Abstract
5-α-Reductase type 2 enzyme catalyzes the conversion of testosterone into dihydrotestosterone, a potent androgen responsible for male sexual development during the fetal period and later during puberty. Its deficiency causes an autosomal recessive disorder of sex development characterized by a wide range of under-virilization of external genitalia in patients with a 46,XY karyotype. Mutations in the SRD5A2 gene cause 5-α-Reductase deficiency; although it is an infrequent disorder, it has been reported worldwide, with mutational heterogeneity. Furthermore, it has been proposed that there is no genotype-phenotype correlation, even in patients carrying the same mutation. The aim of this review was to perform an extensive search in various databases and to select those articles with a comprehensive genotype and phenotype description of the patients, classifying their phenotypes using the external masculinization score (EMS). Thus, it was possible to objectively compare the eventual genotype-phenotype correlation between them. The analysis showed that for most of the studied mutations no correlation can be established, although the specific location of the mutation in the protein has an effect on the severity of the phenotype. Nevertheless, even in patients carrying the same homozygous mutation, a variable phenotype was observed, suggesting that additional genetic factors might be influencing it. Due to the clinical variability of the disorder, an accurate diagnosis and adequate medical management might be difficult to carry out, as is highlighted in the review.
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Introduction
Gender assignment at birth based on the appearance of the external genitalia is a routine protocol in medical practice. The pathway for the development of the external and internal genitalia acts during fetal life, being a continuum with a hormonal independent phase followed by a hormonal dependent one. Mutations affecting any component of these genes and perturbation of the hormonal pathways could impair the normal development of the genitalia structure, causing different grades of masculinization or under-virilization in newborns with 46,XX or 46,XY karyotypes, respectively [1, 2]. When this situation occurs, it is not possible to arbitrarily assign a sex to the newborn.
These disorders, formerly called male pseudohermaphroditism, group a wide variety of conditions now termed “disorders of sex development” (DSD), the definition of which was established by the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrinology Society in a document known as the Chicago Consensus. It was defined as a congenital condition in which there is no concordance between chromosomal, gonadal, or anatomical sex [3, 4].
Among the 46,XY DSD group, 5-α-Reductase type 2 deficiency (OMIM 264600) is infrequent; it is an autosomal recessive sex-limited condition resulting in the inability to convert testosterone (T) to the more physiologically active dihydrotestosterone (DHT), thus producing a wide range of genital ambiguity at birth and pronounced masculinization at puberty.
This disorder was first reported in 1974 in two siblings from Dallas and in a large kindred from the Dominican Republic, all of whom had pseudovaginal perineoscrotal hypospadias, ambiguous external genitalia and marked masculinization at puberty [5, 6]. From that time to the present, the etiology of the disease has been elucidated, as well as its molecular basis.
The disorder, although infrequent, has been reported in many populations worldwide (Caucasian, Arabic, Asian, and South American). To date, more than 60 mutations have been described, some of these shared by patients of different ethnic origin and others associated with a unique origin [7].
The aim of this review was to collect the main information generated to date assessing the genotype-phenotype correlation in patients worldwide. The need to upgrade our knowledge about the pathways involved in sex differentiation and thereby to improve the medical management of patients is discussed.
5-α-Reductase type 2 deficiency
5-α-Reductase type 2 enzymatic activity
The microsomal enzyme steroid 5-α-Reductase catalyzes testosterone (T) to dihydrotestosterone (DHT) conversion by double-bounded reduction, using NADPH as a cofactor. Both hormones (T and DHT) bind to a unique receptor, the androgen receptor (AR). T-AR or DHT-AR complexes participate in several physiological reactions, acting as transcription factors of genes involved in sexual differentiation [8, 9]. The initial data about its mode of action were obtained from fibroblast cultured studies in which two enzyme activities were observed in two pH ranges with a markedly different cellular distribution. A 5.5 optimum pH was found in fibroblast derived from genital skin and a second enzyme activity with an alkaline optimum pH was widely located in fibroblast from non-genital skin. Furthermore, patients with 46,XY DSD presented no activity of 5-α-Reductase at pH 5.5, but the activity at pH 9 was unaltered. This finding suggested the existence of at least two different 5-α-Reductase activities that represent two enzymes, or one enzyme with post-translational modifications [10,11,12]. The cloning and expression of the two different cDNA (from rat liver and prostate) showed different biochemical features, demonstrating that both genes codify for two different proteins which catalyze the same reaction. Thus, two isozymes were described, type 1 the first cloned and type 2 the second one, which was associated with 5-α-Reductase deficiency. Type 1 isozyme comprises 259 amino acids and has a molecular weight of 29.5 KDa and an optimum pH between 6 and 8.5. On the other hand, type 2 isozyme is formed of 254 amino acids and has a molecular weight of 28.4 KDa and an acidic optimum pH near to 5.0. Both isozymes also differ in T affinity, type 2 showing higher affinity (apparent Km = 0.1–1.0 μM). Conversely, apparent Km between 1.0 and 5.0 was detected for type 1 isozyme. A third characteristic is that both enzymes differ in their inhibitor susceptibility: type 1 5-α-Reductase is insensitive to the inhibitor finasteride [8, 13,14,15].
The SRD5A2 gene
SRD5A2 belongs to a family of isozyme genes. As mentioned, two members were identified, SRD5A1 and SRD5A2, named in the order of their cloning. Both genes share 50% identity and both have five exons and four introns, but SRD5A1 is located on chromosome 5 at 5p15 and SRD5A2 on chromosome 2 at 2p23, being differentially expressed [13, 15,16,17]. Subsequently, other members of this family were identified, belonging to two different subfamilies. SRD5A3 is located on chromosome 4 at 4q12 and does not show 5-α-Reductase activity; recently its function was established, being mainly involved in protein N-glycosylation [18, 19]. The third subfamily is composed of two genes: GPSN2 and GPSN2-like located on chromosomes 19 and 4, respectively, both participating in de novo synthesis of fatty acids [20]. Despite the fact that each subfamily has been associated with different substrates, its biochemical characteristic of double-bounded reduction is preserved.
Phenotype
The first patients presenting male pseudohermaphroditism, identified as having 5-α-Reductase deficiency, were described by Imperato-McGinley and Walsh in 1974. They reported that at birth the patients presented genital ambiguity, with a clitoris-like phallus, a blind vagina pouch, palpable testes in the scrotum that resembled mayor labia or cryptorchidism and no Müllerian structures. A relevant characteristic was that at puberty they virilized and male physiognomies appeared, i.e., deep voice, phallus enlargement, with no breast development [5, 21]. Since then several cases have been described with a wide phenotypic range. In an extensive cohort studying 55 patients of different ethnic origins, the main characteristics shared by them were female external genitalia with clitoromegaly or microphallus and variable grades of hypospadias [22]. In the current review, an extensive search for all published articles regarding the 5-α-Reductase deficiency was undertaken using the PubMed resource. Unfortunately, specific clinical phenotype descriptions are scarce; thus, only articles providing ample phenotype and genotype details were selected.
A total of 256 patients were included in the review. The main phenotypic findings were grouped as follows: clitoromegaly or microphalus was reported in 66.1% (169/256) of patients; different grades of hypospadias was the second most common feature presented in 39.84% (102/256) of cases; unilateral and bilateral cryptorchidism were found to be reported in 19.92% (51/256) of cases. Those phenotypes considered mostly male or female were infrequent, 7.03% (18/256) and 3.9% (10/256) of cases, respectively. Among all cases, virilization at puberty has been extensively reported in SRD5A2 deficiency and gender change from female to male has been described frequently, the latter attributed to brain exposition to T in fetal, neonatal, and puberty stages [23,24,25].
Genotype
To date, more than 100 mutations have been described; 84 missense and nonsense mutations are scattered through the SRD5A2 gene, 10 alter splicing, 1 localized in a regulatory region, 14 small deletions, 6 small insertions, 3 small indels, and 4 large deletions (Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). After an extensive search for reported cases with SRD5A2 mutations, it was found that approximately 60% (150/250) were homozygous and 40% (100/250) were compound heterozygous; these percentages are slightly lower than those reported by Maimoun et al. in 55 patients of whom 69.1% were homozygous and 29.9% compound heterozygous, including the V89 L polymorphism [22]. Exons 1 and 4 are considered hot spots in the gene [22, 26, 27]. All of these mutations can produce either complete loss of activity, affecting the binding domain to testosterone, or diminished NADPH Km, producing a poor assembly of a functional protein or decreasing its half-life [9, 28,29,30]. As a consequence, a wide phenotypic range has been described attributed to the residual enzymatic activity and probably to the individual genetic background. The most studied SRD5A2 gene polymorphism is V89L, produced by a change of guanine to cytosine in exon 1 that results in a substitution of valine for leucine at position 89. In vitro studies showed that V89L decreases enzymatic activity by around 30% [31]. Leucine in codon 89 has been associated with an increased hypospadias risk among Chinese and Indian children [32,33,34]. Another less frequently studied polymorphism is A49T; in vitro studies revealed that it produces increased enzymatic activity and has been associated with a higher risk for prostate cancer, mainly in African-American and Latino-American populations [31]. Conversely, a modest association has been proposed for this polymorphism with less severe forms of hypospadias [33, 35].
Genotype-phenotype correlation
Many reports about SRD5A2 deficiency have been published in the last 20 years, and it is very commonly mentioned that there is no genotype-phenotype correlation among patients carrying the same genotype. In our study, in order to methodically assess this topic, all patients reported in the literature with a detailed description of their phenotype from 1992 to the present were phenotypically classified using the external masculinization score (EMS), which constitutes a very useful method to standardize the clinical features observed. The use of EMS was first proposed by Ahmed et al., who scored specific features of the external genitalia, assigning a score range between 0 to 12, with those nearer to 12 composing a normal male phenotype [36]. Of the nearly 250 patients reported in the literature, 126 were included in this analysis. Only cases with homozygous genotypes were selected to avoid variability of the phenotype produced by two different mutations in the compound heterozygotes.
Tables 1, 2, and 3 show the main mutations reported at least three times in the literature in the homozygous condition and the average EMS with its standard deviation, which indicates how variable the phenotype is depending on the mutation. The most frequently reported mutations were those that increase testosterone and NADPH Km or those that decrease enzymatic activity.
Table 1 shows the most cited mutations that diminish testosterone affinity. Comparing the phenotypes of p.G34R, p.H231R, and p.G115D mutation carriers, it was observed that the EMS varied between 2.0 to 3.3, indicating a predominantly female phenotype. It is interesting to note that the average EMS for mutation p.G115D had a low standard deviation, despite having few observed patients; thus, when in homozygosis, this genotype seems to produce less variability as compared to the other two depicted in Table 1.
Table 2 summarizes mutations that interfere with the NADPH binding domain. EMS varied between 2.67 to 4.17, being slightly higher than the above-mentioned EMS averages (Table 1). Although there was no statistical difference between the EMS for mutations that affect testosterone and those affecting NADPH Km (Tables 1 and 2), a great variability in the EMS was observed in the second instance, with five out of the six described mutations showing ample standard deviation values (Table 2). Only the p.G196S mutation, with many reported cases (n = 12), seems to produce a less variable phenotype. Several other known mutations affecting NADPH domain, such as R171S found frequently in different populations (Mexican, Turkish, Spanish, Mediterranean), had very few homozygous reported cases, being found more frequently in compound heterozygotes.
Table 3 shows these mutations decreasing enzymatic activity. It is interesting to note that this patient group had less severe phenotypes, with EMS values ranging from 3.0 to 8.0, attributable to different residual enzymatic activities caused by different mutations. It is important to highlight that the standard deviations of the average EMS values for these mutations were the highest among the three groups (Tables 1, 2, 3); thus, in patients carrying mutations belonging to this group, a genotype-phenotype correlation seems to be the most difficult to establish, masculinized external genitalia being the most predominant phenotype. The frequent Mediterranean IVS1-2A > G mutation, which is thought to abolish enzymatic activity, had a low EMS value (average 4) nearer to a female phenotype, as is expected for mutations that severely impair enzymatic activity [62, 63].
The statistical Student t test was performed to compare each group according to the protein mutation effect (i.e., T binding, NADPH cofactor binding or enzymatic activity failure). When mutations affecting T Km were compared with those that affect NADPH Km, no statistic difference was found between EMS values; conversely, when these two groups were compared independently with mutations affecting protein activity (Table 3), significant statistic differences were obtained in both instances with p < 0.001 (p = 1.48 × 10−5 and p = 6.89 × 10−6, respectively). According to these analyses, although there is no strong genotype-phenotype correlation, the effect of the location of the mutation in the protein is an important variable to consider because it has influence on the patient’s phenotype.
Regarding the possible effect of the genetic background on the phenotype, the population-specific prevalence of mutations has been studied, showing that many mutations are ethnic-specific, whereas certain others are found among different populations [34]. Among the mutations shown in Tables 1 to 3, p.G34R and p.N160D are only found in Egyptians, p.L55Q has only been described in Turkish patients, p.G183S in Brazilian patients, and IVS1-2A>G with a 0.98% carrier frequency in the Cyprus population [63]. Other mutations such as p.G196S, p.Q126R, and p.H231R are widely distributed among Caucasians. p.Y91H and p.R227Q have been reported in patients from the middle East and Asia, respectively. Conversely, p.G115D, p.G196S, p.R246Q, and p.G246W have been reported in patients of different ethnic origins including American, European, Asian, and North Indian, mutations that are considered hot spots. Thus, ethnic origin does not seem to have a relevant effect on the phenotype-genotype correlation according to the EMS (Tables 1 to 3).
Diagnosis
Several reports have been published in which patients diagnosed as suffering from a partial insensitivity androgen syndrome (PAIS) are indeed carriers of mutations in the SRD5A2 gene. A correct diagnosis of these cases is essential for appropriate patient management. Biochemical diagnosis was the first diagnostic approach to the disease. Serum T and DHT concentration post hCG (human chorionic gonadotropin) stimulation was measured in many cases and T:DHT ratio was calculated [64] and almost always a normal to high T concentration was found along with a low concentration of DHT and an increased T:DHT ratio. Establishing a cutoff value for T:DHT ratio has been controversial. Though the first proposed value was 20, Walter et al. suggested 8.5 after hCG stimulation as a much more reliable cutoff value [24, 64, 65]. However, in many instances, this method has failed as a good predictor and various other approaches have been proposed [22, 39, 41, 45, 49], urinary steroid profiling (UPS) and gene mutation analysis being two alternatives. Chan et al. suggested that UPS results can be misinterpreted; thus, molecular analysis was considered the most effective diagnostic method also taking into account the small size of the gene makes the diagnostic procedure easier [50].
Treatment
A psychological evaluation must be performed in individuals prior to 27 months of age before any hormonal or surgical treatment can be undertaken. Frequently, pre- or postnatal brain exposure to androgens in 46,XY individuals raised as girls causes a later development of male gender identity in adolescence or early adulthood [66]. A prevalence of around 60% of gender changes has been reported in individuals who were raised as female [67]. Thus, it is recommended that the sex reassignment should be done before 27 months of age to avoid identity conflicts [24].
Hormonal therapy
Testosterone replacement is not usually required in male patients given that most of them have retained testicular function during puberty. However, high doses of intramuscular testosterone (e.g., testosterone cipionate 200–500 mg twice a week) or dihydrotestosterone gel (e.g., 5–10 mg/day) can be used to improve body hair and penile length. Maximum penis enlargement is obtained after 6 months of high-dose treatment, but without reaching a normal length. Treatment with dihydrotestosterone gel has the advantages of being more active than testosterone, promoting faster increase of penis size and glans before any eventual surgery [57, 66]. In addition, since dihydrotestosterone is not an aromatizable molecule, it would not be expected to promote bone maturation or cause gynecomastia, while it would enable the use of higher doses than testosterone and, consequently, attaining a higher degree of virilization [66].
For those patients raised as females, the rationale of hormonal therapy is the development of female sexual characteristics. The treatment must simulate normal puberty. Low estrogen doses (0.07–0.3 mg of conjugated estrogen) should be administered at 10 to 11 years of age to avoid excessive bone maturation except in tall girls, in whom adult estrogen doses are indicated. After breast development is completed, adult estrogen doses (0.625–1.25 mg/day of conjugated estrogen) are maintained continuously. Progesterone replacement is not necessary due to the absence of the uterus. Vaginal dilation with acrylic molds has been shown to be an excellent management choice. It should be started when these patients express a desire to initiate sexual intercourse [66].
Surgical treatment
Genital surgery is widely performed in children with genital ambiguity. Penile construction remains a challenging task for surgeons. However, new techniques are available in males with severe micropenis and aphalia [24]. The aim is to build adequate external genitalia and remove internal structures incompatible with the assigned sex. For children assigned as female, laparoscopy is the ideal technique to perform gonadectomy and resection of internal organs if appropriate [66].
Feminizing genitoplasty should provide an adequate vaginal opening into the perineum, create a normal-looking vaginal introitus, fully separate the urethra from the vaginal orifice, remove phallic erectile tissue preserving glandular innervation and blood supply, and prevent urinary tract complications. The most reasonable technique to perform clitoroplasty is based on the concept of maintaining the clitoral glands and sensory input which facilitates orgasm. The use of an adequate size of tissue flap is mandatory in the Y-V vaginoplasty technique. Failure to interpose an adequate flap will result in persistent introital stenosis, requiring a later surgical procedure [66].
For those raised as males, surgery consists of orthophaloplasty, scrotumplasty with vaginal removal, proximal and distal urethroplasty, and orchidopexy when necessary [57, 66]. In patients with perineal hypospadias, surgeries can be performed in 2 or 3 steps (masculinizing genitoplasty using a modified Denis Browne technique). The most frequent surgical complications are urethral fistula in the penoscrotal angle and urethral stenosis that can occur several years after surgery [66].
Conclusions
5-α-Reductase type 2 deficiency causes pronounced ambiguity of the external genitalia with a wide phenotypic spectrum. It is an infrequent disorder, reported in many different populations worldwide, that is caused by diverse mutations scattered throughout the SRD5A2 gene. Although it is well known that there is no strong genotype-phenotype correlation, the herein described analysis performed in 126 patients showed that the specific location of the mutation in the protein has an effect on the severity of the phenotype, the loss of enzymatic activity being the most relevant variable of statistical significance (p < 0.001). Nevertheless, even in patients carrying the same homozygous mutation, a variable phenotype can be observed, suggesting that genetic factors other than 5-α-Reductase enzyme activity contribute to the phenotype. Extensive studies on different pathways affecting sexual development should be undertaken to identify genetic modulators of the external genitalia differentiation.
Parents of patients with DSD must be offered appropriate medical guidance, receiving all necessary information regarding diagnosis and gender assignment, as well as the benefits, risks, and complications of the different treatment options. A better understanding of the genetic factors influencing the condition could improve the decision as to the assignment of the correct adult gender identity.
References
Brennan J, Capel B (2004) One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet 5:509–521
Sharpe RM (2006) Pathways of endocrine disruption during male sexual differentiation and masculinisation. Best Pract Res Clin Endocrinol Metab 20:91–110
Hughes I (2008) Disorders of sex development: a new definition and classification. Best Pract Res Clin Endocrinol Metab 22:119–134
Kim KS, Kim J (2012) Disorders of sex development. Korean J Urol 53:1–8
Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE (1974) Steroid 5α-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 186:1213–1216
Walsh PC, Madden JD, Harrod MJ, Goldstein JL, MacDonald PC, Wilson JD (1974) Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 291:944–949
Samtani R, Bajpai M, Ghosh PK, Saraswathy KN (2010) SRD5A2 gene mutations : a population-based review. Pediatr Endocrinol Rev 8:34–40
Thigpen AE, Davis DL, Milatovich A, Mendonca BB et al (1992) Molecular genetics of steroid 5 alpha-reductase 2 deficiency. J Clin Invest 90:799–809
Russell DW, Wilson JD (1994) Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem 63:25–61
Moore RJ, Griffin JE, Wilson JD (1975) Diminished 5α-reductase activity in extracts of fibroblasts cultured from patients with familial incomplete male Pseudohermaphroditism, type 2. J Biol Chem 250:7168–7172
Wilson JD (1975) Dihydrotestosterone formation in clutured human fibroblasts. J Biol Chem 250:3498–3505
Moore RJ, Wilson JD (1976) Steroid 5α-reductase in cultured human fibroblasts. J Biol Chem 251:5895–5900
Andersson S, Berman DM, Jenkins EP, Russell DW (1991) Deletion of steroid 5 alpha-reductase 2 gene in male pseudohermaphroditism. Nature 354:159–161
Andersson S, Russell DW (1990) Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases. Proc Natl Acad Sci 87:3640–3644
Jenkins EP, Hsieh C-L, Milatovich A, Normington K et al (1991) Characterization and chromosomal mapping of a human steroid 5alpha-reductase gene and pseudogene and mapping of the mouse homologue. Genomics 1:1102–1112
Labrie F, Sugimoto Y, Luu-The V, Simard J et al (1992) Structure of human type II 5α- reductase gene. Endocrinology 131:1571–1573
Normington K, Russell DW (1992) Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes. Evidence for distinct physiological functions. J Biol Chem 267:19548–19554
Azzouni F, Godoy A, Li Y, Mohler J (2012) The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases. Adv Urol: 530121
Stiles AR, Russell DW (2010) SRD5A3: a surprising role in glycosylation. Cell 142:196–198
Moon YA, Horton JD (2003) Identification of two mammalian reductases involved in the two-carbon fatty acyl elongation cascade. J Biol Chem 278:7335–7343
Walsh PC, Madden JD, Harrod MJ, Goldstein JI, MacDonald PC, Wilson JD (1974) Familial incomplete male pseudohermaphroditism, type 2. N Engl J Med 291:944–949
Maimoun L, Philibert P, Cammas B et al (2011) Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients. J Clin Endocrinol Metab 96:296–307
Méndez JP, Ulloa-Aguirre A, Imperato-McGinley J et al (1995) Male pseudohermaphroditism due to primary 5 alpha-reductase deficiency: variation in gender identity reversal in seven Mexican patients from five different pedigrees. J Endocrinol Investig 18:205–213
Deeb A, Al SH, Ibukunoluwa F, Attia S (2016) Phenotype, sex of rearing, gender re-assignment, and response to medical treatment in extended family members with a novel mutation in the SRD5A2 gene. J Clin Res Pediatr Endocrinol 8:236–240
Berra M, Williams EL, Muroni B et al (2011) Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic. Eur J Endocrinol 164:1019–1025
Yang Y, Wang B, Guo Q et al (2012) Clinical and genetic analysis of three Chinese patients with steroid 5α-reductase type 2 deficiency. J Pediatr Endocrinol Metab 25:1077–1082
Nie M, Zhou Q, Mao J, Lu S, Wu X (2011) Five novel mutations of SRD5A2 found in eight Chinese patients with 46,XY disorders of sex development. Mol Hum Reprod 17:57–62
Imperato-McGinley J, Zhu YS (2002) Androgens and male physiology the syndrome of 5α-reductase-2 deficiency. Mol Cell Endocrinol 198:51–59
Can S, Zhu Y, Cai L et al (1998) The identification of 5α -reductase-2 and 17 β- hydroxysteroid dehydrogenase-3 gene defects in male pseudohermaphrodites from a Turkish kindred. J Clin Endocrinol Metab 83:560–569
Wigley WC, Prihoda JS, Mowszowicz I et al (1994) Natural mutagenesis study of the human steroid 5 α-reductase 2 isozyme. Biochemistry 33:1265–1270
Makridakis NM, Di Salle E, Reichardt JK (2000) Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Pharmacogenetics 10:407–413
Wang Y, Li Q, Xu J, Liu Q et al (2004) Mutation analysis of five candidate genes in Chinese patients with hypospadias. Eur J Hum Genet 12:706–712
Thai HTT, Kalbasi M, Lagerstedt K, Frisén L, Kockum I, Nordenskjöld A (2005) The valine allele of the V89L polymorphism in the 5-α-Reductase gene confers a reduced risk for hypospadias. J Clin Endocrinol Metab 90:6695–6698
Samtani R, Bajpai M, Vashisht K, Ghosh PK, Saraswathy KN (2011) Hypospadias risk and polymorphism in SRD5A2 and CYP17 genes: case-control study among Indian children. J Urol 185:2334–2339
Silver RI, Russell DW (1999) 5α-reductase type 2 mutations are present in some boys with isolated hypospadias. J Urol 162:1142–1145
Ahmed SF, Khwaja O, Hughes IA (2000) The role of a clinical score in the assessment of ambiguous genitalia. BJU Int 85:120–124
Mazen I, Gad YZ, Hafez M, Sultan C, Lumbroso S (2003) Molecular analysis of 5alpha-reductase type 2 gene in eight unrelated egyptian children with suspected 5alpha-reductase deficiency: prevalence of the G34R mutation. Clin Endocrinol 58:627–631
Soliman H, Amr K, El-Ruby M, Mekkawy M, Elaidy A, Mazen I (2015) Mutational pattern in the 5α reductase 2 (SRD5A2) gene in 46,XY Egyptian DSD patients. Middle East J Med Genet 4:77–82
Maimoun L, Philibert P, Bouchard P et al (2011) Primary amenorrhea in four adolescents revealed 5α-reductase deficiency confirmed by molecular analysis. Fertil Steril 95:804.e1–804.e5
Boudon C, Lumbroso S, Lobaccaro JM et al (1995) Molecular study of the 5 alpha-reductase type 2 gene in three European families with 5 alpha-reductase deficiency. J Clin Endocrinol Metab 80:2149–2153
Maimoun L, Philibert P, Cammas B et al (2010) Undervirilization in XY newborns may hide a 5α-reductase deficiency: report of three new SRD5A2 gene mutations. Int J Androl 33:841–847
Vilchis F, Méndez JP, Canto P, Liebermen E, Chávez B (2000) Identification of missense mutations in the SRD5A2 gene from patients with steroid 5 a -reductase 2 deficiency. Clin Endocrinol 52:383–387
Nicoletti A, Baldazzi L, Balsamo A et al (2005) SRD5A2 gene analysis in an Italian population of under-masculinized 46,XY subjects. Clin Endocrinol 63:375–380
Hackel C, Eduardo L, Oliveira C et al (2005) New mutations, hotspots, and founder effects in Brazilian patients with steroid 5 α -reductase deficiency type 2. J Mol Med 83:569–576
Baldinotti F, Majore S, Fogli A et al (2008) Molecular characterization of 6 unrelated Italian patients with 5α-reductase type 2 deficiency. J Androl 29:20–28
Caldas Ferraz LF, Guerra G Jr, Matias Baptista MT, Maciel-Guerra AT, Hackel C (1998) Detection of Gly-196-Ser mutation in 5alpha-reductase type II gene in a Brazilian patient with female assignment and behavior. J Pediatr Endocrinol Metab 11:465–466
Hiort O, Willenbring H, Albers N et al (1996) Molecular genetic analysis and human chorionic gonadotropin stimulation tests in the diagnosis of prepubertal patients with partial 5α-reductase deficiency. Eur J Pediatr 155:445–451
Wilson JD, Griffin JE, Russell DW (1993) Steroid 5alpha-reductase 2 deficiency. EndocrRev 14:577–593
Ko JM, Cheon C-K, Kim G-H, Kim SH, Kim KS, Yoo H-W (2010) Clinical characterization and analysis of the SRD5A2 gene in six Korean patients with 5alpha-reductase type 2 deficiency. Horm Res Pædiatrics 73:41–48
Chan AOK, But BWM, Lee CY, Lam YY et al (2013) Diagnosis of 5α-reductase 2 deficiency: is measurement of dihydrotestosterone essential? Clin Chem 59:798–806
Zhu H, Liu W, Han B et al (2014) Phenotypic and molecular characteristics in eleven Chinese patients with 5alphaPhenotypic and molecular characteristics in eleven Chinese patients with 5a-reductase type 2 deficiency. Clin Endocrinol 81:711–720
Sahu R, Boddula R, Sharma P et al (2009) Genetic analysis of the SRD5A2 gene in Indian patients with 5α-reductase deficiency. J Pediatr Endocrinol Metab 22:247–254
Thigpen a E, Davis DL, Gautier T, Imperato-McGinley J, Russell DW (1992) Brief report: the molecular basis of steroid 5 alpha-reductase deficiency in a large Dominican kindred. N Engl J Med 327:1216–1219
Ocal G, Adiyaman P, Berberoğlu M et al (2002) Mutations of the 5alpha-steroid reductase type 2 gene in six Turkish patients from unrelated families and a large pedigree of an isolated Turkish village. J Pediatr Endocrinol Metab 15:411–421
Fernández-Cancio M, Audí L, Andaluz P et al (2011) SRD5A2 gene mutations and polymorphisms in Spanish 46,XY patients with a disorder of sex differentiation. Int J Androl 34:e526–e535
Fernández-Cancio M, Esteban C, Andaluz P et al (2005) SRD5A2 gene Q126R exon-2 point mutation in unrelated Spanish male pseudohermaphrodite patients. Int J Hum Dev 4:71–76
Di Marco C, Bulotta AL, Varetti C et al (2013) Ambiguous external genitalia due to defect of 5-α-reductase in seven Iraqi patients: prevalence of a novel mutation. Gene 526:490–493
Akcay T, Fernandez-Cancio M, Turan S, Güran T, Audi L, Bereket A (2014) AR and SRD5A2 gene mutations in a series of 51 Turkish 46,XY DSD children with a clinical diagnosis of androgen insensitivity. Andrology 2:572–578
Wang R, Dong Z, Wang W, Xiao Y, Ni J, Wang D (2013) Mutation analysis of the SRD5A2, AR and SF-1 genes in 52 Chinese boys with hypospadias. J Pediatr Endocrinol Metab 26:887–893
Sasaki G, Ogata T, Ishii T et al (2003) Micropenis and the 5α-reductase-2 (SRD5A2) gene: mutation and V89L polymorphism analysis in 81 Japanese patients. J Clin Endocrinol Metab 88:3431–3436
Cheng J, Lin R, Zhang W et al (2015) Phenotype and molecular characteristics in 45 Chinese children with 5α-reductase type 2 deficiency from South China. Clin Endocrinol 83:518–526
Skordis N, Neocleous V, Kyriakou A et al (2010) The IVS1-2A>G mutation in the SRD5A2 gene predominates in Cypriot patients with 5α reductase deficiency. J Endocrinol Investig 33:810–814
Skordis N, Shammas C, Efstathiou E, Sertedaki A, Neocleous V, Phylactou L (2011) Late diagnosis of 5alpha steroid-reductase deficiency due to IVS12A>G mutation of the SRD5a2 gene in an adolescent girl presented with primary amenorrhea. Hormones 10:230–235
Sinnecker GHG, Hiort O, Dibbelt L et al (1996) Phenotypic classification of male pseudohermaphroditism due to steroid 5α-reductase 2 deficiency. Am J Med Genet 63:223–230
Walter KN, Kienzle FB, Frankenschmidt A et al (2010) Difficulties in diagnosis and treatment of 5α-reductase type 2 deficiency in a newborn with 46,XY DSD. Horm Res Paediatr 74:67–71
Costa EMF, Domenice S, Inacio M et al (2012) DSD due to 5 α-reductase 2 deficiency from diagnosis to long term outcome. Semin Reprod Med 30:427–431
Cohen-Kettenis PT (2005) Gender change in 46,XY persons with 5α-reductase-2 deficiency and 17β-hydroxysteroid dehydrogenase-3 deficiency. Arch Sex Behav 34:399–410
Acknowledgements
To Professor Mercedes González-Coira for introducing us to the topic of 5-α-Reductase deficiency and to Dr. Alvaro Rodríguez-Larralde for his guidance concerning the statistical analysis.
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Avendaño, A., Paradisi, I., Cammarata-Scalisi, F. et al. 5-α-Reductase type 2 deficiency: is there a genotype-phenotype correlation? A review. Hormones 17, 197–204 (2018). https://doi.org/10.1007/s42000-018-0013-9
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DOI: https://doi.org/10.1007/s42000-018-0013-9