Entry: 264600
LinkDB: 264600
MIM Entry: 264600
Title:
#264600 PSEUDOVAGINAL PERINEOSCROTAL HYPOSPADIAS; PPSH
;;MALE PSEUDOHERMAPHRODITISM DUE TO 5-ALPHA-REDUCTASE DEFICIENCY;;
FAMILIAL INCOMPLETE MALE PSEUDOHERMAPHRODITISM, TYPE 2
Text:
A number sign (#) is used with this entry because pseudovaginal
perineoscrotal hypospadias is caused by mutation in the steroid
5-alpha-reductase-2 gene (SRD5A2; 607306).
DESCRIPTION
Pseudovaginal perineoscrotal hypopadias is a form of male
pseudohermaphroditism in which 46,XY males show ambiguous genitalia at
birth, including perineal hypospadias and a blind perineal pouch, and
develop masculinization at puberty. The name of the disorder stems from
the finding of a blind-ending perineal opening resembling a vagina and a
severely hypospadiac penis with the urethra opening onto the perineum.
CLINICAL FEATURES
De Vaal (1955) reported 3 brothers who were thought for a time to be
girls. The parents and grandparents on one side were first cousins, and
the great-grandparents were also related. Simpson et al. (1971)
described a family with 3 affected brothers whose parents were double
first cousins. Each of the affected sibs had an XY karyotype and
ambiguous genitalia, leading to rearing as females. No breast
development or menstruation occurred at puberty, and instead typical
masculinization was observed.
PPSH can be difficult to distinguish from the incomplete testicular
feminization syndrome (ITFS; 300068), especially in the young child. The
distinction is obviously important since PPSH is a male-limited
autosomal recessive with a recurrence risk of 1 in 8, whereas ITFS is
probably X-linked recessive (or autosomal dominant male-limited) as is
the complete syndrome. Wilson et al. (1974) chose to refer to PPSH as
type 2 familial incomplete male pseudohermaphroditism, type 1 being the
Reifenstein syndrome (312300). PPSH resembles the most severe form of
type I incomplete male pseudohermaphroditism, but differs from it by the
lack of breasts and by its autosomal inheritance. Dihydrotestosterone
(DHT) formation is defective in this condition. Testosterone and
estrogen levels are normal, hence the lack of gynecomastia. Other
evidence as well suggests that DHT is important to external
virilization.
In a village in the Dominican Republic, Imperato-McGinley et al. (1974)
studied 12 families with 22 male pseudohermaphrodites. The affected
males were born with ambiguous genitalia and masculinized at puberty
without breast development. The testes were normal histologically. The
patients had no mullerian structures, complete wolffian differentiation,
small phallus, bifid scrotum, urogenital sinus with perineal hypospadias
and blind vaginal pouch. At puberty, they showed male habitus with
excellent muscular development, voice change, enlargement of phallus and
production of semen, but small prostate and scanty beard. Plasma
testosterone was normal; plasma 5-alpha-dihydrotestosterone was low. An
abnormally small amount of radioactive testosterone was converted to
dihydrotestosterone. One woman studied showed the same biochemical
defect.
The disorder has been found in blacks, whites, American Indians, and
Latin Americans, as well as in families from Malta, Jordan, and
Pakistan. Imperato-McGinley et al. (1991) described a cluster of male
pseudohermaphrodites in the Simbari Anga linguistic group in the Eastern
Highlands of Papua New Guinea. Their studies revealed a phenotypic and
biochemical profile similar to that in patients studied in the Dominican
Republic, except for a greater abundance of facial and body hair. DHT is
responsible for masculinization of the external genitalia of the fetus
and for masculinization at puberty. The virilization at puberty in PPSH
may be related to the facts that the reductase is not completely absent
and that low levels of DHT are found in plasma.
BIOCHEMICAL FEATURES
Leshin et al. (1978) suggested the existence of two forms of
5-alpha-reductase deficiency. In one form (represented by a family in
Dallas and by the Dominican kindred), an abnormal Km for substrate and
low activity suggested a structural alteration in the enzyme. In a
second form, represented by a Los Angeles family, activity in the biopsy
specimen was not detectable, although cultured fibroblasts showed normal
activity with normal Km for testosterone. The authors postulated either
a structural mutation that was corrected or compensated for in tissue
culture or a regulatory mutant. These persons have plasma testosterone
levels in the high normal range. Although raised as girls, most change
to a male-gender identity at puberty. This indicates that the effects of
testosterone on the brain override sociocultural factors. Hydroxylation
at the fifth position, converting testosterone to dihydrotestosterone,
seems like an insignificant change; however, functionally it produces a
marked change because in steric configuration the molecule becomes much
flatter and fits its receptor in a way that testosterone cannot (Wilson,
1981). Wilson (1981) studied 14 families; in 11, the enzyme was
virtually undetectable. In the other 3, a qualitative abnormality of the
enzyme was found.
INHERITANCE
Chavez et al. (2000) performed DNA analyses in 2 unrelated subjects with
SRD5A enzyme deficiency and found differences in the mode of
transmission for the disease. Their data showed that in both families
the fathers were carriers for a glu197-to-asp mutation (E197D;
607306.0014), whereas the mothers were carriers for a pro212-to-arg
mutation (P212R; 607306.0013). While patient 1 was identified as a
compound heterozygote for both alterations, patient 2 was found to be
homozygous for the paternal mutation. The reduction to homozygosity for
the E197D mutation, as confirmed by restriction analysis, supported this
view. The authors concluded that their study gives evidence of the first
case of SRD5A deficiency resulting from uniparental disomy and reveals
an alternate mechanism whereby this enzymatic disorder can be derived
from a single parent.
PATHOGENESIS
Thigpen et al. (1993) provided evidence that the 5-alpha-reductase type
1 enzyme is responsible for the virilization in type 2-deficient
subjects during puberty.
CLINICAL MANAGEMENT
Price et al. (1984) presented evidence that high dose androgen therapy
may improve virilization, self-image, and sexual performance in patients
with alpha-reductase deficiency who have male-gender behavior and in
those patients with Reifenstein syndrome (312100) who have normal
amounts of a qualitatively abnormal androgen receptor.
A number of male pseudohermaphrodites have married and expressed a
desire to father a child. However, a deficiency in dihydrotestosterone
production not only impairs differentiation of male external genitalia
but also affects the development and secretory function of the prostate
and seminal vesicles. Consequently, affected adults have a rudimentary
prostate and underdeveloped seminal vesicles, resulting in a highly
viscous semen and an extremely low volume of ejaculate, although sperm
counts may be normal. Katz et al. (1997) described the use of
intrauterine insemination with sperm from a man with this disorder and a
history of infertility. The first pregnancy gave rise to a normal son;
the second pregnancy produced fraternal twins. All 3 children were
heterozygous for the father’s C-to-T mutation in exon 5 of the SRD5A2
gene.
MOLECULAR GENETICS
Jenkins et al. (1992) showed that the enzyme encoded by SRD5A1 (184753)
on chromosome 5 is not the site of the defect in classic PPSH; in 16
patients with deficiency of 5-alpha-reductase, no SRD5A1 gene
rearrangements were detected; in 5 of these subjects, sequence analysis
revealed no mutation in the coding regions of the SRD5A1 gene; linkage
studies with a RFLP showed recombination and heterozygosity, which would
not occur in an autosomal recessive disease. These findings provided
evidence for the existence of 2 steroid 5-alpha-reductase enzymes (see
SRD5A2; 607306).
In 2 related pseudohermaphrodites from the Simbari Anga linguistic group
in the Highlands of Papua New Guinea, Andersson et al. (1991) found
deletion of most of the SRD5A2 gene (607306.0001).
See Also:
Boudon et al. (1995); Cai et al. (1996); Can et al. (1998); Forti
et al. (1996); Greene et al. (1978); Hochberg et al. (1996); Imperato-McGinley
and Gautier (1986); Imperato-McGinley et al. (1975); Imperato-McGinley
et al. (1979); Imperato-McGinley et al. (1980); Jakimiuk et al. (1999);
Komp (1979); Leshin et al. (1978); Makridakis et al. (1999); Moore
et al. (1975); Nordenskjold and Ivarsson (1998); Nordenskjold et al.
(1998); Opitz et al. (1972); Peterson et al. (1977); Pinsky et al.
(1978); Savage et al. (1980); Soderstrom et al. (2001); Thigpen et
al. (1992); Thigpen et al. (1992); Vilchis et al. (1997); Walsh et
al. (1974)
References:
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Deletion of steroid 5-alpha-reductase 2 gene in male pseudohermaphroditism. Natu re 354:
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Boudon, C.; Lobaccaro, J. M.; Lumbroso, S.; Ogur, G.; Ocal, G.;
Belon, C.; Sultan, C.: A new deletion of the 5-alpha-reductase type
2 gene in a Turkish family with 5-alpha-reductase deficiency. Clin.
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gene mutations in the Dominican Republic. J. Clin. Endocr. Metab. 81:
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E.: Steroid 5-alpha-reductase deficiency in man: an inherited form
of male pseudohermaphroditism. Science 186: 1213-1215, 1974. -
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E.; Shackleton, C.; Gajdusek, D. C.: A cluster of male pseudohermaphrodites
with 5-alpha-reductase deficiency in Papua New Guinea. Clin. Endocr. 34:
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: Androgens and the evolution of male-gender identity among male pseudohermaphro dites
with 5-alpha-reductase deficiency. New Eng. J. Med. 300: 1233-1237, -
Imperato-McGinley, J.; Peterson, R. E.; Leshin, M.; Griffin, J.
E.; Cooper, G.; Draghi, S.; Berenyi, M.; Wilson, J. D.: Steroid 5
alpha-reductase deficiency in a 65-year-old male pseudohermaphrodite:
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Jakimiuk, A. J.; Weitsman, S. R.; Magoffin, D. A.: 5-alpha-reductase
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M.; Zervoudakis, I.; Rosenwaks, Z.; Imperato-McGinley, J.: Paternity
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Makridakis, N. M.; Ross, R. K.; Pike, M. C.; Crocitto, L. E.;
Kolonel, L. N.; Pearce, C. L.; Henderson, B. E.; Reichardt, J. K.
V.: Association of mis-sense substitution in SRD5A2 gene with prostate
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activity in extracts of fibroblasts cultured from patients with familial
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7168-7172, 1975. -
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Clinical Synopsis:
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[External genitalia, male];
Pseudohermaphroditism;
Ambiguous genitalia;
Small penis;
Bifid scrotum;
Perineal hypospadias;
Urogenital sinus;
Blind perineal pouch resembling vagina;
[Internal genitalia, male];
Wolffian differentiation;
No Mullerian structures;
Cryptorchid testes;
Small prostate
SKIN, NAILS, HAIR:
[Hair];
Scanty pubertal beard
VOICE:
Male pubertal voice change
ENDOCRINE FEATURES:
Masculinization at puberty;
No breast development or menstruation at puberty;
Plasma dihydrotestosterone (DHT) is decreased;
Defective DHT formation;
Plasma testosterone is normal or increased
LABORATORY ABNORMALITIES:
5-alpha-reductase-2 enzyme deficiency
MISCELLANEOUS:
XY karyotype;
Uniparental disomy;
Often reared as females until puberty;
Variable phenotype (range from completely female to males with mild
undermasculinization)
MOLECULAR BASIS:
Caused by mutations in the 5-alpha-reductase-2 gene (SRD5A2, 607306.0001)
Contributors:
Cassandra L. Kniffin - revised: 10/18/2002
Creation Date:
John F. Jackson: 6/15/1995