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Identification of a novel compound heterozygous mutation of the 5 Alpha-Reductase type 2 (SRD5A2) gene in an extreme premature 46, XY male infant

Objective: To describe the clinical and biochemical
features in a very premature male infant with confirmed
5-alpha reductase type 2 deficiency (SRD5A2).
Case Presentation: A 46, XY male infant born at 26
weeks of gestation presented at day of life 1 with micropenis
and severe hypospadias. Family history was lacking
for consanguinity or genetic diseases. At day of life 3,
Endocrine service was consulted for evaluation of ambiguous
genitalia. Physical examination revealed a small
penile length measured at 1.2 cm (-2.2 SD), penoscrotal
hypospadias, bifid scrotum, cryptoorchid testes and blind
vaginal pouch. Pelvic ultrasonography confirmed bilateral
testicular structures present in the superior aspect of the
inguinal canal. No Mullerian structures were identified.
Persistently elevated testosterone to dihydrotestosterone
(T: DHT) ratio lead to direct sequencing of the SRD5A2
gene using exon specific polymerase chain reaction. DNA
comparative studies revealed a novel missense mutation
within exon 1 of the first allele, with a G>T change altering
codon 69 from Alanine to Serine [Ala69Ser]. A second
previously reported G>A base change was detected
in exon 4, changing the encoded amino acid Glycine to
Serine at codon 196 [p.Gly196Ser] in the other allele. Both
mutations are predicted to be functionally significant.
Discussion: SRD5A2 catalyzes the conversion of testosterone
into DHT. This isoenzyme (type 2) is expressed
in high levels in the prostate and other androgen-sensitive
tissue. The SRD5A2 is located on chromosome 2, region
p23 and is comprised of five exons and four introns (Labrie
et al 1992). Various studies have demonstrated that any
single base mutation of the SRD5A2 gene may result in
reduced enzymatic activity (Andersson et al 1991) and
incomplete virilization.A second isoenzyme (SRD5A1 or
type 1) with 50% sequence identity also exists. Mutations
in the SRD5A2 gene associated with male pseudohermaphroditism
were first described by Thigpen et al (1992).
At least 50 different mutations in the SRD5A2 gene have
been compiled by the Human Gene Mutation Database.
Of these reported cases, about 60% were homozygous.
Conclusion: We describe a novel missense mutation
of the SRD5A2 in an extremely premature, genetically
male infant. This mutation underscores the importance of
the stability of the gene in order to achieve full enzymatic
activity. Early identification allowed timely genetic counseling
for the family in addition to providing a framework
for future care of the patient. Molecular analysis of the
SRD5A2 gene should be pursued in genetic males born
with clinical evidence of hypovirilization and abnormal T:
DHT ratio regardless of gestational age.
Journal/Publication - AACE, April 2010

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