NOVEL GENOTYPE IN TWO SIBLINGS WITH 5-α-
REDUCTASE 2 DEFICIENCY: DIFFERENT CLINICAL
COURSE DUE TO THE TIME OF DIAGNOSIS
Kocova M1,*, Plaseska-Karanfilska D2, Noveski P2, Kuzmanovska M2
*Corresponding Author: Professor Dr. Mirjana Kocova, University Pediatric Clinic, Department of
Endocrinology & Genetics, M. Tereza 17, Skopje 1000, Republic of North Macedonia. Tel: +389-70-
242-694. Fax: +389-317-6167. E-mail: mirjanakocova@yahoo.com
page: 69
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DISCUSSION
The SRD5A2 gene encodes the 5-α-steroid reductase
2, which is a protein (isoenzyme) that catalyzes conversion
of testosterone to DHT and a very potent androgen
with a crucial role in the formation of male urethra, prostate,
urogenital sinus, penis and scrotum in the fetal and
postnatal period. Mutations in the SRD5A2 gene result
in a decreased DHT level that produces different sexual
phenotypes. Depending on the DHT level, the genital phenotype
can vary from normal female external genitalia,
isolated hypospadias and micropenis associated with perineal
hypospadias independently of the genotype [9,11,12].
Virilization caused by the existing testes and higher levels
of testosterone, further complicates the prediction of the
phenotype during puberty. Patient 1 had low grade sexual
ambiguity with a slightly enlarged clitoris and palpable
testes in the inguinal region, whereas Patient 2 who was
first seen at the age of 7 had a similar phenotype escalating
to overt male pseudohermaphroditism with a phallus
of 4 cm, perineal hypospadia, one perineal opening, and
labia resembling scrota. Due to the large pubertal testes in
the inguinal channel, virilization was enhanced with the
enlarged Adam’s apple, deep voice, and masculine muscles.
In fact, Patient 2 was a natural history of the disorder
that would have also been the case in Patient 1 if the early
gonadectomy had not been performed.
Delayed diagnosis of 5-ARD is still common [12-14].
The XY karyotype in an individual with female or undermasculinized
external genitalia should raise suspicion of
5-ARD. The measurement of DHT and testosterone/DHT
ratio is not always possible, fully informative, or consistent
with the diagnosis of 5-ARD [3,15,16]. Urinary steroid
profiling using tandem mass spectrometry is proposed
when available [6]. If clinical criteria for 5-ARD are met,
mutational analysis is preferable for the final diagnosis
and it has become increasingly available [13,16,17]. In
Patient 1 the diagnosis was made clinically and on the
basis of testosterone/DHT ratio, and in Patient 2, based
on the family history and virilization during puberty. Later
molecular analysis confirmed an unusual genetic constellation
including a novel SRD5A2 gene deleterious mutation.
Mutations causing 5-ARD are commonly located on
exons 1 and 4 [3].
About 100 different changes in the SRD5A2 gene
have been described, most of which are missense/nonsense
loss of function mutations, including 65.0% homozygous
and 35.0% compound heterozygous ones [3,7,17]. So far,
only a few deletions have been described, without details
about the borders of the deletions [3,4,14]. Our patients
carry two changes in exon 1 of the SRD5A2 gene, one novel
mis-sense mutation inherited from the mother, and a large
deletion encompassing the entire exon 1 including part of
the adjacent intron, inherited from the father.
To the best of our knowledge, the c.146C>A mutation
is novel and has not been previously described in association
with 5-ARD. In the gnomAD v2.1.1 database [18],
this mutation was found in a heterozygous state in only
one subject of Bulgarian descent. The exact mechanism
of the action of the alanine to aspartic acid substitution on
the SRD5A2 protein function remains to be elucidated.
Another amino acid substitution at the same position
(p.Ala49Thr) was present in a hemizygous state in the
father and in a heterozygous state in the healthy sibling
with apparently no effect on normal sexual development.
This variant was previously described in association with
hypospadias [19-21] and prostate cancer, although with
inconsistent findings [22,23].
Our analysis suggested that one of the deletion breakpoints
lies in intron 1, in the region located between the
sequence detected with primers 3 and 4 for reverse transcription-
PCR (rtPCR) [Figure 3(B)]. In this region, there
are several interspersed repeats and low complexity DNA
sequences, however, no such sequences are present upstream
of the SRD5A2 gene. Thus, we have no explanation
of the exact mechanism of the deletion occurrence.
Although some SRD5A2 mutations cause no enzyme
activity and others just influence the proportion of inactivation,
no genotype/phenotype correlation has been
reported, even in patients carrying the same mutations
[3,13]. However, the clinical variability in our patients was
probably due to the timing of the therapeutic procedures.
If mutational analysis had been available earlier in our
patients, it might have changed the sex of rearing, or made
the treatment less complicated.
Sex of Rearing. Most of the patients with 5-ARD
have been assigned with a female sex in the past due to
the severe undervirilization of the external genitalia [24].
Sex reversal later in life can be chosen due to virilization
during puberty. Those raised as females, rarely decide to
change sex, well accepted in society even in the cases with
a clear gender dysphoria although it requires removal of the
testes, breast implantation, vaginoplasty and long-term, if
not lifelong, hormonal therapy [25]. Male sex of rearing,
on the other hand, helps to avoid lifelong hormonal therapy
and allows the potential for fertility [10,26]. However, infrequent
collision of the child’s and/or parents’ wishes, as
well as the recommendations of the medical team, makes
the process of decision making in these children among
the most complicated issues in medicine. In Patient 1,
presenting with a severe under virilization, the decision of
the parents and the medical team recommendations were
similar, and female sex assignment occurred early. Due
to the early orchiectomy, no virilization occurred during puberty, however, she had to undergo breast implantation
and vaginoplasty. Patient 2 was more complicated, due to
the later diagnosis and underestimating of the problem by
the parents until puberty, when significant virilization had
occurred. In this patient many procedures such as extensive
information about the therapy and outcome, psychological
assessment and counseling of the child and parents, and
consultations with an ethics committee were undertaken.
Complicated procedures of female sex completion will
be necessary in the near future. Both patients are psychologically
stable and feel comfortable as females. Keeping
in mind the responsibility of these decisions, the recent
guidelines should be followed in 46,XY under virilized
babies, and leave the possibility for sex reversal for later
in life, if needed [27]. Timing of putative sex reversal
is important, for example, 5-ARD deficiency has been
confirmed in female athletes excelling in athletics, thus
complicating their sports life [28].
In conclusion, we report the first family with two
siblings with 5-ARD from the RN of Macedonia who were
molecularly analyzed in detail and carry a novel genotype
causing the disease. Our data confirm that molecular diagnosis
in under virilized XY children should be undertaken
as early as possible, as it can help timely consultation with
the family in order to carefully and appropriately choose
the sex of rearing.
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