsequently grows into the latter mass, forming the parts of the nephron. Other changes include e.g. the translocation of the ureteric opening directly into the cloaca.


The rudiments of the permanent  kidneys  make their appearance about the end of the first or the beginning of the second month. Each kidney originates as a  ureteric bud  from the caudal end of the Wolffian duct, which, in turn, originates from  intermediate mesoderm . The ureteric bud starts close to where the Wolffian duct opens into the cloaca, and grows dorsalward and  rostralward  along the posterior abdominal wall, where its blind extremity expands and subsequently divides into several buds, which form the rudiments of the  renal pelvis  and  renal calyces ; by continued growth and subdivision it gives rise to the  collecting duct system  of the kidney. The other, more superficial, portion of the diverticulum, on the other hand, becomes the ureter.


The  renal corpuscles  and  renal tubules , in contrast, are developed from the metanephrogenic blastema instead of from the ureteric bud. The metanephrogenic blastema is moulded over the growing end of the latter, and becomes a part of the metanephros in this way. The renal tubules of the metanephros, unlike those of the pronephros and mesonephros, do not open into the Wolffian duct. Instead, the tubules rapidly elongate to form the parts of the  nephron : the  proximal tubules , the  loops of Henle  and the  distal convoluted tubules . These last join and establish communications with the collecting duct system derived from the ultimate ramifications of the ureteric bud. In the other end, the renal tubules give rise to  Bowman's capsules  and  glomeruli .


The mesoderm around the tubules becomes condensed to form the connective tissue of the kidney. The ureter opens at first into the hind-end of the Wolffian duct; after the sixth week it separates from the Wolffian duct, and opens independently into the part of the cloaca which ultimately becomes the  urinary bladder . The renal tubules become arranged into  renal pyramids , and the lobulated condition of the kidneys exists for some time after birth, while traces of it may be found even in the adult. The kidney of the ox and many other animals, on the other hand, remains lobulated throughout life.


The  urinary bladder  is formed partly from the endodermal  cloaca  and partly from the ends of the Wolffian ducts. In other words, the  allantois  takes no share in its formation.


After the separation of the rectum from the dorsal part of the cloaca, the ventral part becomes the primary  urogenital sinus . [ 2 ]  The urogenital sinus, in turn, divides into the superficial definitive urogenital sinus and the deeper anterior vesico-urethral portion.


The definitive urogenital sinus consists of a caudal phallic portion and an intermediate narrow channel, the pelvic portion.


The vesico-urethral portion is the deepest, continuous with the allantois. It absorbs the ends of the Wolffian ducts and the associated ends of the renal diverticula, and these give rise to the  trigone of urinary bladder  and part of the  prostatic urethra . The remainder of the vesico-urethral portion forms the body of the bladder and part of the prostatic urethra; its apex is prolonged to the umbilicus as a narrow canal, the  urachus , which later is obliterated and becomes the  median umbilical ligament  of the adult.


Until about the ninth week of gestational age, [ 3 ]  the  sex organs  of males and females look the same, and follow a common development. This includes the development of a genital tubercle and a membrane dorsally to it, covering the developing  urogenital opening , and the development of labioscrotal folds.


Even after differentiation can be seen between the sexes, some stages are common, e.g. the disappearing of the membrane. On the other hand, sex-dependent development include further protrusion of the genital tubercle in the male to form the penis. Furthermore, the labioscrotal folds evolve into the scrotum in males, while they evolve into labia in females.


In  embryology , the  genital ridge  ( genital fold  or  gonadal ridge ) is the  developmental precursor  to the  gonads . The genital ridge initially consists mainly of  mesenchyme  and cells of underlying mesonephric origin. Once  oogonia   [ clarification needed ]  enter this area they attempt to associate with these somatic cells. Development proceeds and the oogonia become fully surrounded by a layer of cells (pre- granulosa cells ).


The genital ridge appears at approximately five weeks, and gives rise to the  sex cords .


Genes associated with the developing gonad can be categorized into those that form the sexually indifferent gonad, those that determine whether the indifferent gonad will differentiate as male or female, and those that promote differentiation into male or female parts.  Genes that form the sexually indifferent gonad are  SF1  and  WT1 . Genes that determine sex are  SRY ,  SOX9 , and  DAX1 .  Genes driving the differentiation into male or female structures are  SF1 ,  WT1 , and  WNT4 . The other genes have roles in development that are not exclusively sex-related.


Evidence suggests that a DM domain gene,  DMRT1 , is involved in sexual development. This gene is located on chromosome 9.  Its location suggests that it is required for the development of testis. XY humans hemizygous for the chromosome 9p, where  DMRT1  is located, are often feminized. This feminization can range from ambiguous genitalia to XY sex reversal.
The  DMRT1  homolog from chicken has been localized on the Z chromosome. Birds have heterogametic females (ZW) and homogametic males (ZZ). The avian Z chromosome shows conserved synteny with chromosome 9 of humans. ZZ embryos have a higher dose of DMRT1 and therefore have the potential to have a higher expression. It has been suggested that embryos with a higher expression of Dmrt1 expression develop into males while embryos with a lower expression are led to female development. [ 1 ]


In the mouse gonadal primordium, the genital ridge, which forms from intermediate mesoderm, becomes morphologically distinct at E10.5. By E12, sexual differentiation of the gonad is apparent, indicating that genes involved in the formation of the bipotential gonad are expressed before E10.5 and E12. Before E10.5, Dmrt1 is expressed at similar levels in the genital ridges of XX as well as XY embryos. By E12.5 and E13.5, DMRT1 is expressed deferentially as sex specific structures start to form.  By E14.5 and E15.5, DMRT1 expression is maintained in the testis while it has begun to decrease in the ovary.


In mice, the genital ridge houses the transcript for  SRY , the Y-chromosomal gene responsible for sex determination in mammals. The urogenital ridge is made up of the gonadal  anlage  and the mesonephros.  The  mesonephros  is involved in the development of the testis, but its role is in differentiation, and not determination. This is indicated by the absence of SRY expression in the mesonephros. SRY expression is expressed exclusively in the developing gonad, lacking a presence in any other tissue in embryos or adults. [ 2 ]


A  genital tubercle ,  phallic tubercle , or  clitorophallic structure [ 2 ]  is a body of tissue present in the  development of the reproductive system  of  amniotes . [ 3 ]  It forms in the ventral, caudal region of  mammalian   embryos  of both  sexes , and eventually develops into a  primordial phallus . In the human  fetus , the genital tubercle develops around week four of  gestation , and by week nine, becomes recognizably either a  clitoris  or  penis . This should not be confused with the  sinus tubercle  which is a proliferation of  endoderm  induced by paramesonephric ducts. Even after the phallus is developed (either a  penile shaft  or  clitoral shaft ), [ 4 ]  the term genital tubercle remains, but only as the terminal end of it, [ 5 ]  which develops into either the  glans penis  or the  glans clitoridis .


In the development of the male fetus, the two sides of the tubercle approach ventrally forming a hollow tube that encloses the  male urethra . The two glans wings merge in the midline forming the  septum glandis . [ 6 ]  In the female fetus, the tubercle is attached to the vestibular folds that remain unfused forming the  labia minora  and the  vaginal vestibule  in between. [ 7 ]  The genital tubercle is sensitive to  dihydrotestosterone  and rich in  5-alpha-reductase , so that the amount of fetal  testosterone  present after the second month is a major determinant of phallus size at birth.


The paired  gubernacula  (from Ancient Greek κυβερνάω = pilot, steer), also called the  caudal genital ligament , are embryonic structures which begin as undifferentiated  mesenchyme  attaching to the  caudal  end of the  gonads  ( testicles  in males and  ovaries  in females).


The gubernaculum is present only during the  development of the reproductive system . It is later replaced by distinct vestiges in males and females. The gubernaculum arises in the upper abdomen from the lower end of the gonadal ridge and helps guide the testis in its descent to the inguinal region.


As the  scrotum  and  labia majora  form in males and females respectively, the gubernaculum aids in the descent of the gonads (both testes and ovaries). [ 3 ]


The testes descend to a greater degree than the  ovaries  and ultimately pass through the  inguinal canal  into the  scrotum . [ 3 ]  The mechanism of this movement is still debated. [ 3 ]


The gubernaculum was first described by  John Hunter  in 1762. [ 3 ]  The term comes from  Ancient Greek  meaning to steer, pilot or the  rudder  or helm. [ 3 ]


Intermediate mesoderm  or  intermediate mesenchyme  is a narrow section of the  mesoderm  (one of the three primary  germ layers ) located between the  paraxial mesoderm  and the  lateral plate  of the developing  embryo . [ 1 ]  The intermediate mesoderm develops into vital parts of the  urogenital system  ( kidneys ,  gonads  and respective tracts).


Factors regulating the formation of the intermediate mesoderm are not fully understood. It is believed that  bone morphogenic proteins , or BMPs, specify regions of growth along the  dorsal-ventral  axis of the mesoderm and plays a central role in formation of the intermediate mesoderm. [ 2 ]  Vg1/ Nodal  signalling is an identified regulator of intermediate mesoderm formation acting through BMP signalling. [ 3 ]  Excess Vg1/Nodal signalling during early  gastrulation  stages results in expansion of the intermediate mesoderm at the expense of the adjacent paraxial mesoderm, whereas inhibition of Vg1/Nodal signalling represses intermediate mesoderm formation. [ 4 ]  A link has been established between Vg1/Nodal signalling and BMP signalling, whereby Vg1/Nodal signalling regulates intermediate mesoderm formation by modulating the growth-inducing effects of BMP signalling. [ 4 ]


Other necessary markers of intermediate mesoderm induction include the odd-skipped related gene ( Osr1 ) and paired-box-2 gene ( Pax2 ) which require intermediate levels of BMP signalling to activate  [ 3 ]  Markers of early intermediate mesoderm formation are often not exclusive to the intermediate mesoderm. This can be seen in early stages of intermediate mesoderm differentiation where higher levels of BMP stimulate growth of lateral plate tissue, whilst lower concentrations lead to paraxial mesoderm and  somite  formation. [ 5 ]  Osr1, which encodes a  zinc-finger  DNA-binding protein, and LIM-type homeobox gene ( Lhx1 ) expression overlaps the intermediate mesoderm as well as the lateral plate.  Osr1  has expression domains encompassing the entire length of the  anterior-posterior  (AP) axis from the first somites. It is not until the 4th-8th somite stage that markers with greater specificity to the intermediate mesoderm are identified including  Pax2/8  genes activated from the 6th somite (Bouchard, 2002).  Lhx1  expression also becomes more restricted to the intermediate mesoderm. [ 1 ]  Genetic analyses in animal studies show that  Lhx1 ,  Osr1  and  Pax2/8  signalling are all critical in specification of the intermediate mesoderm into its early derivatives. [ 5 ]


As development proceeds, the intermediate mesoderm differentiates sequentially along the anterior-posterior axis into three successive stages of the early  mammalian  and  avian  urogenital system, named  pronephros ,  mesonephros  and  metanephros  respectively ( anamniote  embryos form only a pronephros and mesonephros). [ 2 ]  The intermediate mesoderm will eventually develop into the kidney and parts of both male and female reproductive systems.


Early  kidney  structures include the pronephros and mesonephros, whose complexity, size and duration can vary greatly between  vertebrate  species. [ 1 ]  The adult kidney, also referred to as the  metanephric kidney , forms at the  posterior  end of the intermediate mesoderm after the degeneration of previous, less complex kidney structures. [ 1 ]


During early development (approximately day 22 in  humans ), the  pronephric duct  forms from the intermediate mesoderm,  ventral  to the  anterior  somites. The  cells  of the pronephric duct migrate  caudally  whilst inducing adjacent  mesenchyme  to form the  tubules  of the initial kidney-like structure called the pronephros. [ 6 ]  This process is regulated by Pax2/8 markers. [ 7 ]  The pronephros is active in adult forms of some primitive fish and acts as the primary  excretory system  in  amphibious  larvae and embryonic forms of more advanced  fish . [ 8 ]   In mammals however, the pronephric tubules and the anterior portion of the pronephric duct degenerates in 3.5 weeks to be succeeded by the mesonephros, the embryonic kidney. [ 6 ]


The mesonephros is constituted of a set of new tubules formed from the  lateral  and  ventral  sides of the  gonadal ridge  joining the  cloaca . [ 5 ]  The mesonephros functions between the 6th and 10th weeks of embryological life of mammals as a temporary kidney, but serves as the permanent excretory organ of aquatic vertebrates. By 8 weeks post- conception , the human mesonephros reaches maximum size and begins to regress, with complete regression occurring by week 16. [ 6 ]  Despite its transiency, the mesonephros is crucial for the development of structures such as the  Wolffian duct  (or mesonephric duct), which in turn gives rise to the  ureteric bud  of the metanephric kidney. [ 9 ]


The permanent kidney of  amniotes , the metanephros, develops during the 10th week in human embryos and is formed by the reciprocal interactions of the  metanephrogenic blastema  (or metaneophrogenic mesenchyme) and the ureteric bud. [ 6 ]   Gonadal derived neurotrophic factor  (GDNF) secreted by the metanephrogenic blastema activates the receptor tyrosine kinase  RET , via the co-receptor  GFRα1  and triggers outgrowth of Ret positive cells from the  nephric duct  towards the GDNF signal, promoting ureteric bud outgrowth and invasion. [ 1 ]  Once the bud invades the metanephrogenic blastema, a permissive signal in the form of  Wnt  proteins is activated and stimulates the  condensation  of metanephric mesenchymal cells around the ureteric bud tips, beginning the  polarisation  of the blastema to generate the  epithelial  cells of parts of the  nephron : the  proximal   tubules ,  loops of Henle  and the  distal convoluted tubules . [ 1 ]  The ureteric bud secretes  FGF2  (fibroblast growth factor 2) and  BMP7  (bone morphogenic protein 7) to prevent  apoptosis  in the kidney mesenchyme. [ 2 ]  Condensing mesenchyme then secretes  paracrine  factors that mediate branching of the ureteric bud to give rise to the  ureter  and  collecting duct  of the adult kidney. [ 10 ]


Wilms' tumor  (WT), also known as nephroblastoma, is an embryonic  tumor  originating from metanephric blastemal cells that are incapable of completing the  mesenchymal-epithelial transition  (MET), a crucial process during kidney differentiation involving the transition from a multipolar, spindle-shaped mesenchymal cell to a planar assembly of polarized epithelial cells. [ 11 ]  As a consequence, WTs have a triphasic histology composed of three morphogenically distinct cell types: undifferentiated  blastemal  cells,  epithelial  cells, and  stromal  cells. [ 11 ]  The Wnt/ βcatenin   signalling pathway  is crucial for initiating MET, where specifically the  WNT4  protein is required for induction of epithelial renal  vesicles  and the transition from mesenchymal to epithelial cells. [ 12 ]  WTs are often a result of a genetic  deletions  or inactivating  mutations  in  WT1  (Wilms tumor 1), which subsequently inhibits Wnt/βcatenin signalling and prevents MET progression. [ 11 ] [ 12 ]


Persistent Müllerian duct syndrome  (PMDS) is a congenital disorder of  male  sexual development and is a form of  pseudohermaphroditism . Males with PMDS retain normal male reproductive organs and external  genitalia , but also possess internal female reproductive organs such as the  uterus  and  fallopian tubes . [ 13 ]  PMDS is primarily caused by a mutation in the  anti-Müllerian hormone  (AMH) gene (PMDS Type 1) or  AMHR2  gene (PMDS Type 2). In PMDS Type 1, AMH is either not produced, produced in deficient quantities, defective, or secreted at the wrong critical time for male differentiation. PMDS Type 2 is a result of AMH receptor insensitivity to AMH molecules. [ 14 ]  In a smaller percentage of cases, the cause of PMDS is not fully understood but is related to complex malformations of the urogenital region and  paramesonephric ducts  during male gonadal development. [ 13 ]


Kidney development , or  nephrogenesis , describes the  embryologic  origins of the  kidney , a major organ in the  urinary system .  This article covers a 3 part developmental process that is observed in most reptiles, birds and mammals, including humans. Nephrogenesis is often considered in the broader context of the  development of the urinary and reproductive organs .


The development of the kidney proceeds through a series of successive phases, each marked by the development of a more advanced kidney: the archinephros, pronephros, mesonephros, and metanephros. [ 1 ]  The pronephros is the most immature form of kidney, while the metanephros is most developed. The metanephros persists as the definitive adult kidney. [ citation needed ]


The  archinephros  is considered as hypothetical or primitive kidney.


The pronephros develops in the cervical region of the embryo.
During approximately day 22 of human  gestation , the paired pronephri appears towards the cranial end of the  intermediate mesoderm . In this region,  epithelial  cells arrange themselves in a series of tubules called  nephrotomes  and join laterally with the  pronephric duct . This duct is fully contained within the embryo and thus cannot excrete filtered material outside the embryo; therefore the pronephros is considered nonfunctional in humans.


The development of the pronephric duct proceeds in a cranial-to-caudal direction. As it elongates caudally, the pronephric duct induces nearby intermediate mesoderm in the thoracolumbar area to become epithelial tubules called  mesonephric tubules . Each mesonephric tubule receives a blood supply from a branch of the  aorta , ending in a capillary tuft analogous to the  glomerulus  of the definitive  nephron . The mesonephric tubule forms a capsule around the capillary tuft, allowing for filtration of blood. This filtrate flows through the mesonephric tubule and is drained into the continuation of the pronephric duct, now called the mesonephric duct or  Wolffian duct . The nephrotomes of the pronephros degenerate while the mesonephric duct extends towards the most caudal end of the embryo, ultimately attaching to the  cloaca . The mammalian mesonephros is similar to the kidneys of  aquatic amphibians  and  fishes .


During the fifth week of gestation, the mesonephric duct develops an outpouching, the  ureteric bud , near its attachment to the cloaca. This bud, also called the metanephrogenic diverticulum, grows posteriorly and towards the head of the embryo. The elongated stalk of the ureteric bud, called the  metanephric duct , later forms the  ureter . As the cranial end of the bud extends into the intermediate mesoderm, it undergoes a series of branchings to form the  collecting duct system  of the kidney. It also forms the major and minor  calyces  and the  renal pelvis .


The portion of undifferentiated intermediate mesoderm in contact with the tips of the branching ureteric bud is known as the metanephrogenic blastema. Signals released from the ureteric bud induce the differentiation of the metanephrogenic blastema into the  renal tubules . As the renal tubules grow, they come into contact and join with  connecting tubules  of the collecting duct system, forming a continuous passage for flow from the renal tubule to the collecting duct. Simultaneously, precursors of vascular endothelial cells begin to take their position at the tips of the renal tubules. These cells differentiate into the cells of the definitive  glomerulus .


In humans, all of the branches of the ureteric bud and the nephronic units have been formed by 32 to 36 weeks of gestation. However, these structures are not yet mature, and will continue to mature after birth. Once matured, humans have an estimated two million nephrons (approximately 1,000,000 per kidney) but this number is highly variable ranging widely from approximately 200,000 to over 2.5 million per kidney. [ 2 ]


After inducing the metanephric mesenchyme the lower portions of the nephric duct will migrate caudally (downward) and connect with the  bladder , thereby forming the  ureters . The ureters will carry urine from the  kidneys  to the bladder for excretion from the  fetus  into the  amniotic sac . As the  fetus  develops, the  torso  elongates and the  kidneys  rotate and migrate upwards within the  abdomen  which causes the length of the  ureters  to increase.


The  labioscrotal swellings  ( genital swellings  or  labioscrotal folds ) are paired structures in the  mammalian   embryo  that represent the final stage of development of the  caudal  end of the external  genitals  before  sexual differentiation . In humans, the two swellings merge:


This article incorporates text in the  public domain  from  page 1214  of the 20th edition of   Gray's Anatomy   (1918)


The  lateral plate mesoderm  is the  mesoderm  that is found at the periphery of the  embryo . It is to the side of the  paraxial mesoderm , and further to the  axial mesoderm . The lateral plate mesoderm is separated from the paraxial mesoderm by a narrow region of  intermediate mesoderm . The mesoderm is the middle layer of the three  germ layers , between the outer  ectoderm  and inner  endoderm .


During the third week of  embryonic development  the lateral plate mesoderm splits into two layers forming the  intraembryonic coelom .


The outer layer of lateral plate mesoderm adheres to the ectoderm to become the somatic or parietal layer known as the  somatopleure . The inner layer adheres to the  endoderm  to become the splanchnic or visceral layer known as the  splanchnopleure .


The lateral plate mesoderm will split into two layers, the  somatopleuric mesenchyme , and the  splanchnopleuric mesenchyme .


Spaces within the lateral plate are enclosed and forms the  intraembryonic coelom .


It is formed by the secretion of  BMP-4  by the ectoderm. [ 1 ]


Lateral plate mesoderm gives rise to the serosal mesoderms. [ 2 ]


In the 4th week the coelom divides into  pericardial ,  pleural  and  peritoneal  cavities. [ 2 ]


Cells from the lateral plate mesoderm and the myotome migrate to the limb field and proliferate to create the limb bud. The lateral plate cells produce the cartilaginous and skeletal portions of the limb while the myotome cells produce the muscle components. The lateral plate mesodermal cells secrete a fibroblast growth factor (FGF7 and FGF10, presumably) to induce the overlying ectoderm to form an important organizing structure called the  apical ectodermal ridge  (AER). The AER reciprocatively secretes FGF8 and FGF4 which maintains the FGF10 signal and induces proliferation in the mesoderm. [ 3 ]  The position of FGF10 expression is regulated by Wnt8c in the hindlimb and Wnt2b in the forelimb. The forelimb and the hindlimb are specified by their position along the anterior/posterior axis and possibly by two T-box containing transcription factors: Tbx5 and Tbx4, respectively.


This article incorporates text in the  public domain  from  page 50  of the 20th edition of   Gray's Anatomy   (1918)


This  list of related male and female reproductive organs  shows how the  male  and  female  reproductive organs and the  development of the reproductive system  are related, sharing a common developmental path. This makes them biological  homologues . These organs differentiate into the respective sex organs in males and females.


The external genitalia of both  males  and  females  have similar origins. They arise from the  genital tubercle  that forms anterior to the cloacal folds (proliferating mesenchymal cells around the cloacal membrane). The caudal aspect of the cloacal folds further subdivides into the posterior anal folds and the anterior urethral folds. Bilateral to the urethral fold, genital swellings become prominent. These structures are the future  scrotum  and  labia majora  in males and females, respectively.


The genital tubercles of an eight-week-old embryo of either sex are identical. They both have a  glans  area, which will go on to form the  clitoral glans  (females) or  penile glans  (males), a urogenital fold and groove, and an anal tubercle. At around ten weeks, the external genitalia are still similar. At the base of the glans, there is a groove known as the coronal sulcus or corona glandis. It is the site of attachment of the future prepuce. Just anterior to the anal tubercle, the caudal end of the left and right urethral folds fuse to form the urethral raphe. The lateral part of the genital tubercle (called the lateral tubercle) grows longitudinally and is about the same length in either sex.


The male external genitalia include the  penis  and the  scrotum . The female external genitalia include the  clitoris , the  labia , and the  vestibule , which are collectively called the  vulva . External genitalia vary widely in external appearance among different people.


One difference between the glans penis and the glans clitoridis is that the glans clitoridis packs nerve endings into a volume only about one-tenth the size of the glans penis. Therefore, the glans clitoridis has greater variability in cutaneous corpuscular receptor density (1-14 per 100× high-powered field) compared with the glans penis (1-3 per 100× high-power field). Touch for touch, this concentration of nerves makes the glans clitoridis more sensitive than the glans penis. As a result, many women can feel discomfort or pain with anything more than a gentle touch. [ 3 ]


This article incorporates text in the  public domain  from the 20th edition of   Gray's Anatomy   (1918)


The  mesonephric duct , also known as the  Wolffian duct ,  archinephric duct ,  Leydig's duct  or  nephric duct , is a paired  organ  that develops in the early stages of  embryonic development  in humans and other mammals. It is an important structure that plays a critical role in the formation of  male reproductive organs . The duct is named after  Caspar Friedrich Wolff , a German  physiologist  and  embryologist  who first described it in 1759. [ 1 ]


During embryonic development, the mesonephric ducts form as a part of the  urogenital system . [ 2 ]


The mesonephric duct connects the primitive kidney, the  mesonephros , to the  cloaca . It also serves as the  primordium  for male  urogenital  structures including the  epididymides ,  vasa deferentia , and  seminal vesicles .


In both males and females, the mesonephric ducts develop into the  trigone of urinary bladder , a part of the bladder wall, but the sexes differentiate in other ways during development of the  urinary  and  reproductive  organs.


In a  male , they develop into a system of connected organs between the  efferent ducts  of the  testis  and the prostate, namely the  epididymis , the  vas deferens , and the  seminal vesicle . The  prostate  forms from the  urogenital sinus  and the efferent ducts form from the  mesonephric tubules .


For this, it is critical that the ducts are exposed to  testosterone  during  embryogenesis . Testosterone binds to and activates  androgen receptor , affecting intracellular signals and modifying the expression of numerous genes. [ 3 ]


In the mature male, the function of this system is to store and mature  sperm , and provide accessory  semen  fluid.The mesonephric duct (precursor of the male reproductive system) forms around the 3-4th week of pregnancy, present before the paramesonephric duct (precursor of the female reproductive system), so basically, Everyone begins life with a mesonephric duct (Wolffian duct), the precursor to the male reproductive system.


In the  female , with the absence of  anti-Müllerian hormone  secretion by the  Sertoli cells  and subsequent Müllerian  apoptosis , the mesonephric ducts regress, although inclusions may persist. The vestigial  epoophoron  arises from these ducts. Also, lateral to the wall of the vagina, a  Gartner's duct  could develop as a remnant.


It is named after  Caspar Friedrich Wolff  who described the  mesonephros  and its ducts in his  dissertation  in 1759. [ 1 ]


Mesonephric tubules  are genital ridges that are next to the  mesonephros .


In males, some of the mesonephric kidney tubules, instead of being used to filter blood like the rest, "grow" over to the developing  testes , penetrate them, and become connected to the  seminiferous tubules  of the testes. They also form the  paradidymis . [ 1 ] : 185