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Original Studies |
-Reductase Type 2 Deficiency and Fertility in a Swedish Family1
Department of Molecular Medicine, Clinical Genetics Unit and Pediatric Surgery (A.N.), Karolinska Hospital/St. Görans Hospital, Stockholm; and Department of Pediatrics (S.-A.I.), University of Lund, University Hospital, Malmö, Sweden
Address all correspondence and requests for reprints to: A. Nordenskjöld, Department of Molecular Medicine, CMM 02, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: agneta.nordenskjold{at}cmm.ki.se
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Abstract |
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-reductase type 2 deficiency was
investigated in a Swedish family with no known consanguinity and in
which the affected males were fertile. The three male siblings
were born with ambiguous external genitalia, and the diagnosis of
5-reductase deficiency was established at the ages of 16, 14, and 10
yr, respectively. All three siblings underwent surgery for hypospadias
repair. At least two of the brothers are demonstrably fertile.
Molecular analysis showed the three brothers to be compound
heterozygotes, carrying two different mutations in exon 4 of the
5-reductase type 2 gene. The two mutations (G196S and H231R) have
been described previously and reported to give rise to partially
functioning enzymes, which may explain the milder phenotype and perhaps
the fertility in the preset three patients. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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-reductase type 2 converts
testosterone to dihydrotestosterone and is crucial for the development
of male external genital organs including the prostate gland (1). The
rare form of male pseudohermaphroditism caused by 5-reductase type 2
enzyme deficiency is inherited in an autosomal recessive fashion.
Neonates with deficiency of this enzyme are usually assigned female
gender at birth and raised as girls, although they are 46,XY
individuals with bilateral testes and male wolffian duct structures. A
predominant characteristic of the disorder is the spontaneous
virilization, both physically and psychologically, that occurs during
puberty because of the effects of testosterone itself (or of
dihydrotestosterone formed by the mutant enzyme) or to an increased
activity of the isoenzyme (5-reductase type 1) or a combination of
both of these (2, 3, 4). Over 30 different mutations variously localized
over the gene have been described (5, 6, 7, 8, 9, 10). The majority of these are
missense or nonsense mutations, giving rise to a nonfunctional or
subfunctional protein (11). Deletions have been described in five
families (1, 7, 10, 12). The clinical spectrum arising from this
deficiency ranges from a male phenotype with hypospadias to a female
phenotype with normal wolffian structures (10). Of the mutations
described to date, 60% are homozygous and 40% are associated with
documented consanguinity (1). Here we report the molecular basis of a
previously reported Swedish 5-reductase type 2-deficient family with
male siblings operated on for hypospadias (13), of whom two are the
first cases of proven fertility to have been reported (14). |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The patients were three siblings born with ambiguous genitalia
and normal male karyotype, 46,XY (13). They all manifested severe
hypospadias, microphallus, well-developed scrotum, and cryptorchidism.
The 5-reductase deficiency was diagnosed after biochemical analysis
at the ages of 16, 14, and 10 yr, respectively. The boys had no
axillary hair, no temporal recession of the hairline, and no
gynecomastia. The phallus sizes when they were diagnosed were 4.5, 2.5,
and 1.3 cm, respectively. Dihydrotestosterone levels were low (0.67
nmol/L in one boy and not measurable in the other two boys;
normal, 0.76–3.0 nmol/L) and testosterone levels were high (31.0, 9.4,
and 1.2 nmol/L, respectively; normal, 0–3.5 nmol/L in children and
6–30 nmol/L in adults), especially in the oldest boy who had reached
puberty. All three brothers were operated on several times for
hypospadias and cryptorchidism. There is no known consanguinity in the
family. Two of the brothers each have a child, and paternity has been
verified (14).
Mutation screening
Constitutional DNA was prepared from the family members according to routine protocols. PCR products generated by exon flanking primers according to the published sequence of the SRD5A2 gene (15) were screened for mutations using a combination of denaturing gradient gel electrophoresis (DGGE) (exons 2 and 4) and single-stranded conformational polymorphism (exons 1, 3, and 5). Fragments manifesting divergent migration were sequenced. Details are available on request.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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, middle
sequence). DNA sequence analysis also showed a mutation in codon 196
that resulted in a change from GGT (glycine) to AGT (serine) (G196S)
(Fig. 1B, middle sequence). Further studies of the individuals in this
family showed that the G196S mutation was inherited from the mother and
the H231R mutation from the father (Fig. 1). The results of the DGGE
screening in the whole family are shown in Fig. 2. The two grandchildren each inherited
the H231R mutation in heterozygous form from their grandfather.
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The H231R mutation in a homozygous form has previously been described in three separate cases from different ethnic groups: Polish, Italian, and German. These cases were all considered to be girls at birth (6, 8, 10). The mutation has even been reported in a heterozygous form in two cases regarded as presumed compound heterozygotes, one in an Afro-American and the other in an American Caucasian proband (1). The American Caucasian patient had ambiguous genitalia from birth and was assigned to be female and the gonads were removed (5).
Most men with 5-reductase deficiency are infertile because of a
number of factors. Deficiency of dihydrotestosterone results in a low
volume ejaculate of high viscosity. Many have azospermia or
oligospermia associated with undescended testes and complications of
genitourinary surgery. Early correction of cryptorchidism and
hypospadias is crucial to prevent damage to the seminiferous tubules
and to preserve spermatogenesis and future fertility.
Even in affected men with adequate spermatogenesis who have undergone
surgical correction of the genitalia, the characteristic very low semen
volume and increased viscosity can reduce fertility (9, 16). Whether
this abnormality is a direct effect of the mutation or a secondary
consequence of incomplete testicular descent is uncertain. Recently,
one couple in which the male had 5-reductase deficiency and a low
semen volume successfully became parents after intrauterine
insemination of his sperm (17).
As mentioned above, G196S (homozygosity) produces a predominantly male phenotype, and in all of these children that have been reported, the phallus is so large that they are identified as males with hypospadias and raised as boys. Comparison of the phenotypes with this mutation show a correlation to exist between the mutation and the phenotype of a given subject.
Biochemical analysis suggested a correlation existed between clinical
expression and severity of the impairment of enzyme function. Eight
mutations including G196S decreased the affinity of the type 2
isoenzyme for nicotinamide adenine dinucleotide phosphate (NADPH) (11).
The other mutation in our patients (i.e. H231R) primarily
affected the ability of the enzyme to bind testosterone (11). The H231R
mutant protein possesses about 15% of the activity of the normal
enzyme and the G196S mutant protein 10% when they are expressed in
cultured cells (11). This may be an alternative explanation of the
masculinization and perhaps the fertility of our patients, because the
majority of missense mutations in the steroid 5-reductase 2 gene are
associated with <0.4% of normal enzyme activity (11).
The H231R mutation has been found in individuals of widely differing geographical and ethnic backgrounds, suggesting that this sequence in exon 4 is a mutational hot spot. The finding that almost half of the subjects are known or presumed compound heterozygotes suggests that the carrier frequency of mutations in the type 2 gene maybe quite high, and thus that the putative mutational hot spots in the gene might result in an increased carrier frequency. Alternatively, there may be an as yet unidentified selective advantage to being a heterozygous carrier.
The diagnosis of 5-reductase deficiency must be taken into
consideration in the differential diagnosis of boys with hypospadias
(at least familial hypospadias), especially in cases with
cryptorchidism and/or a small phallus. It is important that the
diagnosis be made in infancy by means of biochemical and molecular
techniques, because these patients should be considered to be boys from
birth.
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Acknowledgments |
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Footnotes |
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Received November 17, 1997.
Revised June 2, 1998.
Accepted June 9, 1998.
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References |
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5-reductase deficiency. Clin Endocrinol (Oxf). 43:183–188.[Medline]
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in early infancy may be due to partial function of mutant enzyme. Clin
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-reductase deficiency. Am J Med Genet. 63:223–230.[CrossRef][Medline]
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isoenzyme. Biochemistry. 33:1265–1270.[CrossRef][Medline]
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pseudohermaphroditism. Nature. 354:159–161.[CrossRef][Medline]
-reductase deficiency in a
Swedish family. Eur J Pediatr. 147:532–535.[CrossRef][Medline]
-reductase deficient men are
fertile. Eur J Pediatr. 155:425.
-reductase gene. Endocrinology. 131:1571–1573.-reductase deficiency. J Clin
Endocrinol Metab. 79:409–414.[Abstract]
-
reductase-2 deficiency. N Engl J Med. 336:994–997.This article has been cited by other articles:
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  F. Baldinotti, S. Majore, A. Fogli, G. Marrocco, P. Ghirri, M. Vuerich, S. Tumini, B. Boscherini, M. Vetri, S. Scommegna, et al. Molecular Characterization of 6 Unrelated Italian Patients With 5{alpha}-Reductase Type 2 Deficiency J Androl, January 1, 2008; 29(1): 20 - 28. [Abstract] [Full Text] [PDF]
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 H. T. T. Thai, M. Kalbasi, K. Lagerstedt, L. Frisen, I. Kockum, and A. Nordenskjold The Valine Allele of the V89L Polymorphism in the 5-{alpha}-Reductase Gene Confers a Reduced Risk for Hypospadias J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6695 - 6698. [Abstract] [Full Text] [PDF]
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M. Fernandez-Cancio, M. Nistal, R. Gracia, M. A. Molina, J. A. Tovar, C. Esteban, A. Carrascosa, and L. Audi Compound Heterozygous Mutations in the SRD5A2 Gene Exon 4 in a Male Pseudohermaphrodite Patient of Chinese Origin J Androl, May 1, 2004; 25(3): 412 - 416. [Abstract] [Full Text] [PDF]
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