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In a patient studied by Wilkins (1957),
the hair follicles of the axillary and pubic areas, although anatomically
normal, were unresponsive to local or parenteral administration of
androgens and the beard, voice, and clitoris were similarly unresponsive.
This was the first demonstration that the basic defect in cases of
the hairless pseudofemale type is end-organ unresponsiveness to androgen,
a situation comparable to nephrogenic diabetes insipidus and pseudohypoparathyroidism.
(These conditions are analogous to the situation in the Sebright Bantam
cock which has a female comb structure despite obvious demonstrations
of virility.
Albright et al. (1942) misspelled 'Sebright'
in their classic article.) It is likely that more than one distinct
entity is included in the testicular feminization syndrome.
Wilkins stated: 'in about one-third of the cases of male pseudohermaphroditism
'of feminine type' sexual hair has been entirely lacking.'
Morris (1962) called attention to the following
case of Gayral et al. (1960): a woman,
who was sister, mother, and grandmother of affected males, showed
asymmetry in the development of the breasts, body hair, and vulva.
The right breast was smaller than the left and there was no pubic
hair to the right of the mid-line.
She had always had menstrual irregularity but had 3 children, an affected
male, a carrier daughter, and a daughter who was the mother of 3 unaffected
sons.
The findings may be best explained by an X-linked recessive (or incompletely
recessive) gene whose effects are to render tissues resistant to male
hormone, the patchy changes in the heterozygous female representing
the Lyon phenomenon.
According to Wilson (1976), Morris
(1953) first described incomplete testicular feminization and
concluded that the complete and incomplete forms never occur in the
same family.
The incomplete syndrome resembles the complete form in respect to
female phenotype, bilateral testes and 46,XY karyotype, but differs
by clitoral enlargement from birth and virilization at puberty.
The abnormality of the external genitalia is characteristic; fusion
of the labioscrotal folds occurs for about half of the dorsal portion.
Although the degree of masculinization of the external genitalia is
variable, most patients are raised as females.
In the family described by Lubs et al. (1959),
some spermatogenesis was found.
There is partial responsiveness to androgen (Winterborn
et al., 1970) in this form of the disorder.
It can be difficult to distinguish clinically the incomplete testicular
feminization syndrome from pseudovaginal perineoscrotal hypospadias
(264600), which is autosomal
recessive.
Opitz et al. (1972) concluded that the
consanguineous family reported by Philip and
Trolle (1965) had pseudovaginal perineoscrotal hypoplasia.
Boczkowski and Teter (1965) described 3
cases of incomplete testicular feminization among the children of
2 sisters.
Wilson (1981) studied 35 families with
1 of the 4 forms of androgen insensitivity: testicular feminization,
incomplete testicular feminization, Reifenstein syndrome, or infertile
male syndrome.
In 31 of the families, he found an abnormality of the androgen receptor:
abnormal binding, qualitatively abnormal receptor or decreased amount
of receptor.
In the other 4, no abnormality of receptor could be demonstrated.
Bals-Pratsch et al. (1990) found qualitative
and quantitative abnormalities of the androgen receptor in 3 brothers
with prepenile scrotum (congenital transposition of the penis), bifid
scrotum, scrotal hypospadias, and bilateral undescended testes.
In 2 brothers with perineal hypospadias, Batch
et al. (1993) found a qualitative androgen binding defect and
a point mutation in the AR gene (313700.0020);
they suggested that familial hypospadias is part of the phenotypic
spectrum of partial androgen sensitivity.
Kaufman et al. (1984) studied an XY patient,
with ambiguous genitalia at birth and breast development at puberty,
whose cultured fibroblasts showed normal initial formation of low-affinity
androgen-receptor complexes but defective transformation of these
complexes to a higher affinity state.
They presumed that the defect was in the X-linked structural gene
for androgen receptor.
A qualitative defect of the androgen receptor was demonstrated (Kovacs et al., 1984); although its binding
properties were normal, it was unstable on sucrose density gradient
centrifugation.
Hughes and Evans (1986) described 2 sibs
with classic complete androgen insensitivity syndrome but increased
androgen receptor concentrations in genital skin fibroblasts.
The steroid-receptor complex appeared to be translocated normally
into the nucleus.
They concluded that 'the gene coding for the androgen receptor is
intact and does not account for the androgen insensitivity.' But is
it not possible that the mutation is in the part of the receptor that
is concerned with its effects on DNA? Pinsky
et al. (1987) described a family in which the proposita and her
aunt had partial androgen resistance of a type different from those
previously described.
Although there was normal maximum binding capacity, there was an increased
apparent equilibrium dissociation constant with dihydrotestosterone
and 2 synthetic androgens.
Grino et al. (1988) described a family
in which gynecomastia and undervirilization occurred in 5 men, 4 of
whom had fathered children, in a pedigree pattern consistent with
X-linked recessive inheritance.
In fibroblasts cultured from genital skin from 2 of the men, the levels
of androgen receptor and the affinity of receptor for dihydrotestosterone
were normal.
However, androgen binding in fibroblast monolayers was thermolabile,
up-regulation of receptor levels did not occur after prolonged incubation
with dihydrotestosterone or methyltrienolone, and dissociation rates
at 37 degrees centigrade were increased with the synthetic androgen
mibolerone.
In addition, in cytosol preparations the androgen receptor protein
was unstable.
Grino et al. (1988) suggested that this
disorder represents the most subtle functional abnormality of androgen
receptor characterized to date, since it was compatible with normal
male phenotypic development and in some affected men with fertility.
Davies et al. (1997) described 2 patients
with complete androgen insensitivity syndrome (CAIS) and mental retardation
associated with submicroscopic deletion of the AR gene.
They pointed to the report of another patient with associated CAIS
and MR.
They postulated that the deletion involves, in addition to the AR
gene, 1 or more neighboring genes that are implicated in nonspecific
MR.
Additional abridged information regarding clinical features is available in the clinical synopsis.
Griffin (1979) found a qualitative abnormality
of androgen receptor, manifested by thermolability, in some cases
of testicular feminization.
Binding overlapped the normal range at 26 degrees C. It was half-normal
at 37 degrees and less than 20% of normal at 42 degrees.
Gerli et al. (1979) described a case of
complete testicular feminization syndrome in a person with the 47,XXY
karyotype.
Obviously, nondisjunction occurred in the carrier mother, who was
40 years old.
Two sibs and a daughter of each of 2 sisters of the patient also had
testicular feminization.
Unlike the usual cases, the patient had low plasma testosterone and
high gonadotropins.
German and Vesell (1966) reported this
situation in monozygotic twins.
Kaufman et al. (1979) reported 2 'receptor-positive'
cases of complete androgen insensitivity.
One of these had maternally related affected relatives in 3 successive
generations.
Kaufman et al. (1981) suggested that whereas one class of mutation that affects the structural domain of the androgen receptor confers increased dissociability and defective up-regulation (a term they coined), a second impairs up-regulation only.
Also see the mapping section under androgen receptor (AR; 313700).
Edwards et al. (1992) demonstrated that
the distribution of the number of CAG repeats in exon 1 of the AR
gene was lowest in African-Americans, intermediate in non-Hispanic
whites, and highest in Asians.
The distribution of allele size was bimodal in African-Americans,
and only in African-Americans was there a deviation from Hardy-Weinberg
equilibrium.
Irvine et al. (1995) studied the distribution
of the CAG and GC repeats (microsatellites) in exon 1 of the AR gene
in African-Americans, non-Hispanic whites, and Asians (Japanese and
Chinese) and confirmed the findings of Edwards
et al. (1992).
The frequency of prostatic cancer (176807)
in the 3 racial groups is inversely proportional to the length of
the repeats.
One of the critical functions of the product of the AR gene is to
activate the expression of target genes.
This transactivation activity resides in the N-terminal domain of
the protein which is encoded in exon 1 which contains the polymorphic
repeats.
The smaller size of the CAG repeat is associated with a higher level
of receptor transactivation function, thereby possibly resulting in
a higher risk of prostate cancer.
Irvine et al. (1995) noted that Schoenberg
et al. (1994) had observed a somatic mutation resulting in a contraction
of the CAG repeat from 24 to 18 in an adenocarcinoma prostate and
the effects of the shorter allele were implicated in the development
of the tumor.
Bullock and Bardin (1972) concluded that
androgen-binding proteins are absent from the cytosol of preputial
gland of Tfm rats and from the kidney of Tfm mice.
Testicular feminization rats, despite female external sexual development,
show masculine sexual behavior and little feminine sexual behavior.
In the Tfm mouse, Charest et al. (1991)
demonstrated a single base deletion in the N-terminal domain of the
androgen receptor, resulting in a frameshift mutation.
Gaspar et al. (1991) independently demonstrated
the same abnormality.
They found no structural aberration in the coding region of the messenger
by a series of RNase-protection assays.
However, cell-free translation of RNAs transcribed in vitro from enzymatically
amplified overlapping segments of exon 1 demonstrated a truncated
receptor protein.
Sequence analysis showed deletion of a single nucleotide in the hexacytidine
stretch at position 1107-1112 altering the reading frame of the messenger
and introducing 41 missense amino acids before the premature termination
codon at position 1235-1237.
In female mice heterozygous for the Tfm gene, Takeda et al. (1987) demonstrated mosaicism in 2 androgen target tissues by steroid autoradiographic techniques, thus documenting X-linked inheritance. See also Takeda et al. (1987).
Miller (1961) considered 'feminizing labial
testes' of the type described by Lubs et al.
(1959) to be a separate form of male pseudohermaphroditism.
However, Wilson et al. (1984) described
well-studied cases that indicated that the Lubs syndrome (Lubs
et al., 1959), like classic testicular feminization, is due to
mutation in the androgen receptor.
The patients were first cousins; their mothers were sisters.