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

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 Adamís 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 childís and/or parentsí 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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