Reifenstein syndrome
PAIS; Androgen insensitivity syndrome - partial; Incomplete testicular feminization; Type I familial incomplete male pseudohermaphroditism; Lubs syndrome; Reifenstein syndrome; Rosewater syndrome; Partial androgen insensitivity syndrome - Intersex; Differences of sex development
Partial androgen insensitivity syndrome (PAIS) is when a person who has one X and one Y chromosome (typically seen in males) but is resistant to hormones that produce a male appearance (called androgens). As a result, the person has some of the physical traits of a female, but the genetic makeup of a male.
PAIS is a type of androgen insensitivity syndrome (AIS). AIS is one of the conditions that are described as differences of sex development (DSD).
The male reproductive system, viewed from a sagittal section.
Causes
In the first 2 to 3 months of pregnancy, all babies have the same genitals. As a baby grows inside the womb, male or female genitals develop depending on the pair of sex chromosomes the baby has from the parents (XY for male, XX for female). It also depends on the levels of androgens. In a baby with XY chromosomes, high levels of androgens are made in the testes. This baby will develop male genitals. In a baby with XX chromosomes, there are no testes and the levels of androgens are very low. This baby will develop female genitals.
PAIS is caused by genetic defects on the X chromosome. These defects make the body less able to respond to androgens. This leads to problems with the development of the male sex organs. At birth, the baby may have ambiguous external genitals. This means that they do not look typically either male or female.
The syndrome is passed down genetically (X-linked recessive inheritance). People with two X chromosomes are not affected if only one copy of the X chromosome carries the genetic variant. Males who inherit the gene from their mothers will have the condition. There is a 50% chance that a male child of a mother with the genetic trait will be affected. Every female child of a mother with the genetic trait has a 50% chance of carrying the genetic trait. Family history is important in determining risk factors of PAIS.
Symptoms
People with PAIS may have both male and female physical characteristics. These characteristics vary from person to person. These may include:
- Inguinal hernia.
- Male breast development at the time of puberty. (gynecomastia)
- Testes in the abdomen or other atypical places in the body (undescended testicles).
- A very small penis (micropenis).
- The opening of the urethra is on the underside of the penis, not the tip (hypospadias).
- Scrotum that is split in two (bifid scrotum).
- A vagina but no cervix or uterus.
- A short vagina.
- A very large clitoris.
- Partial closing of the labia.
- Sexual dysfunction.
- Infertility.
Exams and Tests
PAIS is often discovered during childhood because the person may have both male and female physical characteristics. The health care provider will perform a physical exam.
Tests may include:
- Blood tests to check levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH)
- Genetic tests such as karyotyping to determine the person's genetic makeup
- Sperm count
- Testicular biopsy
- Pelvic ultrasound to check if female reproductive organs are present
Treatment
Infants with PAIS may be assigned a gender depending on the extent of genital ambiguity. However, gender assignment is a complex issue, and the need for it and the timing of it must be considered carefully. PAIS can be distressing for parents and families. While early surgery may make the parents feel more comfortable, the child may not be happy with the decision as they become older. Many health experts and intersex advocates suggest waiting until the child is old enough to be involved in the decision, unless surgery is needed for the health of the infant.
Possible treatments for PAIS include:
- Surgery may be done to reduce breasts, repair undescended testicles, or reshape the penis to provide a more male appearance. They may also receive androgens to help facial hair grow and deepen the voice.
- Surgery may be done to remove the testicles and reshape the genitals to provide a more female appearance. The female hormone estrogen is then given during puberty.
Treatment and gender assignment can be a very complex issue and must be targeted to each individual person. Treatment guidelines are still evolving.
It is vital that children with PAIS and their parents receive care and support from a health care team that includes different specialists with expertise in gender medicine. This should include mental health professionals to help provide support for both children and their parents.
Support Groups
The following groups can provide more information on PAIS:
- Interact Advocates for Intersex Youth --
interactadvocates.org - NIH Genetic and Rare Diseases Information Center --
rarediseases.info.nih.gov/diseases/5692/partial-androgen-insensitivity-syndrome
Outlook (Prognosis)
Androgens are most important during early development in the womb. People with PAIS can have a normal lifespan and be totally healthy, but they may have difficulty conceiving a child.
Possible Complications
Possible complications may include:
- Infertility
- Psychological and social issues
- Testicular cancer
When to Contact a Medical Professional
Contact your health care provider if your child has signs or symptoms of the syndrome. Genetic testing and counseling are recommended if PAIS is suspected.
Prevention
Prenatal testing is available. People with a family history of PAIS should consider genetic counseling.
References
Chan Y-M, Hannema SE, Achermann JC, Hughes IA. Disorders of sex development. In: Melmed S, Auchus, RJ, Goldfine AB, Koenig RJ, Rosen CJ, eds. Williams Textbook of Endocrinology. 14th ed. Philadelphia, PA: Elsevier; 2020:chap 24.
Délot EC, Vilain E. Differences of sex development. In: Strauss JF, Barbieri R, Dokras A, Williams CJ, Williams Z, eds. Yen & Jaffe's Reproductive Endocrinology. 9th ed. Elsevier; 2024:chap 17.
Donohoue PA. Disorders of sex development. In: Kliegman RM, St. Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson Textbook of Pediatrics. 21st ed. Philadelphia, PA: Elsevier; 2020:chap 606.
Genetic and Rare Diseases Information Center website. Partial androgen insensitivity syndrome.
Matsumoto AM, Anawalt BD. Testicular disorders. In: Melmed S, Auchus RJ, Goldfine AB, Koenig RJ, Rosen CJ, eds. Williams Textbook of Endocrinology. 14th ed. Philadelphia, PA: Elsevier; 2020:chap 19.
Shnorhavorian M, Fechner PY. Differences in sex development. In: Gleason CA, Sawyer T, eds. Avery's Diseases of the Newborn. 11th ed. Philadelphia, PA: Elsevier; 2024:chap 85.
Yu RN, Diamond DA. Disorders of sexual development: etiology, evaluation, and medical management. In: Partin AW, Dmochowski RR, Kavoussi LR, Peters CA, eds. Campbell-Walsh-Wein Urology. 12th ed. Philadelphia, PA: Elsevier; 2021:chap 48.
Version Info
Last reviewed on: 10/13/2022
Reviewed by: Anna C. Edens Hurst, MD, MS, Associate Professor in Medical Genetics, The University of Alabama at Birmingham, Birmingham, AL. Review provided by VeriMed Healthcare Network. Also reviewed by David C. Dugdale, MD, Medical Director, Brenda Conaway, Editorial Director, and the A.D.A.M. Editorial team. Editorial update 03/12/2024.
