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Disorders of sex development

For the 2015 annual report the team responsible for CARIS chose to focus on disorders of sexual development which had been reported to CARIS between 1998 and 2014. There are a number of different relevant disorders and the causes of each disorder varies. Many of the conditions present on a spectrum, and the severity of the condition can vary from child to child.

There are some congenital conditions in which children who have the outward appearance of one sex, may genetically be of the opposite sex. There are also conditions where children have extra chromosomes in different combinations such as XXY, XXXY or XXYY or missing chromosomes (45X). Most people are born with 46 chromosomes, 44 of which are in 22 pairs. The remaining two are what determines sex at birth. Most males have one X chromosome and one Y chromosome, while most females have two X chromosomes.

There are further conditions where children for various reasons are born with congenital conditions that have affected the development of their genitalia while they were in utero but their chromosomes are as unaffected. 

Several umbrella terms exist to describe children affected by the various conditions. Some professionals and patient groups promote use of the term “intersex” to describe children affected by Androgen Insensitivity Syndrome (AIS) and similar conditions and also ‘children with disorders of sexual development’ or ‘children with ambiguous genitalia’.

5 alpha reductace deficiency

What is it?

This is the lack of an enzyme that converts testosterone to 5 alpha-dihydrotestosterone (DHT) in peripheral tissues. The enzyme is also active in the formation of other hormones. It affects males with a XY chromosome complement. Those affected can have normal looking male genitalia, ambiguous genitalia or normal looking female genitalia at birth. Puberty results in amenorrhoea in those thought to be female and virilisation may occur.

What causes it?

Gene mutations in SRD5A2 (2p23.1) are responsible. The condition is prevalent in the Dominican Republic, Lebanon and Papua New Guinea. It is relatively rare in

Any risk factors?

The transmission is autosomal recessive so genetic counselling is advisable for those at risk in terms of family history and origin.


A fetal karyotype if done antenatally for other reasons will show an XY picture. This may not match up at birth if there are changes in the genitalia.

What is the management and outcome?

The literature says that 2/3 babies are initially assigned female gender. Puberty usually provokes further investigation with amenorrhoea and lack of breast development. Surgery and hormone therapy is necessary and will depend on how the child has been brought up. Most men are infertile due to a low/absent sperm count associated with undescended testes. Those brought up as female are infertile due to the absence of a uterus, Fallopian tubes and ovaries.

What is the pattern in Wales and the world?

This is extremely rare with most cases reported in the Dominican Republic.  See website:

Lay explanation

This is a genetic condition which may be passed down through families. Changes in a specific gene results in a lack of the enzymes called 5-alpha-reductase.  These enzymes are used by the body to make essential changes in the hormone testosterone while the testosterone is being stored in various places in the body. Without the enzymes, testosterone cannot be converted to dihydrotestosterone (DHT) which is needed to form the external sex organs in male children while they are in the womb / uterus. Because the changes don’t take place, this has an impact upon the sexual development of a baby. The impact on the physical development varies. This is why all of the children with the condition are genetically male, with an X and Y chromosome, but some may be assigned as female at birth, while those who are born with ambiguous genitalia may need to have blood tests taken before they are classified as male. As well as the external sexual organs being affected, men with the condition may have a very low sperm count and will therefore be infertile.  The condition is very rare with most of the cases born to parents who originate in the Dominican Republic.

Androgen Insensitivity Syndrome

What is it?

This occurs in a male with a normal XY karyotype but when the body’s cells are partially or completely unresponsive to the male hormones, androgens. This affects the development of male genitalia in the fetus and at puberty. The syndrome can be complete resulting in normal female external genitalia or partial where the external genitalia are partially masculinised.

What causes it?

It’s due to a mutation in the gene that produces androgen receptors. Without enough receptors, cells cannot react to androgen or the reaction is weaker than normal. There is thought to be a spontaneous mutation in a third of cases. It is inherited from the mother’s X chromosome in two thirds of cases.

Any risk factors?

Having a mother who is a carrier gives a chance of 1 in 4 of having an affected boy and 1 in 4 chance of having a girl who is a carrier.


None in the antenatal period. At birth those with partial androgen insensitivity will appear to have ambiguous genitalia. Those with complete androgen insensitivity appear as normal females and the diagnosis is more difficult. The testes that are not visible cause hernias and are discovered when the hernias are repaired.

What is the management and outcome?

Psychological support is valuable as the child gets older, particularly in preparation for puberty. In girls the testes  are normally removed at some stage in their lives, and this is done to reduce the risk of malignancy. Oestrogen therapy is necessary to encourage female development during puberty and maintain secondary sexual characteristics as an adult. Boys may need to take testosterone to encourage facial hair growth and deepening of the voice.

What is the pattern in Wales and the world?

This is a rare condition that may be under diagnosed because of its subtle and late presentation. 6 cases have been reported to CARIS since 1998 giving a rate of 0.1 per 10,000 live births in Wales.

Lay explanation Children born with Androgen Insensitivity Syndrome (AIS) have an X and Y chromosome which is the combination regarded as genetically male. However while they are in the womb they do not develop male sexual characteristics as their bodies do not react to androgens. Androgens are male hormones which includes testosterone, and are necessary for male characteristics to develop.

The syndrome may be complete (CAIS) or partial (PAIS). CAIS is much less common than PAIS. For children with CAIS, their genitals will appear completely female but they will not have ovaries or a womb/uterus, while for children with PAIS there is a spectrum ranging from genitalia that are apparently female to apparently male. All the children are born with testicles, but these may not be obvious externally. The children may respond to female hormone supplements but children with CAIS will not respond to male hormone supplements. Because the baby’s genitalia appear as female at birth, most of the children are raised as females from birth. Diagnosis may not be made until puberty, when the child has investigations into why they are not having periods or developing pubic hair. It is a rare condition, thought to occur in about 1 in 20,000 births  and care of children with the condition should be provided by a specialist team with expertise in dealing with this and similar conditions.

Cryptorchidism / Undescended testes

What is it?

Cryptorchidism is defined as incomplete descent of one or both testes and absence from the scrotum. The testis or testes usually remain in the abdomen or inguinal canal. Unilateral lack of descent is 4 times more common than bilateral lack of descent.

Any risk factors?

Risk factors include family history of a first degree relative, premature delivery, low birth weight and any other genital abnormality.


This is based on a clinical examination but it is important to distinguish between undescended and retractile testes.

What is the management and outcome?

In most cases the testes will move down into the scrotum during the first 3 to 6 months of life. Referral to a paediatric surgeon is usually made before the boy is 6 months of age. If treatment is recommended then an orchidopexy is done, usually before the boy is 2,  to move the testis and secure it in the scrotum. If the testes remain undescended then there is an increase in fertility problems and testicular cancer in later life.

What is the pattern in Wales and the world?

In Wales data remains incomplete for the years before 2008. The overall rate given on the CARIS database is 24.3 per 10,000 live births. However, this rises to 35-40 per 10,000 live births for the years where more complete data is available. NICE quotes a prevalence rate of 3.7% at birth and 1.0% at 3 months of age.  This can be a difficult condition to get accurate numbers as suspected cases may not be reported. Those requiring surgery probably give a more accurate idea of the prevalence. Rates in Wales are comparable to those reported from Western Australia in recent years.


What is it?

This is an anomaly of the male urethra where the urinary meatus (opening) is not at the correct location on the head of the penis[i],[ii].The meatus is on or near the head of the penis in most cases (distal). In the remainder of cases it is near or on the scrotum. The foreskin is usually underdeveloped. Hypospadias is classified using the World Health Organisation’s ICD-10 codes, according to where the meatus is located,

Hypospadias cases registered on the CARIS database 1998 – 2014

Type of hypospadias


% of total known cases

Glanular (Q54.0)



Penile (Q54.1)



Penoscrotal (Q54.2)



Perineal (Q54.3)




There are an additional 501 cases registered on CARIS where the type of hypospadias hasn’t been specified.

All the cases of hypospadias reported to the CARIS database are in males. There is mention of female hypospadias in medical journals and textbooks, however this is much less common than in males and there are no reports of any cases in Wales. In the case of female hypospadias, the urethral opening is situated in the vagina.

What causes it?

This is not known but rising prevalence rates have led to the suggestion that adverse environmental influences including female hormones and pesticides may be implicated.

What are the risk factors?

Clomiphene, a drug used in fertility treatment to stimulate ovulation has been associated with an increased risk of hypospadias[iii]. In 1% of the hypospadias cases reported on the CARIS database, the mothers are known to have taken clomiphene.

Growth restriction has been associated with Hypospadias[iv]. CARIS data shows that 18.4% of cases weigh less than 2.5kgs at birth.

The prevalence in twins has also been found to be increased[v]. CARIS data showed that  4.5% of cases are in twins, in a small number of cases both twins are affected.

What about detection?

This is not seen on antenatal ultrasound. It is diagnosed at birth.

Any associated anomalies?

The most commonly associated anomaly is an undescended testes. (3.2% of cases are associated with undescended testes but data on cyrptorchidism is not complete for some years so this is likely to be an under-estimate). Hypospadias and undescended testes may suggest a disorder of sexual differentiation.

What problems does it cause?

Passing urine may be difficult when the baby is potty trained and in later life, having an adequate erection and having sex may be difficult.

What is the management and outcome?

Mild hypospadias on the glans is usually insignificant and surgery is not always required unless the meatus is stenosed. Surgery may be carried out for cosmetic reasons. If the opening is proximal to the glans (on the shaft of the penis or at the scrotum or perineum) then surgery is necessary which normally takes place after 6 months.

What is the pattern in Wales and the world?

Rates in Wales have been stable for several years at around 30 per 10,000 live births. This is higher than the EUROCAT average of 18 per 10,000 live births but similar to the rate reported in Western Australia[vi].

CARIS tries to collect data on when surgery takes place. Our data is incomplete for the period before 2005. From 2005 to 2012 the date of first surgical correction is known for 419 cases.

Age at first surgical procedure


% of cases

<  2 years old



< 3 years old



< 4 years old



< 5 years old



5+ years old



In summary this data shows that 78.3% of cases notified to CARIS have surgery before their 3rd birthday.

[i] Hypospadias in the Neonate, Stokowski L et al, Advances in Neonatal Care 2004; 4(4)


[iii] Meijer, W. M., de Jong-Van den Berg, L. T.W., van den Berg, M. D., Verheij, J. B.G.M. and de Walle, H. E.K. (2006), Clomiphene and hypospadias on a detailed level: Signal or chance?. Birth Defects Research Part A: Clinical and Molecular Teratology, 76: 249–252. doi: 10.1002/bdra.20243

[iv] Hussein et al “Hypospadias and early gestational growth restriction in infants”  , Pediatrics Vol.109 No 3 March 1, 2002 pp.473-478 (doi: 10.1542/peds 109.2.473)

[v] Fredell L, Kockum I, Hansson E, Holmner S, Lundquist L, Lackgren G, Pedersen J, Stenberg A, Westbacke G, Nordenskjold A “Heredity of hypospadias and the significance of low birth weight” J Urol 167: 1423-1427


Klinefelter’s syndrome

What is it?

Klinefelter’s syndrome results from an extra X chromosome in a male giving a karyotype of 47XXY. It is one of the more common chromosomal anomalies. There may also be undescended testes at birth. Often the diagnosis is not made until puberty as the symptoms are subtle. Symptoms may include muscle weakness, sparse body hair, small genitalia and breast growth and the child may also have developmental delay.  In later life infertility is a primary feature.

What causes it?

The syndrome  originates at an early stage of cell division when an error in splitting of the parental sex chromosomes results in an extra X chromosome in the fetus, either from the mother or the father.

Any risk factors?

Increasing maternal age increases the risk.

Can the syndrome be detected antenatally?

Not usually unless there has been a karyotype done via amniocentesis or chorionic villous sampling for another indication, eg to investigate a high risk Down screening result. If cell free DNA testing of maternal blood becomes available then it is likely that antenatal diagnoses will increase.

What is the management and outcome?

Testosterone replacement therapy and fertility treatment may be needed. Surgery can also be necessary to remove excess breast tissue. Speech therapy, educational and emotional support can also be helpful.

What is the pattern in Wales and the world?

Klinefelters syndrome is underdiagnosed. One study[i] estimated a birth ratio of as many as 1:500 male births. CARIS reports a birth ratio of 1:10,000 live births which is approximately 1:5000 males births

[i] Nielsen J, Wohlert M: Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arthus, Denmark. In Children and Young Adults with Sex Chromosome Aneuploidy. Birth Defects: Original Article SeriesVolume 26. Edited by Evans JA, Hamerton JL. New York: Wiley-Liss, for the March of Dimes Birth Defects Foundation; 1991::209-223~

Micropenis [i]

What is it?

This is an unusually small penis normally diagnosed at birth. The penis itself is otherwise normal as is the scrotum and perineum.

What causes it?

There are many causes mostly associated with reduced production of androgens in the antenatal period. These include gonadal dysgenesis, Klinefelter syndrome, 5 alpha-reductase deficiency, androgen insensitivity syndromes and hypogonadism. Problems with the pituitary gland may also be a cause, as can maternal oestrogen (diethylstilboestrol) ingestion in the antenatal period.


Though a micropenis may make the diagnosis of fetal gender difficult, the presence of a normal scrotum would confirm male sex.

What is the management and outcome?

Testosterone for a short interval is often used in infancy. Surgery is not usually performed in childhood. In the past gender reassignment was considered for severe cases but this is rare these days.

Any recorded cases in Wales?

This condition is perhaps not so well defined or reported.  17 cases have been reported since 1998 giving a rate of 0.3 per 10,000 live births. This may be an underestimate.

[i] Lee, Mazur, Danish et al (1980) Micropenis. Criteria, etiologies and classification The Johns Hopkins medical journal 146(4) 156-163

Mixed Gonadal Dysgenesis

What is it?

This is a disorder of sex development that results in abnormal and asymmetrical development of the gonads. The gonads are also known as sex glands or reproductive glands and occur in both males and females. 

What causes it?

There is an abnormality in the sex chromosomes usually related to mosaicism (45,X/46,XY). Mosaicism is a condition where there are two (or more)chromosomally distinct cell lines within one person. 

What is the clinical picture?

These are very variable ranging from a baby having ambiguous genitalia to a baby with a complete male or female appearance. Commonly the gonads develop asymmetrically. This can result in a testis on one side and only a streak gonad on the other. Other presentations include cryptorchidism and hypospadias.

Those assigned with female sex may have virilisation and features of Turner syndrome (45XO). Short stature may be present in both sexes.


Diagnosis is usually made by checking cytogenetic analysis of the chromosomes. Antenatally this would be done if an amniocentesis or chorion villus sampling was planned e.g. high risk for Down screening. This also may be done if there appears to be a genital problem on ultrasound. Counselling is challenging with an antenatal diagnosis as the outcome can be so varied.

After birth the finding of ambiguous genitalia would prompt investigation with a karyotype.

What is the management and outcome?

The ideal management would involve a multidisciplinary team to plan sex assignment and any surgical procedures which may include the removal of dysgenetic gonads. The role of a supporting psychologist can improve outcomes.

Any recorded cases in Wales?

22 cases have been reported to CARIS between 1998 and 2014. This give a prevalence rate of 0.4 per 10,000 live births in Wales. Prevalence data from other parts of the world are not available.