complete androgen insensitivity syndrome

The androgen insensitivity syndrome (AIS) is caused by a defect in the androgen receptor (AR) gene, which results in com­plete (CAIS) or partial (PAIS) androgen insensiti­vity with variable phenotypic expression.

The androgen insensitivity syndrome (AIS) is a rare (approximately 1:20,000 male births), X-linked disorder characterized by 46,XY karyotype, pres­ence of normal testes and normal androgen produc­tion and metabolism.

While in­dividuals with CAIS have female external genitalia (male pseudohermaphrodism), PAIS cases have variable genitalia ambiguity. In the case of PAIS, if the gonads have not descended into the scrotum, the patients must undergo gonadecto­my to eliminate the risk of gonadal malignancy.

Etiology

The AR gene is located on chromosomal locus Xq11-q12. More than 300 mutations have been de­scribed in patients with AIS, which include complete and partial gene deletions, point mutations and small insertions/deletions. It is, however, unclear wheth­er there is a relationship between the site and type of mutation and the abnormality in androgen bind­ing.

Prenatal diagnosis as well as decisions about sex of rearing are hindered because of the clinical heterogeneity of phenotype for a specific mutation.

The AR gene is composed of eight exons, of which exon 1 encodes the N-terminal transcriptional activation domain, exons 2 and 3 encode the DNA-binding domain and exons 4-8 encode the C-terminal ligand-binding do­main.

Individuals with CAIS present at various stages of life, the timing of presentation having changed over the past 50 years as the index of suspicion for the diagnosis has increased.

A very common pre­sentation is the development of inguinal hernia, of­ten bilateral, during infancy. A proportion of indi­viduals, undiagnosed throughout childhood, present after puberty with primary amenorrhea, as was the case in this report.

Karyotypic male individuals with CAIS have unambiguously female external genita­lia, sparse or absent axillary and pubic hair, a blind­ly-ended vagina (which may be shortened or, less often, of normal depth), no uterus and normal breast development at puberty.

The testes may be located at any site along the normal course of testicular de­scent: abdominal, inguinal or in the labia majora. In some cases remnants of the Mullerian or Wolffi­an ducts or their derivatives may be found.

Classically, although not universally, postpuber­tal individuals with CAIS have increased serum con­centrations of LH, normal or elevated serum con­centrations of FSH, T similar to those of normal males and upper limit of normal or elevated blood or urinary estrogens.

The LH-dependent stimula­tion of Leydig cells increases both the testicular an­drogens and estrogens and simultaneously the in­creased testosterone is aromatized to estradiol.

Consequently, the increased estrogens induce breast growth.

Tumor predisposition

Testicular tumors of germ cell and non-germ cell precursors occur with increased frequency in indi­viduals with AIS, although series are small and it is unclear whether the incidence is any greater than that seen in simple cryptorchidism.

Germ cell neo­plasia is usually low grade, such as intratubular germ cell neoplasia (former nomenclature: carcinoma in situ), but seminomas (also called germinomas or dysgerminomas) have occasionally been reported, especially in postpubertal patients.

Tumors of non-germ cell origin also tend to be low grade, the most frequent being adenomas of Sertoli or Leydig cells.

Sertoli-cell adenomas are common, occurring in 23% of the cases.

Although Leydig-cell adenomas are less common, Leydig-cell hyperplasia is well recognized, as chronic gonadot­ropin stimulation may play a role in induction of Leydig-cell hyperplasia and subsequent neoplasia.

Benign lesions, such as hamartomatous nodules, consisting of all components of normal testicular parenchyma but with a disrupted architecture, can also be found, as occurred in our patient.

Inhibin and calretinin were used for immunohistochemi­cal staining of Sertoli and Leydig cells, respectively, suggesting that they constitute valuable markers of normal and neoplastic testicular tissue.

The co-existence of testicular hamartoma with parates­ticular leiomyoma seems to be an extremely rare finding.

Synopsis

 Epididymides/vasa deferentia present (36%)
 varying degrees of seminiferous tubule maturation at puberty
 testicular degeneration
 testicular dysgenesis
 germ cell development delayed

• prolonged expression of the gonocyte markers (placental-like alkaline phosphatase and activator protein-2gamma)

Macroscopical synopsis

 male pseudohermaphroditism
 hypogonadism
 absent vas deferens
 normal female external genitalia
 normal breast development
 sparse pubic hair
 absence of axillary hair
 short blind vagina pouch
 absence of cervix and uterus
 A vagina but no cervix or uterus
 Inguinal hernia with a testis that can be felt during a physical exam
 Normal female breast development
 Testes in the abdomen or other unusual places in the body

Microscopical synopsis

 Leydig cell hyperplasia
 hyaline tubular ghosts
 mitotic germ cells but no spermatozoa
 tumors

• Sertoli cell adenoma
• Ledydig cell adenoma
• possible carcinoma in situ
• bilateral testicular hamartomata (16950754)

 hamartomatous testicles

• hama­rtomatous nodules separated by fibrous tissue
• immature seminiferous tubules lined by im­mature Sertoli cells, spindle-cell stroma resembling ovarian stroma and prominent Leydig cells.
• The immature tubules contain rare spermatogonia.
• all components of normal testicular parenchyma (seminiferous tubules and in­terstitial tissue) with disrupted architecture.
• The seminiferous tubules are normal but pre­pubertal.
• Excess fibrous tissue
• The architecture of the seminiferous tubules can be disrupted.

 serous cyst
 bilateral paratesticular leiomyoma (16950754, 16236398)

 Sertoli and Leydig cells were immunoreactive for inhibin and calretinin, respec­tively.

Etiology

 mutations in the androgen receptor gene (AR - MIM.313700)

• AR-R831X (16950754)

Tumoral predisposition

Germ cell numbers rapidly declined after the first year of life. The risk of premalignant change in germ cells is low before and during puberty. Patients can be advised, therefore, that gonadectomy can be delayed to allow for a natural puberty, with low risk of malignant transformation.

See also

 androgen insensitivity syndrome (AIS)

• incomplete androgen insensitivity syndrome (IAIS)

References

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