Genital System - Abnormalities

Embryology - 2 Dec 2023 Expand to Translate
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ICD-11

Structural developmental anomalies of the female genital system - Structural developmental anomalies of vulva | Structural developmental anomalies of clitoris | Structural developmental anomalies of vagina | Structural developmental anomalies of cervix uteri | Structural developmental anomalies of uterus, except cervix | Structural developmental anomalies of ovaries, fallopian tubes or broad ligaments | Hydrocele of the canal of Nuck

Introduction

Cryptorchidism

How and why do things go wrong in development?

Human genital abnormalities are currently described as "Disorders of Sex Development" (DSD) and includes: chromosomal, gonadal dysfunction, tract abnormalities, external genitalia and gonadal descent. The genital system is closely associated developmentally and anatomically with the renal system, often called the "urogenital system", therefore abnormalities of renal development should also be considered when studying this topic.

The earlier term "intersex" and a variety of other previously applied terms related to genetic abnormalities have been replaced by the term "Disorders of sex development" (DSD).

Links: cryptorchidism | hypospadias

Historic Embryology - Genital
General: 1901 Urinogenital Tract \| 1902 The Uro-Genital System \| 1904 Ovary and Testis \| 1912 Urinogenital Organ Development \| 1914 External Genitalia \| 1921 Urogenital Development \| 1921 External Genital \| 1942 Sex Cords \| 1953 Germ Cells \| Historic Embryology Papers \| Historic Disclaimer
Female: 1904 Ovary and Testis \| 1904 Hymen \| 1912 Urinogenital Organ Development \| 1914 External Genitalia \| 1914 Female \| 1921 External Genital \| 1927 Female Foetus 15 cm \| 1927 Vagina \| 1932 Postnatal Ovary
Male: 1887-88 Testis \| 1904 Ovary and Testis \| 1904 Leydig Cells \| 1906 Testis vascular \| 1909 Prostate \| 1912 Prostate \| 1914 External Genitalia \| 1915 Cowper’s and Bartholin’s Glands \| 1920 Wolffian tubules \| 1935 Prepuce \| 1935 Wolffian Duct \| 1942 Sex Cords \| 1943 Testes Descent \| Historic Embryology Papers \| Historic Disclaimer

System Abnormalities

Historic Embryology
1915 Congenital Cardiac Disease \| 1917 Frequency of Anomalies in Human Embryos \| 1920 Hydatiform Degeneration Tubal Pregnancy \| 1921 Anencephalic Embryo \| 1921 Rat and Man \| 1966 Congenital Malformations

Some Recent Findings

Ovotesticular Disorders of Sex Development (DSD) in FGF9 Mouse Models of Human Synostosis Syndromes^[1] "In mice, male sex determination depends on FGF9 signalling via FGFR2c in the bipotential gonads to maintain expression of the key testis gene SOX9. In humans however, while FGFR2 mutations have been linked to 46,XY disorders of sex development (DSD), the role of FGF9 is unresolved. The only reported pathogenic mutations in human FGF9; FGF9S99N and FGF9R62G, are dominant, and result in craniosynostosis (fusion of cranial sutures) or multiple synostoses (fusion of limb joints). Whether these synostosis-causing FGF9 mutations impact upon gonadal development and DSD etiology has not been explored. We therefore examined embryonic gonads in the well-characterised Fgf9 missense mouse mutants; Fgf9S99N and Fgf9N143T, which phenocopy the skeletal defects of FGF9S99N and FGF9R62G variants respectively. XY Fgf9S99N/S99N and XY Fgf9N143T/N143T fetal mouse gonads showed severely disorganised testis cords and partial XY sex reversal at E12.5 days postcoitum (dpc), suggesting loss of FGF9 function. By E15.5 dpc, testis development in both mutants had partly recovered. Mitotic analysis in vivo and in vitro suggested that the testicular phenotypes in these mutants arise in part through reduced proliferation of the gonadal supporting cells. These data raise the possibility that human FGF9 mutations causative for dominant skeletal conditions can also lead to loss of FGF9 function in the developing testis, at least in mice. Our data suggest that in humans, testis development is largely tolerant of deleterious FGF9 mutations which lead to skeletal defects, thus offering an explanation as to why XY DSDs are rare in patients with pathogenic FGF9 variants."

Differences of sex development: the road to diagnosis^[2] "The diagnosis and management of children born with ambiguous genitalia is challenging for clinicians. Such differences of sex development (DSDs) are congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. The aetiology of DSDs is very heterogenous and a precise diagnosis is essential for management of genetic, endocrine, surgical, reproductive, and psychosocial issues. In this Review, we outline a step-by-step approach, compiled in a diagnostic algorithm, for the clinical assessment and molecular diagnosis of a patient with ambiguity of the external genitalia on initial presentation. We appraise established and emerging technologies and their effect on diagnosis, and discuss current controversies."

Ultrasonographic and multimodal imaging of pediatric genital female diseases^[3] "Ultrasonography is the first-line imaging modality in the evaluation of the female pelvis in childhood and adolescence, because it is easy to perform, non-invasive and it does not require sedation. The transabdominal approach is preferred in children and adolescents, after filling the bladder to move away the bowel loops from the pelvis. The probe frequency must be adapted to age, thickness of tissues and depth of the structures under examination. High-frequency (4-12 MHz) linear or convex probes are used in newborns; high-frequency linear probes (4-12 MHz) in toddler, convex 5-7.5 MHz probes in girls and convex 3.5-5 MHz probes in teenagers. In this article, the main pathological conditions of the genital female tract in pediatric age are examined, such as congenital anomalies, disorders of sex development, ovarian cysts, ovarian tumors, adnexal torsion, primary amenorrhea, precocious puberty and pelvic inflammatory disease." ultrasound

Germany - Variations of sex development: The first German interdisciplinary consensus paper^[4] "The term variations of sex development subsumes a large number of congenital conditions including chromosomal mosaics and variations of chromosomal, gonadal, and phenotypic sex. A situation of this nature may cause severe distress to both, parents and affected persons. One of the reasons for this is the binary form of gender classification in the society. In the past, because of a fear of possible stigmatization and an inability to cope with complex situations, it has been medical policy and practice for newborns to undergo early, mostly 'feminizing' elective surgery with the aim of achieving an outer genital appearance that is unambiguously male or female. Protests by advocacy groups for the most part as well as the results of outcome studies have shown that the development of affected persons may be very different to what has been expected and often does not result in the intended clear female or male gender identity as had been intended. CONCLUSION: The introduction of the consensus paper reflects on the emerging paradigm shift and the necessity for a more open view of gender within society. The paper is intended to aid the performance of appropriate diagnostics in DSD-affected newborns and especially to help parents and affected persons cope with the biological and social consequences of DSD. With regard to medical or surgical therapy, it gives information about the most recent treatment trends."

India - Clinical Spectrum of Disorders of Sex Development: A Cross-sectional Observational Study^[5] "Disorders of sex development (DSD) constitutes a small but difficult and equally important area of endocrinology. SUBJECTS AND METHODS: This study was a cross-sectional observational study carried out in the department of pediatrics of a tertiary care hospital from August 2012 to August 2014. CONCLUSION: 46, XX DSD were the commonest etiological group in our study and CAH was the commonest individual disease. There is a need for educating general public and practitioners regarding DSD to allow early intervention. Moreover, there is a need to introduce routine neonatal screening for CAH in our country."

Japan - Nationwide Increase in cryptorchidism after the Fukushima Nuclear Accident^[6] "To estimate the change of discharge rate after cryptorchidism surgery between pre- and post-disaster in Japan. The change in discharge rate between pre- and post-disaster was analysed using a Bayesian Generalized Linear Mixed Model (GLMM). Nationwide, a 13.4 % (95% credible interval 4.7-23.0 %) increase in discharge rates was estimated. The results of all sensitivity analyses were similar to the reported main results. The discharge rate of cryptorchidism was increased nationwide. The rates of low-weight babies or preterm births, risk factors of cryptorchidism, were almost constant during the study period, and age distribution of the surgery was also not changed, which suggested that the other factors that associated with the disaster increased the incidence of cryptorchidism." Japan Statistics cryptorchidism

More recent papers
This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. More? References \| Discussion Page \| Journal Searches \| 2019 References \| 2020 References Search term: Genital Abnormalities \| Disorders of Sex Development \| Trisomy X \| Turner syndrome \| Klinefelter syndrome \| Hypospadias \| Cryptorchidism

Older papers
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table. See also the Discussion Page for other references listed by year and References on this current page. A collection of XY female cell lines^[7] "Discordance between sexual phenotype and the 46,XY sex chromosome complement may be found in certain disorders of sexual development (DSD). Many of these DSD patients with female external genitalia and secondary sex characteristics have undescended testes and male internal genitalia. Causative mutations involving genes of the sex determining pathway, including the androgen receptor, SRY and the 5-alpha-reductase genes, are well-known, but the origin of other cases remain unresolved. In this report, we introduce our collection of lymphoblastoid lines derived from female patients with a 46,XY karyotype. These cell lines have been deposited and registered with the JCRB Cell Bank. They are available for comparison with other DSD cases and for further characterization of genetic loci involved in the mammalian sex determining pathway." Nationwide Prevalence of Groin Hernia Repair^[8] "Groin hernia repair is a commonly performed surgical procedure in the western world but large-scaled epidemiologic data are sparse. Large-scale data on the occurrence of groin hernia repair may provide further understanding to the pathophysiology of groin hernia development. This study was undertaken to investigate the age and gender dependent prevalence of groin hernia repair." Anogenital Distance (AGD) and fertility.^[9] "A longer anogenital distance is associated with fatherhood and may predict normal male reproductive potential. Thus, AGD may provide a novel metric to assess reproductive potential in men." The European Disorder of Sex Development Registry: A Virtual Research Environment.^[10] "The EU-funded EuroDSD programme (www.eurodsd.eu) is one such collaboration involving clinical centres and clinical and genetic experts across Europe. At the heart of the EuroDSD collaboration is a European DSD registry and a targeted virtual research environment (VRE) that supports the sharing of DSD data." Low testosterone levels in pre-term newborns born small for gestational age.{{#pmid:20503482\|PMID20503482 "Previous studies showed that small for gestational age (SGA) newborns have an increased prevalence of hypospadias and other congenital defects of external genitalia. We observed that in the first days of life, SGA male pre-term newborns have reduced testosterone levels compared with adequate for gestational age pre-term newborns, independently from the presence of abnormalities of the external genitalia."

Human Genital Development Critical Periods

Disorders of Sex Development

The previous human sex development terminology (true hermaphrodites, male pseudohermaphrodites and female pseudohermaphrodites) are considered outdated and stigmatising and have been replaced with the general term Disorders of Sex Development (DSD) established by the Consensus statement on management of intersex disorders.^[11] See also the Medical Journal of Australia 2009 editorial article.^[12]

**Disorders of Sexual Development - Terminology**
New Terminology	Previous Terminology
DSD	Intersex
46,XY DSD	Male pseudohermaphrodite undervirilization of an XY male undermasculinization of an XY male
46,XX DSD	Female pseudohermaphrodite overvirilization of an XX female masculinization of an XX female
Ovotesticular DSD	True hermaphrodite
46,XX testicular DSD	XX male or XX sex reversal
46,XY complete gonadal dysgenesis	XY sex reversal

Contribution of AMH to DSD differential diagnosis^[13]
	UDT - undescended testis cryptorchidism CAH - congenital adrenal hyperplasia DSD - disorders of sex development PMDS - persistent Müllerian duct syndrome AMH - anti-Müllerian hormone T - testosterone AMHR - AMH receptor

International Classification of Diseases

ICD-11

Structural developmental anomalies of the female genital system - Structural developmental anomalies of vulva | Structural developmental anomalies of clitoris | Structural developmental anomalies of vagina | Structural developmental anomalies of cervix uteri | Structural developmental anomalies of uterus, except cervix | Structural developmental anomalies of ovaries, fallopian tubes or broad ligaments | Hydrocele of the canal of Nuck

Sex Chromosome Abnormalities

Trisomy X

ICD-11 Karyotype 47,XXX - Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). Most individuals are only mildly affected or asymptomatic, the most common physical features including tall stature, epicanthal folds, hypotonia and clinodactyly, with seizures, renal and genitourinary abnormalities, and premature ovarian failure being also associated findings.

Trisomy X is a caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). This is also the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births with some individuals are only mildly affected or asymptomatic. It is estimated that only 10% of individuals with trisomy X are actually diagnosed. Common physical features include: tall stature, epicanthal folds, hypotonia and clinodactyly. Other physical features include: neural (seizures), renal and genitourinary abnormalities, and premature ovarian failure (POF) (see review^[14].

Trisomy X karyotype

Links: Trisomy X

Turner Syndrome

ICD-11 Turner syndrome - Karyotype missing one X chromosome (45, X0 or 45,XO/46,XX mosaicism) ; gonads: ovaries (streak); phenotype female with short stature, amenorrhea (hypergonadotrophic hypogonadism), absence of sexual development, webbed neck, low set ears, posterior hairline, widely-spaced nipples, short fourth metacarpals, and increased carrying angle at the elbow (cubitus valgus). Often associated with renal, cardiac and ocular abnormalities.

Turner syndrome or Monosomy X (45,X) feature include gonadal dysgenesis and short stature. Named after Henry Turner, an American clinician who first described (1938) the syndrome.

Turner syndrome karyotype (45,X)

Links: Monosomy X | Student Project - Turner syndrome

Klinefelter Syndrome

ICD-11 Klinefelter syndrome - Klinefelter syndrome defines a group of chromosomal disorders in which there is at least one extra X chromosome compared with the normal 46,XY male karyotype. The effects on physical features and on physical and cognitive development increase with the number of extra X's, and each extra X is associated with an intelligence quotient (IQ) decrease of approximately 15-16 points, with language most affected, particularly expressive language skills.

Klinefelter syndrome (47,XXY) caused by an additional X chromosome (or more) in affected males> Named after Harry F. Klinefelter who first described (1942) the syndrome. Common physical features include reduced fertility and hypogonadism. Some individuals are only mildly affected or asymptomatic and the severity varies greatly between individuals.

Links: Klinefelter syndrome | Student Project - Klinefelter's syndrome

Congenital Adrenal Hyperplasia

ICD-11 Congenital adrenal hyperplasia - Congenital adrenal hyperplasia (CAH) refers to a group of diseases associated with either complete (classical form) or partial (non-classical) anomalies in the biosynthesis of adrenal hormones. The disease is characterized by insufficient production of cortisol, or of aldosterone (classical form with salt wasting), associated with overproduction of adrenal androgens. In the classical form, metabolic decompensation (dehydration with hyponatremia, hyperkalemia and acidosis associated with mineralocorticoid deficiency, and hypoglycemia associated with glucocorticoid deficiency) may be life-threatening from the neonatal period onwards. Genital anomalies may be noted at birth in affected females.

The adrenal abnormality of congenital adrenal hyperplasia (CAH) is an impairment of cortisol production by the adrenal cortex, is one of the most common causes of DSD genitalia at birth

genetically male (XY) infants born with undervirilized genitalia (androgen insensitivity syndrome, cloacal exstrophy) are generally assigned and reared as girls.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be prenatally diagnosed in utero through molecular genetic analysis of fetal DNA. Prenatal treatment by dexamethasone administration to the at-risk pregnant mother has been shown to be effective in reducing genital virilization in the fetus, avoiding unnecessary postnatal genitoplasty in affected females.^[15]

There has been recorded a prevalence of reduced fecundity in men with congenital adrenal hyperplasia, related to testicular adrenal rest tumours and poor semen parameters.^[16]

Deficiency of 21-hydroxylase, resulting from mutations or deletions of CYP21A, is the most common form of CAH, accounting for more than 90% of cases

Deficiency of 17-hydroxylase is the less common form of CAH.

Congenital Adrenal Hyperplasia
Type	Enzyme Deficiency	Female	Male
classic virilizing adrenal hyperplasia	21-hydroxylase, 11-beta-hydroxylase, or 3-beta-hydroxysteroid dehydrogenase	ambiguous genitalia at birth - complete or partial fusion of the labioscrotal folds and a phallic urethra to clitoral enlargement (clitoromegaly), partial fusion of the labioscrotal folds, or both	normal genitalia, present at age 1-4 weeks with salt wasting (classic salt-wasting adrenal hyperplasia)
simple virilizing adrenal hyperplasia	mild 21-hydroxylase	identified later in childhood because of precocious pubic hair, clitoral enlargement (clitoromegaly), or both, often accompanied by accelerated growth and skeletal maturation	early genital development (pubic hair and/or phallic enlargement) accelerated growth and skeletal maturation
nonclassic adrenal hyperplasia	milder deficiencies of 21-hydroxylase or 3-beta-hydroxysteroid dehydrogenase	present at puberty or adult with infrequent menstruation (oligomenorrhea), abnormal hair growth (hirsutism), and/or infertility
17-hydroxylase deficiency syndrome	17-hydroxylase deficiency or 3-beta-hydroxysteroid dehydrogenase	rare, phenotypically female at birth do not develop breasts or menstruate in adolescence and may have hypertension	steroidogenic acute regulatory (StAR) deficiency have ambiguous genitalia or female genitalia, at puberty may lack breast development and may have hypertension
This is a complex steroidogenic abnormality, and the above table of clinical descriptions are provided only a guide. Links: Genital Abnormalities \| Adrenal Development \| Genes and Disease \| OMIM 21 Deficiency \| OMIM 17 Deficiency \| OMIM 3 Deficiency

Prader Stages

Also called the Prader scale, a clinical classification system used to describe virilization of female genitalia, mainly associated with the congenital adrenal hyperplasia (CAH). Two normal (Stage 0 – Normal female genitalia; Stage 6 – Normal male genitalia) and five distinct abnormal stages ( 1 to 5 increasing virilisation). Named after Dr. Andrea Prader (1919 – 2001) an endocrinologist who also discovered the Prader-Willi syndrome and developed a second male testis development scale the Orchidometer.

Prader Stages
Stage 0	Normal female genitalia.
Stage 1	Mildly enlarged clitoris, slightly reduced vaginal opening, usually within normal variations.
Stage 2	Abnormal genitalia clearly seen by eye, phallus being intermediate in size, small vaginal opening with separate urethral opening. Posterior labial fusion present.
Stage 3	Further enlarged phallus than Stage 2, with single urogenital sinus and nearly complete fusion of the labia.
Stage 4	Upon examination, looks more male than female, with an empty scrotum and a normal-sized penis-like phallus, however this structure is not quite as free from the perineum to be pulled onto the abdomen towards the umbilicus. A small urethral/vaginal opening at the base of the shaft/phallus (hypospadias in a male), with an x-ray showing the internal connection with the upper vagina and uterus.
Stage 5	Complete male virilisation, a normally-formed penis is present. Urethral opening at or near the tip, and the scrotum formed, but empty. Internal organs in the pelvis include normal ovaries and uterus, with the vagina connecting internally with the urethra (as in Stage 4). Newborn infants are not seen to be visibly ambiguous, and are assumed to be normal boys (with undescended testes). The diagnosis of CAH is not apparent until signs of salt-wasting develop, about a week later.
Stage 6	Normal male presentation of the penis with normal testes.
	Links: Genital - CAH \| Adrenal - CAH \| Female \| Genital System - Abnormalities \| Genital Terms

Links:Genital - CAH | Adrenal - CAH | genital abnormalities)

Androgen Insensitivity Syndrome

There is a database (Androgen Receptor Gene Mutations) of 1,029 reported androgen receptor mutations.^[17] Complete androgen insensitivity syndrome affects 2 to 5 per 100,000 people.

A recent article has also looked in cell culture at the androgen receptor interacting proteins.^[18]

Partial androgen insensitivity syndrome - (PAIS) associated with impaired male genital development that can be transmitted through mutations in the androgen receptor.

Links: Androgen Receptor Gene Mutations Database

Cryptorchidism

cryptorchidism

ICD-11 LB52 Cryptorchidism - A disorder affecting males, caused by an abnormality occurring in sex development during the antenatal period. This disorder is characterized by the absence of one or both testes from the scrotum. This disorder may also present with reduced fertility, psychological implications, or increased risk of testicular germ cell tumours. Confirmation is by imaging, karyotyping, or identification of male sex hormones in a blood sample.

Newborn - cryptorchidism normal birthweight^[19]

The failure of testis descent is common abnormality in eutherian mammals.^[20] The external location of the testes in the scrotum acts as a local thermo-regulator and provides a temperature environment below that of the general body temperature.^[21] This thermal function is essential for normal spermatogenesis and cryptorchidism therefore affects fertility.

Abnormality of either unilateral or bilateral testicular descent, occurring in up to 30% premature and 3-4% term males.
Descent may complete postnatally in the first year, failure to descend can result in sterility.
Undescended testis has a higher risk of the anatomical anomalies testicular appendices, epididymal anomalies, and processus vaginalis.^[22]
True undescended testis — testis lies along the expected path of descent but has never been present in the scrotum
Ectopic testis — testis is palpated in a location outside the normal path of descent, such as the perineum or femoral area
Ascending testis — previously descended testis that no longer lies within the scrotum. A peak incidence occurs around 10 years of age (affects 1-2%) and may also occur as a complication of inguinal hernia surgery in children.

**Cryptorchidism Types**
True	Ectopic
abdominal inguinal suprascrotal	prepenile superficial ectopic transverse scrotal femoral perineal
Links: cryptorchidism \| testis \| genital abnormalities

Clinically exposed suprascrotal testis^[22]

Testis descent is thought to have 2 phases:

transabdominal descent - dependent on insulin-like hormone 3 (INSL3).
inguinoscrotal descent - dependent on androgens.

Management of cryptorchidism in children: guidelines.^[23] "Cryptorchidism is best diagnosed clinically, and treated by surgical orchiopexy at age 6-12 months, without a routine biopsy. If no testis is palpable, or if other signs of hypovirilisation such as hypospadias are present, the chromosomal sex and hormonal status must be assessed. Laparoscopy is the best way of diagnosing and managing intra-abdominal testes."

Links: testis | cryptorchidism

Undescended Ovaries

reasonably rare gonad abnormality, often detected following clinical assessment of fertility problems and may also be associated with other uterine malformations (unicornuate uterus).
Due to the relative positions of the male (external) and female (internal) gonads and the pathways for their movement, failure of gonad descent is more apparent and common in male cryptorchidism than female undescended ovaries.

Hydrocele

ICD-11

GB00 Hydrocele or spermatocele - A condition characterized by an accumulation of serous fluid in the tunica vaginalis testis or along the spermatic cord, and cystic swelling containing fluid and dead spermatozoa of the testicular epididymis, rete testis or efferent ductuli. Hydrocele of the canal of Nuck

Male Hydrocele is a fluid-filled cavity of either testis or spermatic cord, where peritoneal fluid passes into a patent processus vaginalis.
Female Hydrocele is a similar, but rarer, fluid-filled cavity occuring in the female as a pouch of peritoneum extending into the labium majorum (canal of Nuck).

Anogenital Distance

Human anogenital distance

Anogenital Distance (AGD) is a clinical measurement of a parameter that is sexually dimorphic for genital development. This distance, from the posterior aspect of the scrotum to the anal verge, has been used as a marker for endocrine disruption in animal studies and may also be shorter in infant males with genital anomalies (More? see related references)

A recent study in humans has shown that infertile men possessed significantly shorter mean AGD than fertile men.^[9]

Compared to fathers, childless men had significantly shorter AGD (31.8 vs 44.6 mm, p<0.01).

Tract Abnormalities

Uterus - associated with other anomolies, unicornuate uterus
Vagina - agenesis, atresia
Ductus Deferens - Unilateral or bilateral absence, failure of mesonephric duct to differentiate

Uterine anomalies ESHRE-ESGE classification

Links: uterus abnormalities

Unicornate Uterus

Unicornate uterus

Bicornuate uterus containing conceptus chorionic sac with placental cord on one side.

Uterine Duplication

(uterus didelphys, double uterus, uterus didelphis) A rare uterine developmental abnormality where the paramesonephric ducts (Mullerian ducts) completely fail to fuse generating two separate uterus parts each connected to the cervix and having an ovary each.

Septate Uterus

Cervical: cervical agenesis, cervical duplication

Vaginal: Mayer-Rokitansky syndrome (MRK anomaly, Rokitansky-Küster-Hauser syndrome, RKH syndrome, RKH) congenital absence of the vagina, dyspareunia, vaginal agenesis.

Persistent Müllerian Duct Syndrome

Persistent Müllerian Duct Syndrome (PMDS) men are genotypic and externally phenotypic males with cryptorchidism, sometimes associated with inguinal hernia.^[24]

transverse testicular ectopia - one testis descends into the scrotum pulling the ipsilateral Fallopian tube into the inguinal canal (hernia uteri inguinalis).
bilateral cryptorchidism - the uterus is fixed in the pelvis and both testes are embedded in the broad ligament in ovarian position.

Polycystic Ovary Syndrome

(PCOS) or Stein–Leventhal syndrome (1930s researchers) a metabolic syndrome with many other symptoms, ovarian cysts arise through incomplete follicular development or failure of ovulation. For review see^[25] It has recently been suggested (NIH workshop 2012) that the name "Polycystic Ovary Syndrome" is not appropriate for the condition and should be renamed.

Links: ovary abnormalities

Hypospadias

Classification of Hypospadias^[26]

Hypospadias are the most common penis abnormality (1 in 300) and result from a failure of male urogenital folds to fuse in various regions.^[27] This in turn leads to resulting in a proximally displaced urethral meatus. The cause is unknown, but suggested to involve many factors either individually or in combination including: familial inheritance, low birth weight, assisted reproductive technology, advanced maternal age, paternal subfertility and endocrine-disrupting chemicals.^[26] Maternal hypertension during pregnancy has also been shown to double the risk and a pregnancy diet lacking meat and fish also show an increase in hypospadias.^[28] Infants with hypospadias should not undergo circumcision.

Mouse models have shown that deletion of Fgfr2 or its ligand Fgf10 results in severe hypospadias.^[29] Fgfr2 was expressed in two epithelial populations, the endoderm-derived urethral epithelium and the ectoderm-derived surface epithelium and urethral tubulogenesis, prepuce morphogenesis, and sexually dimorphic patterning of the lower urethra were controlled by discrete regions of Fgfr2 activity.

**Hypospadias Classification**
Classification	ICD-11	Meatus Opening	Image
Anterior	glandular	urinary meatus that opens at the site of the frenulum	A
Coronal	coronal	urinary meatus opens in the ventral portion of the coronal sulcus	B
Distal	penile	urinary meatus that opens along the shaft of the penis	C
Penoscrotal	penoscrotal	urinary meatus opens where the shaft of the penis meets the scrotum	D
Scrotal	scrotal	urinary meatus that opens on the scrotum	E
Perineal	perineal	urinary meatus that opens in the perineum	F
Table reference^[26] Links: hypospadias \| 'ICD-11 Hypospadias

Surgical Repair

Depending on the class of hypospadias there are a number of different surgical repair techniques including: orthoplasty or penile straightening, urethroplasty, meatoplasty and glanuloplasty, scrotoplasty (oscheoplasty) and skin coverage.

Links: Genital Abnormality - Hypospadia

Related Genetic Conditions

Johanson-Blizzard syndrome^[30] - hypospadias, failure to thrive, exocrine pancreatic deficiency, short stature and developmental delay, cutis aplasia on the scalp, aplasia of alae nasi, hypothyroidism, myxomatous mitral valve, and patent ductus arteriosus.

Splenogonadal Fusion

Rare abnormality resulting from fusion of the splenic and gonadal primordia during prenatal development.^[31] On the left side and more common in male and adhesion to the gonad, epididymis or ductus deferens and then follows the caudal descent with the gonad. Failure of complete descent can also result in associated intraabdominal cryptorchism.

Two classifications:

continuous - orthotopic spleen connects to the gonad with a cord of fibrous or splenic tissue.
discontinuous - no connection between the orthotopic spleen and gonad.

Links: Spleen Development

Testicular Microlithiasis

Adult male testis abnormality associated with the deposition of multiple tiny calcifications throughout the testes (usually bilateral), detected by ultrasound. Present in up to 5.6% of the general adult population between 17 and 35 years of age. Also present in about 50% of men with a germ cell tumour.

References

↑ Bird AD, Croft BM, Harada M, Tang L, Zhao L, Ming Z, Bagheri-Fam S, Koopman P, Wang Z, Akita K & Harley VR. (2020). Ovotesticular disorders of sex development (DSD) in FGF9 mouse models of human synostosis syndromes. Hum. Mol. Genet. , , . PMID: 32452519 DOI.
↑ León NY, Reyes AP & Harley VR. (2019). Differences of sex development: the road to diagnosis. Lancet Diabetes Endocrinol , , . PMID: 30803928 DOI.
↑ Caprio MG, Di Serafino M, De Feo A, Guerriero E, Perillo T, Barbuto L, Vezzali N, Rossi E, Ferro F, Vallone G & Orazi C. (2019). Ultrasonographic and multimodal imaging of pediatric genital female diseases. J Ultrasound , , . PMID: 30778893 DOI.
↑ Krege S, Eckoldt F, Richter-Unruh A, Köhler B, Leuschner I, Menzel HJ, Moss A, Schweizer K, Stein R, Werner-Rosen K, Wieacker P, Wiesemann C, Wünsch L & Richter-Appelt H. (2018). Variations of sex development: The first German interdisciplinary consensus paper. J Pediatr Urol , , . PMID: 30713084 DOI.
↑ Dar SA, Nazir M, Lone R, Sameen D, Ahmad I, Wani WA & Charoo BA. (2018). Clinical Spectrum of Disorders of Sex Development: A Cross-sectional Observational Study. Indian J Endocrinol Metab , 22, 774-779. PMID: 30766817 DOI.
↑ Murase K, Murase J, Machidori K, Mizuno K, Hayashi Y & Kohri K. (2018). Nationwide Increase in Cryptorchidism after the Fukushima Nuclear Accident. Urology , , . PMID: 29751027 DOI.
↑ Kasai F & Ferguson-Smith MA. (2018). A collection of XY female cell lines. Hum. Cell , , . PMID: 29330774 DOI.
↑ Burcharth J, Pedersen M, Bisgaard T, Pedersen C & Rosenberg J. (2013). Nationwide prevalence of groin hernia repair. PLoS ONE , 8, e54367. PMID: 23342139 DOI.
↑ ^9.0 ^9.1 Eisenberg ML, Hsieh MH, Walters RC, Krasnow R & Lipshultz LI. (2011). The relationship between anogenital distance, fatherhood, and fertility in adult men. PLoS ONE , 6, e18973. PMID: 21589916 DOI.
↑ Ahmed SF, Rodie M, Jiang J & Sinnott RO. (2010). The European disorder of sex development registry: a virtual research environment. Sex Dev , 4, 192-8. PMID: 20501980 DOI.
↑ Lee PA, Houk CP, Ahmed SF & Hughes IA. (2006). Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics , 118, e488-500. PMID: 16882788 DOI.
↑ Warne GL & Hewitt JK. (2009). Disorders of sex development: current understanding and continuing controversy. Med. J. Aust. , 190, 612-3. PMID: 19485836
↑ Xu HY, Zhang HX, Xiao Z, Qiao J & Li R. (2019). Regulation of anti-Müllerian hormone (AMH) in males and the associations of serum AMH with the disorders of male fertility. Asian J. Androl. , 21, 109-114. PMID: 30381580 DOI.
↑ Tartaglia NR, Howell S, Sutherland A, Wilson R & Wilson L. (2010). A review of trisomy X (47,XXX). Orphanet J Rare Dis , 5, 8. PMID: 20459843 DOI.
↑ Nimkarn S & New MI. (2009). Prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Mol. Cell. Endocrinol. , 300, 192-6. PMID: 19101608 DOI.
↑ Reisch N, Flade L, Scherr M, Rottenkolber M, Pedrosa Gil F, Bidlingmaier M, Wolff H, Schwarz HP, Quinkler M, Beuschlein F & Reincke M. (2009). High prevalence of reduced fecundity in men with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. , 94, 1665-70. PMID: 19258407 DOI.
↑ Gottlieb B, Beitel LK, Nadarajah A, Paliouras M & Trifiro M. (2012). The androgen receptor gene mutations database: 2012 update. Hum. Mutat. , 33, 887-94. PMID: 22334387 DOI.
↑ Mooslehner KA, Davies JD & Hughes IA. (2012). A cell model for conditional profiling of androgen-receptor-interacting proteins. Int J Endocrinol , 2012, 381824. PMID: 22518120 DOI.
↑ Virtanen HE & Toppari J. (2008). Epidemiology and pathogenesis of cryptorchidism. Hum. Reprod. Update , 14, 49-58. PMID: 18032558 DOI.
↑ Amann RP & Veeramachaneni DN. (2007). Cryptorchidism in common eutherian mammals. Reproduction , 133, 541-61. PMID: 17379650 DOI.
↑ Moore CR. (1924). THE BEHAVIOR OF THE GERMINAL EPITHELIUM IN TESTIS GRAFTS AND IN EXPERIMENTAL CRYPTORCHID TESTES (RAT AND GUINEA PIG). Science , 59, 41-4. PMID: 17839834 DOI.
↑ ^22.0 ^22.1 Favorito LA, Riberio Julio-Junior H & Sampaio FJ. (2017). Relationship between Undescended Testis Position and Prevalence of Testicular Appendices, Epididymal Anomalies, and Patency of Processus Vaginalis. Biomed Res Int , 2017, 5926370. PMID: 29445742 DOI.
↑ Gapany C, Frey P, Cachat F, Gudinchet F, Jichlinski P, Meyrat BJ, Ramseyer P, Theintz G & Burnand B. (2008). Management of cryptorchidism in children: guidelines. Swiss Med Wkly , 138, 492-8. PMID: 18726735 DOI.
↑ Rey R. (2005). Anti-Müllerian hormone in disorders of sex determination and differentiation. Arq Bras Endocrinol Metabol , 49, 26-36. PMID: 16544032 DOI.
↑ Norman RJ, Wu R & Stankiewicz MT. (2004). 4: Polycystic ovary syndrome. Med. J. Aust. , 180, 132-7. PMID: 14748678
↑ ^26.0 ^26.1 ^26.2 Baskin LS, Himes K & Colborn T. (2001). Hypospadias and endocrine disruption: is there a connection?. Environ. Health Perspect. , 109, 1175-83. PMID: 11713004
↑ Cunha GR, Sinclair A, Risbridger G, Hutson J & Baskin LS. (2015). Current understanding of hypospadias: relevance of animal models. Nat Rev Urol , 12, 271-80. PMID: 25850792 DOI.
↑ Akre O, Boyd HA, Ahlgren M, Wilbrand K, Westergaard T, Hjalgrim H, Nordenskjöld A, Ekbom A & Melbye M. (2008). Maternal and gestational risk factors for hypospadias. Environ. Health Perspect. , 116, 1071-6. PMID: 18709149 DOI.
↑ Gredler ML, Seifert AW & Cohn MJ. (2015). Tissue-specific roles of Fgfr2 in development of the external genitalia. Development , 142, 2203-12. PMID: 26081573 DOI.
↑ Fallahi GH, Sabbaghian M, Khalili M, Parvaneh N, Zenker M & Rezaei N. (2011). Novel UBR1 gene mutation in a patient with typical phenotype of Johanson-Blizzard syndrome. Eur. J. Pediatr. , 170, 233-5. PMID: 20556423 DOI.
↑ Carragher AM. (1990). One hundred years of splenogonadal fusion. Urology , 35, 471-5. PMID: 2191479

Reviews

Passos IMPE & Britto RL. (2020). Diagnosis and treatment of müllerian malformations. Taiwan J Obstet Gynecol , 59, 183-188. PMID: 32127135 DOI.

van der Horst HJ & de Wall LL. (2017). Hypospadias, all there is to know. Eur. J. Pediatr. , 176, 435-441. PMID: 28190103 DOI.

Acién P & Acién MI. (2011). The history of female genital tract malformation classifications and proposal of an updated system. Hum. Reprod. Update , 17, 693-705. PMID: 21727142 DOI.

Ostrer, H. 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis GeneReviews Pagon RA, Bird TD, Dolan CR, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-

Articles

Austin J, Tamar-Mattis A, Mazur T, Henwood MJ & Rossi WC. (2011). Disorders of sex development-when and how to tell the patient. Pediatr Endocrinol Rev , 8, 213-7; quiz 223. PMID: 21525798

Books

Evaluation and Treatment of Cryptorchidism. Penson DF, Krishnaswami S, Jules A, Seroogy JC, McPheeters ML. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Dec. PMID 23326894

Search Pubmed

Search Pubmed: Genital System Abnormalities | Disorders of Sex Development | Hypospadia

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

DSD Consortium Guidelines | Handbook for Parents
EuroDSD EuroDSD programme is a collaboration of doctors and scientists from all over Europe. Long-term outcome studies on the various DSD entities are desperately needed in order to establish a basis for evidence-based medicine regarding sex assignment and conservative and surgical treatment options.
German DSD network
Italian registry for DSD
UK
Intersex Society of North America
Turner Syndrome Society of the U.S.
Androgen Receptor Gene Mutations Database

Historic Embryology
1915 Congenital Cardiac Disease \| 1917 Frequency of Anomalies in Human Embryos \| 1920 Hydatiform Degeneration Tubal Pregnancy \| 1921 Anencephalic Embryo \| 1921 Rat and Man \| 1966 Congenital Malformations

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Cite this page: Hill, M.A. (2023, December 2) Embryology Genital System - Abnormalities. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Genital_System_-_Abnormalities

What Links Here?

[PMID32452519-1] Bird AD, Croft BM, Harada M, Tang L, Zhao L, Ming Z, Bagheri-Fam S, Koopman P, Wang Z, Akita K & Harley VR. (2020). Ovotesticular disorders of sex development (DSD) in FGF9 mouse models of human synostosis syndromes. Hum. Mol. Genet. , , . PMID: 32452519 DOI.

[PMID30803928-2] León NY, Reyes AP & Harley VR. (2019). Differences of sex development: the road to diagnosis. Lancet Diabetes Endocrinol , , . PMID: 30803928 DOI.

[PMID30778893-3] Caprio MG, Di Serafino M, De Feo A, Guerriero E, Perillo T, Barbuto L, Vezzali N, Rossi E, Ferro F, Vallone G & Orazi C. (2019). Ultrasonographic and multimodal imaging of pediatric genital female diseases. J Ultrasound , , . PMID: 30778893 DOI.

[PMID30713084-4] Krege S, Eckoldt F, Richter-Unruh A, Köhler B, Leuschner I, Menzel HJ, Moss A, Schweizer K, Stein R, Werner-Rosen K, Wieacker P, Wiesemann C, Wünsch L & Richter-Appelt H. (2018). Variations of sex development: The first German interdisciplinary consensus paper. J Pediatr Urol , , . PMID: 30713084 DOI.

[PMID30766817-5] Dar SA, Nazir M, Lone R, Sameen D, Ahmad I, Wani WA & Charoo BA. (2018). Clinical Spectrum of Disorders of Sex Development: A Cross-sectional Observational Study. Indian J Endocrinol Metab , 22, 774-779. PMID: 30766817 DOI.

[PMID29751027-6] Murase K, Murase J, Machidori K, Mizuno K, Hayashi Y & Kohri K. (2018). Nationwide Increase in Cryptorchidism after the Fukushima Nuclear Accident. Urology , , . PMID: 29751027 DOI.

[PMID29330774-7] Kasai F & Ferguson-Smith MA. (2018). A collection of XY female cell lines. Hum. Cell , , . PMID: 29330774 DOI.

[PMID23342139-8] Burcharth J, Pedersen M, Bisgaard T, Pedersen C & Rosenberg J. (2013). Nationwide prevalence of groin hernia repair. PLoS ONE , 8, e54367. PMID: 23342139 DOI.

[PMID21589916-9] 9.0 ^9.1 Eisenberg ML, Hsieh MH, Walters RC, Krasnow R & Lipshultz LI. (2011). The relationship between anogenital distance, fatherhood, and fertility in adult men. PLoS ONE , 6, e18973. PMID: 21589916 DOI.

[PMID20501980-10] Ahmed SF, Rodie M, Jiang J & Sinnott RO. (2010). The European disorder of sex development registry: a virtual research environment. Sex Dev , 4, 192-8. PMID: 20501980 DOI.

[PMID16882788-11] Lee PA, Houk CP, Ahmed SF & Hughes IA. (2006). Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics , 118, e488-500. PMID: 16882788 DOI.

[PMID19485836-12] Warne GL & Hewitt JK. (2009). Disorders of sex development: current understanding and continuing controversy. Med. J. Aust. , 190, 612-3. PMID: 19485836

[PMID30381580-13] Xu HY, Zhang HX, Xiao Z, Qiao J & Li R. (2019). Regulation of anti-Müllerian hormone (AMH) in males and the associations of serum AMH with the disorders of male fertility. Asian J. Androl. , 21, 109-114. PMID: 30381580 DOI.

[PMID20459843-14] Tartaglia NR, Howell S, Sutherland A, Wilson R & Wilson L. (2010). A review of trisomy X (47,XXX). Orphanet J Rare Dis , 5, 8. PMID: 20459843 DOI.

[PMID19101608-15] Nimkarn S & New MI. (2009). Prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Mol. Cell. Endocrinol. , 300, 192-6. PMID: 19101608 DOI.

[PMID19258407-16] Reisch N, Flade L, Scherr M, Rottenkolber M, Pedrosa Gil F, Bidlingmaier M, Wolff H, Schwarz HP, Quinkler M, Beuschlein F & Reincke M. (2009). High prevalence of reduced fecundity in men with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. , 94, 1665-70. PMID: 19258407 DOI.

[PMID22334387-17] Gottlieb B, Beitel LK, Nadarajah A, Paliouras M & Trifiro M. (2012). The androgen receptor gene mutations database: 2012 update. Hum. Mutat. , 33, 887-94. PMID: 22334387 DOI.

[PMID22518120-18] Mooslehner KA, Davies JD & Hughes IA. (2012). A cell model for conditional profiling of androgen-receptor-interacting proteins. Int J Endocrinol , 2012, 381824. PMID: 22518120 DOI.

[PMID18032558-19] Virtanen HE & Toppari J. (2008). Epidemiology and pathogenesis of cryptorchidism. Hum. Reprod. Update , 14, 49-58. PMID: 18032558 DOI.

[PMID17379650-20] Amann RP & Veeramachaneni DN. (2007). Cryptorchidism in common eutherian mammals. Reproduction , 133, 541-61. PMID: 17379650 DOI.

[PMID17839834-21] Moore CR. (1924). THE BEHAVIOR OF THE GERMINAL EPITHELIUM IN TESTIS GRAFTS AND IN EXPERIMENTAL CRYPTORCHID TESTES (RAT AND GUINEA PIG). Science , 59, 41-4. PMID: 17839834 DOI.

[PMID29445742-22] 22.0 ^22.1 Favorito LA, Riberio Julio-Junior H & Sampaio FJ. (2017). Relationship between Undescended Testis Position and Prevalence of Testicular Appendices, Epididymal Anomalies, and Patency of Processus Vaginalis. Biomed Res Int , 2017, 5926370. PMID: 29445742 DOI.

[PMID18726735-23] Gapany C, Frey P, Cachat F, Gudinchet F, Jichlinski P, Meyrat BJ, Ramseyer P, Theintz G & Burnand B. (2008). Management of cryptorchidism in children: guidelines. Swiss Med Wkly , 138, 492-8. PMID: 18726735 DOI.

[PMID16544032-24] Rey R. (2005). Anti-Müllerian hormone in disorders of sex determination and differentiation. Arq Bras Endocrinol Metabol , 49, 26-36. PMID: 16544032 DOI.

[PMID14748678-25] Norman RJ, Wu R & Stankiewicz MT. (2004). 4: Polycystic ovary syndrome. Med. J. Aust. , 180, 132-7. PMID: 14748678

[PMID11713004-26] 26.0 ^26.1 ^26.2 Baskin LS, Himes K & Colborn T. (2001). Hypospadias and endocrine disruption: is there a connection?. Environ. Health Perspect. , 109, 1175-83. PMID: 11713004

[PMID25850792-27] Cunha GR, Sinclair A, Risbridger G, Hutson J & Baskin LS. (2015). Current understanding of hypospadias: relevance of animal models. Nat Rev Urol , 12, 271-80. PMID: 25850792 DOI.

[PMID18709149-28] Akre O, Boyd HA, Ahlgren M, Wilbrand K, Westergaard T, Hjalgrim H, Nordenskjöld A, Ekbom A & Melbye M. (2008). Maternal and gestational risk factors for hypospadias. Environ. Health Perspect. , 116, 1071-6. PMID: 18709149 DOI.

[PMID26081573-29] Gredler ML, Seifert AW & Cohn MJ. (2015). Tissue-specific roles of Fgfr2 in development of the external genitalia. Development , 142, 2203-12. PMID: 26081573 DOI.

[PMID20556423-30] Fallahi GH, Sabbaghian M, Khalili M, Parvaneh N, Zenker M & Rezaei N. (2011). Novel UBR1 gene mutation in a patient with typical phenotype of Johanson-Blizzard syndrome. Eur. J. Pediatr. , 170, 233-5. PMID: 20556423 DOI.

[PMID2191479-31] Carragher AM. (1990). One hundred years of splenogonadal fusion. Urology , 35, 471-5. PMID: 2191479

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