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Androgen insensitivity syndrome

This is part of Rare diseases.

Diagnosis: Androgen insensitivity syndrome

Synonyms: AIS, Androgen resistance syndrome, Testicular feminisation syndrome

Innehåll


Date of publication: 2009-05-18
Version: 2.0

The disease

Androgen insensitivity syndrome (AIS) is a sex development disorder in which individuals with male chromosomes (XY) respond poorly to male sex hormones (for example testosterone). AIS is the most commonly known reason why children born with male chromosomes and normal levels of sex hormones develop as girls or under-masculinised boys (feminisation).

There are two forms of androgen insensitivity syndrome: complete or partial insensitivity. Children with the complete form have unambiguously female external development, while individuals with the partial form may have a combination of female and male external sexual anatomy, depending on the degree of androgen insensitivity.

Androgen insensitivity syndrome was first described in 1948 by two American physicians, Minni Goldenberg and Alice Maxwell. The physician most closely associated with the syndrome, however, is American gynaecologist John Morris who first coined the term testicular feminisation syndrome in an article from 1953.

Congenital adrenal hyperplasia (CAH) is a different disorder of sex development, in which individuals with female chromosomes (XX) develop as males (virilisation). Separate information about this condition is available in the Swedish rare disease database.

Occurrence

There is great variation in estimates of the occurrence of androgen insensitivity syndrome. The incidence is usually reported to be approximately 1-5 per 100,000 births. Approximately 10 Swedish children per year are born with a sex development disorder, of which about one third are affected by partial androgen insensitivity syndrome. Complete insensitivity to male sex hormones is a very rare condition.

Cause 

Androgen insensitivity is caused by a mutation in the AR gene on the X chromosome. This gene determines the function of the androgen receptor, a protein that responds to signals from male sex hormones and triggers the cell response. In all, over 200 mutations in the AR gene have been described. Some of these mutations impair the ability of the androgen receptor to bind and mediate the effects of testosterone, which plays a crucial role in the development of the male genitalia (the penis, scrotum, prostate, epididymides, and spermatic ducts). If there is no activity in the androgen receptor, no male genitals will develop. Androgen receptor activity is also required for the development of pubic and axillary hair, acne, beard growth, and adult perspiration odours.

In complete androgen insensitivity there is no androgen receptor activity. If some activity remains, or if some cells have normal receptors, the resulting condition is referred to as partial androgen insensitivity syndrome.

Heredity

Androgen insensitivity syndrome is an inherited X-linked recessive disorder. This means that the mutation causing the syndrome is located on the X chromosome, which is one of the sex chromosomes. As a rule, women have two X chromosomes while men have one X chromosome and one Y chromosome. Since the mutated gene is recessive, female carriers are protected by having a second X chromosome with a normal gene, whereas XY individuals who inherit the mutated gene will be affected by the syndrome. XY children (who would normally have become boys) born to female carriers run a 50 per cent risk of inheriting the disorder, and girls (XX) run the same risk of becoming carriers. As affected individuals are generally infertile, the disorder is inherited only via female carriers.

X-linked recessive genetic trait from a healthy woman who is a carrier

Androgen insensitivity syndrome can also be caused by a new mutation, meaning that the mutated gene has not been inherited and is not present in the affected individual’s family. The risk that parents of an affected child will have another child with the disorder is therefore virtually non-existent. The new mutation, however, is hereditary and there is a risk that a person with a new mutation passes it down to the next generation.

Symptoms

Complete and partial type AIS have different symptoms.

In complete androgen insensitivity syndrome (CAIS), the external genitalia are unambiguously female and the diagnosis is not suspected until puberty, when menstruation fails to present. Sometimes the testes are located in the groin, and diagnosis can be made already in infancy when the testes are identified. Girls with CAIS develop little or no pubic and axillary hair. The uterus, ovaries and Fallopian tubes are absent and the vagina is short and blind-ended. These girls have no internal male genitalia (prostate, epididymides, or spermatic ducts), but testicles are always present and appear normal. They may be located in the abdominal cavity or the groin and produce normal amounts of testosterone but no sperm. The absence of gametes and internal genitals results in infertility.

Partial androgen insensitivity syndrome (PAIS) may give rise to a variety of symptoms, and gender assignment is sometimes difficult. Hypospadias is very common, meaning that the urethra opens on the underside of the penis rather than the top. The appearance of the external genitals is often in between male and female: the penis may resemble a large clitoris or the clitoris a small penis. The scrotum is divided and resembles the outer labia of a female.

In very mild cases of PAIS, sex development is unambiguously male, although the penis and scrotum are relatively small and beard growth is sparse. Breasts may develop in puberty, and, in most cases, fertility is impaired.

Diagnosis

When a baby is born with ambiguous genitalia, congenital adrenal hyperplasia (CAH) must be promptly excluded as this condition requires immediate treatment (separate information on CAH is available in the Swedish rare disease database). The diagnosis of androgen insensitivity syndrome is made on the basis of signs and symptoms, gynaecological examination, blood tests for measuring hormone levels, and DNA analysis. The diagnosis is confirmed by the presence of mutations in the androgen receptor gene.

Complete androgen insensitivity syndrome

In CAIS, genital development is unambiguously female, which means that the condition is usually not detected until pubic hair and menstruation fail to appear in puberty. An ultrasound examination is enough to raise strong suspicion of the syndrome, and further examinations and DNA analysis confirm the diagnosis. Undescended testes may cause groin hernias, sometimes leading to earlier diagnosis.

Partial androgen insensitivity syndrome

Visibly atypical genitals enable early diagnosis of partial androgen insensitivity syndrome. External examination is usually not sufficient to determine whether the baby is a feminised genetic male or a virilised genetic female, and gender assignment requires extensive anatomic, genetic, and endocrinological examinations.

Children with androgen insensitivity have male sex chromosomes and produce male sex hormones, but their tissue response to these hormones is poor. As almost all individuals with CAIS and most with PAIS have mutations in the AR gene, DNA-based diagnosis is usually possible.

Following diagnosis, the family should be offered genetic counselling. If the familial mutation is known, prenatal diagnosis is possible.

Treatment/interventions

Because CAH is a condition requiring immediate treatment, it must be considered in all babies with genital ambiguity, and within 24 hours of delivery the child must be referred to a university hospital for investigation and possible CAH treatment. Once this condition has been excluded, the infant is investigated by a multidisciplinary health care team, (a DSD team, Disorders of Sex Development) consisting of specialists in paediatric endocrinology, paediatric surgery, paediatric psychiatry, gynaecology, and genetics. The parents should be given concrete advice in preparation for gender assignment of the baby.

Ethical problems sometimes arise with respect to gender assignment and treatments. The timing and extent of surgical interventions are issues currently under debate, both nationally and internationally, as treatment affects sexuality and sense of self. Treatment goals and planning vary from case to case, but Swedish guidelines specify that examinations and genital surgical procedures should not be performed between the ages of 2 and 12. In most cases, genital surgery is performed early, before the age of 6 months. Additional surgery may be carried out when the child reaches puberty. Some adult women with the syndrome have stressed the importance of restricting early surgical intervention to a minimum, thereby enabling these individuals to participate actively in decision-making affecting their own bodies.

Girls with complete androgen insensitivity may lengthen the vagina non-surgically using manual pressure dilation, which will gradually extend the vagina. This intervention is not begun until the girl is in her teens.

Babies with partial androgen insensitivity should be fully investigated as early as possible so that treatment goals can be set up. The treatment is always individualised and involves careful decision-making. All interventions are planned and consented to by the parents and the physicians involved. In order to facilitate the process of making an informed decision, the parents should be offered several opportunities to discuss the situation with specialist physicians and psychologists.

If it is decided that a child with partial androgen insensitivity should be raised as a girl, the testes are usually removed (gonadectomy). This intervention is performed to prevent pubertal virilisation, as well as to prevent the development of gonadal tumours (the risk of testicular malignancies is elevated from the early teens onwards). In complete androgen insensitivity, it may be preferable to postpone gonadectomy as the testicles produce sufficient female hormones to encourage spontaneous breast development and female body shape in puberty. Delayed surgical intervention also enables the girl to take part in decisions relating to treatment. If androgen insensitivity is complete there is no risk that testosterone from the testicles will virilise the girl. However, if gonadectomy is postponed, the girl must be carefully monitored for early detection of testicular tumours, although these are rare in CAIS.

In girls with partial androgen insensitivity it is important to detect signs of virilisation in puberty. In girls whose testes have been removed, oestrogen replacement therapy is given from the age of 11-12. Gonadectomy is also recommended for girls who have not been diagnosed early.

If gender assignment is male, a biopsy of the testicles should be performed in order to detect early-stage testicular cancer, as this condition requires special treatment. In some cases testosterone supplements are administered in puberty.

Teenagers and adults with the syndrome may feel uncomfortable about their lack of pubic hair. Topical testosterone treatment sometimes stimulates hair growth.

Having a child with a disorder of sex development is an emotionally trying experience for the parents. Under these circumstances it is important how and by whom the parents are informed about the condition. Information must be given by staff with knowledge and experience of the condition, and should comprise medical facts presented lucidly, treatment options, and future prospects. The parents will be better able to support their child if they have had the opportunity to deal with their own thoughts and emotions, and if they learn as much as possible about the condition.

The child needs continuous age-appropriate information and psychological support. Development should be monitored closely, facilitating contact as new questions and problems arise. The need for psychological support may increase in puberty. Teenage girls should be given the opportunity to meet an experienced gynaecologist and discuss the condition, treatment goals, and future plans, including the possibility of having a family.

Girls with the syndrome who have unambiguous external female genitalia, and whose testicles produce enough female sex hormones for breasts and female body shape to develop, usually do not seek medical care until they fail to start menstruation. This means that both the girl and her parents are completely unprepared for the news that she was born with male sex chromosomes and without internal genitalia. Information about the condition should be given and then repeated at a number of appointments with an experienced endocrinologist and/or gynaecologist, possibly together with an experienced paediatric psychiatrist, psychologist, or medical social worker. Surgical interventions must not be planned until the family is fully informed and the girl is able to express her own wishes. The current recommendation is gonadectomy for cancer prevention (it is estimated that the risk of developing gonadal tumours is between 10 and 30 per cent), followed by hormone replacement therapy to maintain breast development, healthy vaginal tissue, and normal bone density.

Adults with the syndrome need continued contact with a physician knowledgeable about the condition, as well as psychological support.

Practical advice

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National and regional resources in Sweden

Specialist knowledge is available at paediatric endocrinology units at university hospital paediatric departments. Clinicians in these units are responsible for the first investigation of the baby. Multidisciplinary teams (consisting of specialists in paediatric endocrinology, paediatric surgery or urology, gynaecology, genetics, and paediatric psychiatry) have been formed at Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, tel +46 8 517 700 00, at The Queen Silvia Children Hospital, Gothenburg, tel +46 31 343 10 00, at the Uppsala University Children’s Hospital, tel +46 18 611 00 00, and at the Centre for Reproductive Medicine in Malmö, tel +46 40 33 10 00. The Centre for Reproductive Medicine is the result of cooperation between the university hospitals in Lund and Malmö. In all these care units, the team liaison is usually a paediatric endocrinologist.

Resource personnel

Paediatric endocrinology

Professor emeritus Sten Ivarsson, Paediatric Endocrinology Research Unit, CRC, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden. Tel +46 040 33 10 00, email: stenanders.ivarsson@telia.com.

Professor emeritus Martin Ritzén, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel +46 8 517 700 00, email: martin.ritzen@ki.se.

Johan Svensson, MD, PhD, Malmö University Hospital, SE-205 02 Malmö, Sweden. Tel +46 40 33 10 00, email: johan.svensson@med.lu.se.

Professor Olle Söder, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel +46 8 517 751 24, email: olle.soder@ki.se.

Anna Nordenström, MD, PhD, Karolinska University Hospital Solna and Huddinge, SE-171 76 Stockholm, Sweden. Tel +46 8 585 800 00, email: anna.nordenstrom@ki.se.

Annika Reims, MD, PhD, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel +46 31 343 40 00, email: annika.reims@vgregion.se.

Associate Professor Otto Westphal, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel +46 31 343 40 00, email: otto.westphal@vgregion.se.

Paediatric surgery/urology

Senior physician Gundela Holmdahl, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel +46 31 343 40 00, email: gundela.holmdahl@vgregion.se.

Professor Göran Läckgren, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel +46 18 611 00 00, email: goran.lackgren@kbh.uu.se.

Professor Agneta Nordenskjöld, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel +46 8 517 777 05, email: agneta.nordenskjold@ki.se.

Christina Clementson Kockum, MD, PhD, Paediatric Surgery Clinic, Lund University Hospital, SE-221 85 Lund, Sweden. Tel +46 46 17 10 00, email: christina.clementsonkockum@skane.se.

Professor Henry Svensson, Plastic Surgery Clinic, Malmö University Hospital, SE-205 02 Malmö, Sweden. Tel +46 40 33 10 00, email: henry.svensson@med.lu.se.

Paediatric psychiatry

Professor Trond Diseth, Paediatric Psychiatry Unit, Rikshospitalet University Hospital, 0027 Oslo, Norway. Tel +47 2307 00 00, email: trond.diseth@rikshospitalet.no.

Professor Per-Anders Rydelius, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel +46 8 517 772 06, email: per-anders.rydelius@kbh.ki.se.

Gynaecology

Professor emerita Kerstin Hagenfeldt (email: kerstin.hagenfeldt@karolinska.se), and Associate Professor Angelica Lindén-Hirschberg (email: angelica.hirschberg@karolinska.se), Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel +46 8 517 700 00.

Professor Martin Stjernquist, Department of Obstetrics and Gynaecology, Malmö University Hospital, SE-205 02 Malmö, Sweden. Tel +46 40 33 10 00, email: martin.stjernquist@med.lu.se.

Genetics

Professor Niklas Dahl, Department of Clinical Genetics, The Rudbeck Laboratory, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel +46 18 611 00 00, email: niklas.dahl@genpat.uu.se.

Associate Professor Yvonne Lundberg Giwercman, CRC, Malmö University Hospital, SE-205 02 Malmö, Sweden. Tel +46 40 39 11 03, email: yvonne.giwercman@med.lu.se.

Maria Soller, MD, PhD, Division of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden. Tel +46 46 17 10 00, email: maria.soller@skane.se.

Professor Anna Wedell, Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel +46 8 517 700 00, email: anna.wedell@ki.se.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations

INIS is a Swedish support group for individuals with disorders of sex development. Email: kontakta@inis-org.se, Internet: www.inis-org.se.

Courses, exchanges of experience for personnel

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Research and development (R&D)

Research aiming to explain the aetiology and treatment of sex development disorders is ongoing at Astrid Lindgren Children’s Hospital and at the Department of Clinical Genetics at the Karolinska University Hospital in Stockholm.

Information material

An information booklet on androgen insensitivity syndrome, which summarises the information in this database text, is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 1998-126-1068). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Information from the Androgen Insensitivity Support Group in Great Britain is available at www.aissg.org.

Information from the North American patient association Accord Alliance can be found at www.accordalliance.org.

The Intersex Society of North America (ISNA) was another North American patient association. It closed down in 2008 when Accord Alliance was formed, but there is still a great deal of information on their website: www.isna.org.

Literature

Brown J, Warne G. Practical management of the intersex infant. J Pediatr Endocrinol Metab 2005; 18: 3-23. Review.

Morris JM, Mahesh VB. Further observations on the syndrome, “testicular feminization”. Am J Obstet Gynecol 1963, 15; 87: 731-748.

Oakes MB, Eyvazzadeh AD, Quint E, Smith YR. Complete androgen insensitivity syndrome - a review. J Pediatr Adolesc Gynecol 2008; 21: 305-310.

Purves JT, Miles-Thomas J, Migeon C, Gearhart JP. Complete androgen insensitivity: the role of the surgeon. J Urol 2008; 180: 1716-1719.

Ritzén M, Gustavson K-H, Wedell A. Genetisk och somatisk könsdifferentiering. I: Sexologi, red P O Lundberg, Liber Förlag, 2002; 17-28.

Thyen U, Richter-Appelt H, Wiesemann C, Holterhus PM, Hiort O. Deciding on gender in children with intersex conditions: considerations and controversies. Treat Endocrinol 2005; 4: 1-8. Review.

Wedell A, Ritzén M, Nordenskjöld A. Pojke eller flicka? Molekylära mekanismer vid könsdifferentiering. Läkartidningen 1997: 449-457, 2000.

Database references

OMIM (Online Mendelian Inheritance in Man)
Internet: http://www.ncbi.nlm.nih.gov/omim
Search: androgen insensitivity syndrome, AIS

GeneReviews (University of Washington)
Internet: www.genetests.org (select Genereviews)
Search: androgen insensitivity syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor emeritus Martin Ritzén, The Astrid Lindgren Children’s Hospital, Stockholm, Sweden.

The relevant organizations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2009-05-18
Version: 2.0
Publication date of the Swedish version: 2009-04-06

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden, tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.