Browse the corpus

Deficiency of 5α-reductase type 2 is a rare autosomal recessive disorder of sex development characterized by impaired conversion of testosterone to dihydrotestosterone, a critical step in androgen synthesis, and is implicated in male genital differentiation, degree of masculinization, and later development of secondary sexual characteristics. This enzymatic defect results in a spectrum of undervirilization in individuals with a 46,XY karyotype, ranging from isolated micropenis at one end to severe hypospadias and or a female-appearing external phenotype. During puberty, partial virilization may occur due to rising testosterone levels, increased dihydrotestosterone production via 5α-reductase type 1, and residual activity of the abnormal 5α-reductase type 2 enzyme, often leading to diagnostic uncertainty and psychosocial distress. This activity provides a comprehensive overview of the pathophysiology, genetics, clinical manifestations, and diagnostic approach to 5α-reductase type 2 deficiency. Learners will be guided through early recognition of signs, appropriate biochemical and genetic investigations, and individualized approaches to sex assignment and management. The activity emphasizes the importance of culturally sensitive communication, long-term psychological support, and evidence-based endocrine and surgical decision-making. By participating in this activity, healthcare professionals will enhance their competence in coordinating care as part of an interprofessional team, applying current guidelines, and navigating the ethical complexities inherent in diagnosing and managing 5α-reductase type 2 deficiency. Objectives: Differentiate 5α-reductase type 2 deficiency from other disorders of sex development based on genotype, hormonal profile, and phenotypic presentation across developmental stages. Apply evidence-based clinical and ethical frameworks to guide sex assignment, endocrine therapy, and surgical intervention in patients with 5α-reductase type 2 deficiency. Interpret the diagnostic utility of biochemical assays and genetic testing to confirm 5α-reductase type 2 deficiency and inform individualized treatment.

Apply evidence-based clinical and ethical frameworks to guide sex assignment, endocrine therapy, and surgical intervention in patients with 5α-reductase type 2 deficiency. Interpret the diagnostic utility of biochemical assays and genetic testing to confirm 5α-reductase type 2 deficiency and inform individualized treatment. Collaborate with interprofessional team members, including endocrinologists, urologists, genetic counselors, mental health professionals, and ethicists to formulate and implement coordinated, culturally sensitive care plans for individuals with disorders of sexual development. Access free multiple choice questions on this topic.

Disorders of sex development (DSDs) encompass a spectrum of congenital conditions characterized by atypical development of chromosomal, gonadal, or anatomical sex. Among these, ambiguous genitalia in neonates is a rare but significant clinical presentation, with an estimated prevalence of approximately 1 in 4500 live births.[1][2] Despite advancements in diagnostic modalities, including hormonal assays, karyotyping, and molecular genetic analyses, a definitive diagnosis is achieved in fewer than 50% of cases among individuals with 46,XY DSD karyotype, underscoring the complexity of these conditions.[3][4] Results from a recent large series reported that a definitive diagnosis was reached in up to 60% of individuals with 46,XY DSD karotype, using a combination of clinical, hormonal, and molecular genetic testing.[5] Deficiency of 5α-reductase type 2 (5α-RD2), caused by mutations in the SRD5A2 gene, is a notable cause of 46,XY DSD and results in impaired conversion of testosterone to dihydrotestosterone (DHT). DHT is crucial for the masculinization of the external genitalia during embryogenesis. Individuals with 5α-RD2 deficiency exhibit a broad phenotypic spectrum, ranging from predominantly female-appearing external genitalia to varying degrees of undervirilization, including isolated micropenis or severe hypospadias with undescended testes. During puberty, increased testosterone levels and increased peripheral conversion of testosterone to DHT may lead to partial virilization, including deepening of the voice, increased muscle mass, and phallic growth; however, the extent of these changes can vary significantly among individuals.[6] The diagnosis of 5α-RD2 deficiency involves a combination of clinical evaluation, hormonal profiling (including elevated testosterone to DHT ratios, and molecular genetic testing to identify pathogenic variants of the SRD5A2 gene. Early and accurate diagnosis is essential for informed decision-making regarding sex assignment, potential surgical interventions, and long-term management strategies. This educational activity aims to provide healthcare professionals with a comprehensive understanding of the pathophysiology, clinical manifestations, diagnostic approaches, and management considerations for 5α-RD2 deficiency, emphasizing the importance of an interdisciplinary approach to care.

Although testosterone is widely recognized as the principal androgen responsible for male sexual differentiation, not all androgen-responsive tissues exhibit equal sensitivity to testosterone. The enzyme 5α-RD2 catalyzes the irreversible conversion of testosterone to DHT, a more potent androgen with higher affinity for the androgen receptor.[7] During male fetal development, testosterone and DHT exert distinct but complementary roles in sexual differentiation. Testosterone primarily facilitates the development of internal genital structures derived from the Wolffian ducts, such as the epididymis, vas deferens, and seminal vesicles. In contrast, DHT is essential for the masculinization of the external genitalia, including the penis, scrotum, and prostate. During puberty, rising testosterone levels initiate spermatogenesis, increase muscle mass, promote laryngeal enlargement and voice deepening, and drive psychosexual behavior. In contrast, DHT plays a critical role in the development of secondary sexual characteristics, including prostate growth, facial and body hair distribution, and male-pattern baldness.[8] In individuals with 5α-RD2 deficiency, rising testosterone levels, increased activity of the unaffected 5α-reductase type 1 enzyme, and residual activity of abnormal 5α-RD2 during puberty may lead to significant virilization. Gender role change from female to male during puberty is common in this condition. Accordingly, the sex of rearing should be considered if an individual with 46,XY DSD has a confirmed SRD5A2 gene defect.[9] However, other factors such as the initial degree of masculinization, initial sex of rearing in delayed diagnosed cases, gender identity of the child, and the preference of the family and child should be considered during gender assignment or reassignment.

Deficiency of 5α-RD2 is a rare condition worldwide, with a significantly lower incidence among individuals of European ancestry. However, prevalence is higher in populations with high consanguineous rates. The disorder has been well-documented in the Dominican Republic, where consanguineous unions have contributed to a higher incidence. The first cases of 5α-RD2 deficiency were described in this region in the 1970s. Other geographic clusters have been reported in southern Lebanon and remote communities in Papua New Guinea, suggesting a founder effect or shared genetic ancestry in these populations.[10] The exact prevalence of the condition is unknown, but it has been reported worldwide.[11][12] The molecular basis of this disorder was first elucidated in 1993, when 2 isoforms of the 5α-reductase enzyme (types 1 and 2) were characterized and their corresponding genes, SRD5A1 and SRD5A2, were successfully cloned. While both isoenzymes catalyze the conversion of testosterone to DHT, deficiency of the type 2 isoenzyme, encoded by SRD5A2, underlies the classic clinical presentation of 5α-RD2 deficiency.[13]

Sexual differentiation in the human embryo is a complex, hormone-dependent process that proceeds through a sequence of genetically and temporally coordinated events. By the sixth week of gestation, the embryo remains morphologically bipotential, possessing undifferentiated gonadal ridges and both mesonephric (Wolffian) and paramesonephric (Müllerian) ductal systems. The determination of phenotypic sex in 46,XY individuals is orchestrated by the SRY gene on the Y chromosome, which directs testicular differentiation. Sertoli cells in the developing testes produce anti-Müllerian hormone (AMH), which induces Müllerian duct regression, while Leydig cells secrete testosterone, promoting the development of Wolffian duct–derived internal structures (epididymis, vas deferens, and seminal vesicles). Masculinization of the external genitalia and prostate is critically dependent on the peripheral conversion of testosterone to DHT via the enzyme 5α-RD2. This isoenzyme, encoded by the SRD5A2 gene on chromosome 2p23.1, is highly expressed in androgen-responsive tissues such as the genital tubercle, urogenital sinus, and labioscrotal swellings. DHT, with a binding affinity for the androgen receptor approximately 2- to 5-fold greater than that of testosterone, is indispensable for normal male external genital development, beginning at approximately 8 to 12 weeks of gestation. Mutations in SRD5A2 are inherited in an autosomal recessive pattern.[13][14] Mechanisms of SRD5A2 Mutations and Phenotypic Variability Pathogenic mutations in the SRD5A2 gene lead to partial or complete loss of 5α-RD2 enzymatic function. More than 120 distinct mutations have been described, including missense mutations (most commonly point mutations), nonsense mutations, splice-site mutations, and small deletions or insertions. The majority are homozygous variants consistent with autosomal recessive inheritance. These mutations variably impair the protein’s catalytic activity, substrate binding, stability, or membrane association, and are distributed throughout the coding region:[11][15] Missense mutations (eg, p.R246Q, p.G34R) may induce conformational changes that reduce enzyme-substrate affinity or disrupt the nicotinamide adenine dinucleotide phosphate (NADPH) cofactor binding site.

Pathogenic mutations in the SRD5A2 gene lead to partial or complete loss of 5α-RD2 enzymatic function. More than 120 distinct mutations have been described, including missense mutations (most commonly point mutations), nonsense mutations, splice-site mutations, and small deletions or insertions. The majority are homozygous variants consistent with autosomal recessive inheritance. These mutations variably impair the protein’s catalytic activity, substrate binding, stability, or membrane association, and are distributed throughout the coding region:[11][15] Missense mutations (eg, p.R246Q, p.G34R) may induce conformational changes that reduce enzyme-substrate affinity or disrupt the nicotinamide adenine dinucleotide phosphate (NADPH) cofactor binding site. Nonsense or frameshift mutations (eg, p.Q6X, p.W230X) typically result in truncated, nonfunctional proteins that are rapidly degraded. Splice-site mutations can result in exon skipping, yielding unstable or catalytically inactive isoforms. The variability in residual enzyme function partially accounts for the phenotypic heterogeneity observed in affected individuals. Although a definitive genotype–phenotype correlation remains elusive, structural and functional studies have elucidated how specific mutations disrupt enzymatic activity, such as by altering NADPH cofactor binding, destabilizing the enzyme’s tertiary structure, or impairing membrane localization.[10] The degree of residual enzymatic activity influences intratissue DHT production during the critical window of genital development. Individuals with null mutations and absent DHT synthesis may present with an entirely female-appearing external phenotype at birth. In contrast, those with hypomorphic variants retain partial enzymatic function and may exhibit signs of limited virilization, such as micropenis, penoscrotal hypospadias, or ambiguous genitalia.[16]

The phenotypic presentation of individuals with 5α-RD2 deficiency is remarkably heterogeneous. Although the condition follows an autosomal recessive inheritance pattern and is associated with biallelic mutations in the SRD5A2 gene, a consistent genotype–phenotype correlation has not been established. Individuals with identical pathogenic variants in SRD5A2 may exhibit widely divergent external genital phenotypes, ranging from a female-appearing phenotype to varying degrees of undervirilization, suggesting the influence of modifier genes, epigenetic factors, and androgen receptor sensitivity.[16] Results from a case series of 46,XY DSDs included 25 children with genetically confirmed 5α-RD2 deficiency. The external masculinization score ranged from 2 to 9 (median, 6), indicating heterogeneous severity of undervirilisation from micropenis to nearly female-appearing genitalia.[12] Results from another large series similarly demonstrated heterogeneity; most children (n = 55) presented with combinations of cryptorchidism, micropenis (or clitoromegaly), and hypospadias, whereas a smaller proportion had more extreme presentations, such as isolated micropenis or female-appearing external genitalia.[17] The usual presentation is at birth or during early infancy, most often because of atypical genitalia. External genitalia virilization may range from female-appearing anatomy to near-male anatomy. Unfused labioscrotal folds may resemble labia majora, and the phallus may resemble a clitoris rather than a penis.[18] Despite undervirilization, the internal genital structures derived from the Wolffian ducts, such as the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts, are generally developed due to intact Leydig cell testosterone production during fetal life. Müllerian structures (eg, uterus and fallopian tubes) are absent due to normal Sertoli cell–derived AMH secretion.[10]

The usual presentation is at birth or during early infancy, most often because of atypical genitalia. External genitalia virilization may range from female-appearing anatomy to near-male anatomy. Unfused labioscrotal folds may resemble labia majora, and the phallus may resemble a clitoris rather than a penis.[18] Despite undervirilization, the internal genital structures derived from the Wolffian ducts, such as the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts, are generally developed due to intact Leydig cell testosterone production during fetal life. Müllerian structures (eg, uterus and fallopian tubes) are absent due to normal Sertoli cell–derived AMH secretion.[10] The testes are often cryptorchid, typically located in the inguinal canal (inguinoscrotal region). In the absence of overt virilization at birth, many affected individuals are assigned and reared as female. In results from a large series, nearly three-fourths of individuals were assigned the female sex of rearing.[17] In results from another series, 11 of 25 (44%) individuals were assigned a female sex of rearing.[12] However, with the onset of puberty, spontaneous virilization frequently occurs due to a surge in circulating testosterone.[18] Clinical signs include phallus enlargement, testicular descent into the labioscrotal folds, deepening of the voice, facial and body hair growth, and increased muscle mass. These secondary sexual characteristics are mediated by rising testosterone levels and additional conversion to DHT via 5α-reductase type 1 and residual 5α-RD2 activity.[17] Patients may present during puberty due to discordant pubertal progression, gender dysphoria, or gender role change. Findings from a large series demonstrated that 12.5% of children presented during puberty, but this proportion varied in other cohorts, depending on sociocultural practices related to recognition of virilization (reflecting exposure to testosterone and DHT).[17] Notably, these children do not have features of salt wasting, in contrast to congenital adrenal hyperplasia, the most common cause of DSD. Because testosterone and estradiol concentrations remain in the male reference range during puberty, gynecomastia is typically absent, which can help distinguish 5α-RD2 deficiency from 46,XY DSD due to androgen insensitivity, in which gynecomastia is more common.

Initial evaluation may include karyotype, pelvic ultrasonography for Müllerian structures, and hormone level testing. Adequate testosterone production, either during puberty or after human chorionic gonadotropin stimulation in early childhood, together with normal AMH levels (making gonadal dysgenesis unlikely) and no features of adrenal involvement, supports a diagnosis of 5α-RD2 deficiency. The diagnosis of 5α-RD2 deficiency relies on a combination of biochemical assays and molecular genetic analysis, each providing complementary diagnostic information. Biochemically, the classic test involves measuring the testosterone to dihydrotestosterone (T:DHT) ratio, assessed during minipuberty or puberty or following human chorionic gonadotropin stimulation between these periods. In individuals with 5α-RD2 deficiency, impaired conversion of testosterone to DHT results in an abnormally elevated T:DHT ratio (≥ 10-20).[12][17][19][20] However, this test is limited by its sensitivity and specificity. A nonelevated ratio does not reliably exclude the diagnosis, particularly in patients with partial enzyme activity or in prepubertal individuals, in whom baseline testosterone production may be insufficient to elicit a clear biochemical response.[21] Furthermore, the T:DHT ratio is influenced by multiple variables, including patient age and pubertal stage, severity of enzyme impairment, and assay methodology. In patients with mild or hypomorphic mutations, the biochemical findings may remain equivocal, rendering interpretation challenging. While the T:DHT ratio remains a useful initial screening test, it is no longer considered definitively diagnostic. Notably, the absence of gynecomastia favors a diagnosis of 5α-RD2 deficiency and may help define equivocal and late-diagnosed cases.

In individuals with 5α-RD2 deficiency, impaired conversion of testosterone to DHT results in an abnormally elevated T:DHT ratio (≥ 10-20).[12][17][19][20] However, this test is limited by its sensitivity and specificity. A nonelevated ratio does not reliably exclude the diagnosis, particularly in patients with partial enzyme activity or in prepubertal individuals, in whom baseline testosterone production may be insufficient to elicit a clear biochemical response.[21] Furthermore, the T:DHT ratio is influenced by multiple variables, including patient age and pubertal stage, severity of enzyme impairment, and assay methodology. In patients with mild or hypomorphic mutations, the biochemical findings may remain equivocal, rendering interpretation challenging. While the T:DHT ratio remains a useful initial screening test, it is no longer considered definitively diagnostic. Notably, the absence of gynecomastia favors a diagnosis of 5α-RD2 deficiency and may help define equivocal and late-diagnosed cases. Molecular genetic analysis of the SRD5A2 gene provides the most definitive diagnosis. The SRD5A2 gene, located on chromosome 2p23.1, encodes the 254 amino acid type 2 isoform of 5α-reductase, which exhibits high substrate specificity for testosterone and is primarily active in androgen-dependent tissues, including the urogenital sinus and external genitalia. More than 120 pathogenic mutations have been described, with missense variants the most common class. Identification of biallelic pathogenic variants confirms the diagnosis, facilitates genetic counseling, and enables carrier screening in families. Moreover, genetic testing is valuable in neonates presenting with ambiguous genitalia because it supports early, precise diagnosis and informs individualized management strategies.[4][12][15][17] Identifying the exact genetic cause is important because impaired bone mineral density has been reported in many DSDs. Although evidence is limited, 5α-RD2 deficiency is usually associated with normal bone mineral density in adulthood.[22]

The management of 5α-RD2 deficiency is individualized and depends on multiple factors, including the degree of undervirilization (the external genital phenotype), age at diagnosis, sex of rearing, and psychosocial factors, including the patient's gender identity considerations. An interdisciplinary approach, involving pediatric endocrinologists, urologists, psychologists, geneticists, and ethicists, is crucial in developing a comprehensive and ethically sound care plan. Surgical and Hormonal Treatment If a child is diagnosed at birth or in early infancy, there has been a trend in recent decades toward male sex of rearing after recognition that many individuals have pubertal virilization and may later change their gender identity to male.[9] In cases of severe undervirilization of the external genitalia (a phallus consistent in size with clitoromegaly and unfused labioscrotal folds) or in late-diagnosis instances in which the child has been reared as female, female gender assignment may be considered. If the child is to be reared as female, bilateral gonadectomy (orchidectomy) may be recommended before the onset of puberty to prevent spontaneous virilization.[23] Surgical management for female sex assignment may include external genital reconstruction, which entails separating the urethral and vaginal tracts and clitorovaginoplasty.[24] Definitive surgical and hormonal intervention should be performed only after an extensive psychosocial evaluation of gender identity and role. Vaginoplasty is generally deferred until adolescence or early adulthood, allowing for informed patient participation and improved anatomical outcomes.[25] Alternatively, puberty can be suppressed with gonadotropin-releasing hormone analogues to allow time for shared decision-making or until the child reaches the age of consent. These decisions vary by region, and legal and ethical considerations should be addressed, with attention to the patient's autonomy and preferences. If gonadectomy is performed and the child is reared as female, estrogen replacement should be initiated at the usual age of puberty to maintain development of age-appropriate secondary sexual characteristics and bone health.

Alternatively, puberty can be suppressed with gonadotropin-releasing hormone analogues to allow time for shared decision-making or until the child reaches the age of consent. These decisions vary by region, and legal and ethical considerations should be addressed, with attention to the patient's autonomy and preferences. If gonadectomy is performed and the child is reared as female, estrogen replacement should be initiated at the usual age of puberty to maintain development of age-appropriate secondary sexual characteristics and bone health. Alternatively, if the child is reared as male, surgical intervention is tailored to the specific genital phenotype. In these cases, androgen stimulation therapy may be initiated before surgery to enhance penile development. Surgical procedures typically include orchiopexy, hypospadias repair, chordee correction, and urethral reconstruction, and are ideally performed within the first 2 years of life to optimize functional and cosmetic outcomes. Please see StatPearls' companion resource, "Ambiguous Genitalia and Disorders of Sexual Differentiation," for further information. The most critical factor in supporting male sex assignment is the potential for penile growth and function, which is often guided by initial phallic length and the tissue's responsiveness to testosterone or DHT.[26] No standard regimen of testosterone and DHT is available that can reliably produce satisfactory phallic growth. High doses of intramuscular testosterone and various doses of DHT cream have been used with variable outcomes.[20][27] Fertility Fertility is significantly compromised in individuals with 5α-RD2 deficiency, and only a minority can conceive a child; however, the use of assisted reproduction technologies may improve fertility outcomes.[28] Parents and legal guardians of children with DSD, including 5α-RD2 deficiency, should receive timely, comprehensive counseling and access to psychosocial support. Decisions regarding gender assignment and surgical intervention should be approached with sensitivity, allowing sufficient time for interdisciplinary discussion and parental reflection. Wherever possible, these decisions should be revisited over time, especially in patients diagnosed later in childhood, to incorporate the individual's developing autonomy and preferences.[29]

The evaluation of a neonate or child presenting with ambiguous genitalia necessitates a meticulous anatomical examination, supplemented by targeted hormonal assays and genetic testing to delineate the underlying etiology. Among the key diagnostic considerations, 5α-RD2 deficiency must be distinguished from several other DSDs that can present with phenotypically similar features.[30]The 2 most clinically significant differential diagnoses are partial androgen insensitivity syndrome and 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency. Androgen insensitivity syndrome, resulting from mutations in the androgen receptor gene, leads to a complete or partial end-organ resistance to circulating androgens. In complete androgen insufficiency syndrome, affected individuals typically present with a female-appearing external phenotype, absent Müllerian structures (due to AMH activity), and intra-abdominal or inguinal testes. These individuals are usually reared as females and may present in adolescence with primary amenorrhea. Unlike 5α-RD2 deficiency, in which DHT synthesis is impaired but androgen receptor signalling is intact, patients with androgen insensitivity syndrome have elevated levels of both testosterone and DHT but lack receptor-mediated action.[31] Partial androgen insensitivity syndrome presents with genital atypia and may have a hormonal profile overlapping with 5α-RD2 deficiency. Clinically, pubertal gynecomastia is almost always present in androgen insensitivity spectrum disorders, but is usually absent in 5α-RD2 deficiency. Deficiency of 17β-HSD3, an autosomal recessive disorder of testosterone biosynthesis, results in impaired conversion of androstenedione to testosterone. Affected individuals typically present with ambiguous genitalia at birth and low testosterone and DHT levels, but a T:DHT ratio within the reference range for the stage of development, helping to distinguish it from 5α-RD2 deficiency. Similar to 5α-RD2 deficiency, spontaneous virilization can occur at puberty due to increased androgen production (gonadal and extragonadal).[31]

Deficiency of 17β-HSD3, an autosomal recessive disorder of testosterone biosynthesis, results in impaired conversion of androstenedione to testosterone. Affected individuals typically present with ambiguous genitalia at birth and low testosterone and DHT levels, but a T:DHT ratio within the reference range for the stage of development, helping to distinguish it from 5α-RD2 deficiency. Similar to 5α-RD2 deficiency, spontaneous virilization can occur at puberty due to increased androgen production (gonadal and extragonadal).[31] Another relevant differential includes Leydig cell hypoplasia, caused by mutations in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene. This disorder leads to underdevelopment of Leydig cells, deficient testosterone production, and ambiguous genitalia in individuals with 46,XY. Hormonal evaluation reveals low testosterone levels with elevated luteinizing hormone levels, in contrast to 5α-RD2 deficiency, where testosterone levels are in the reference range or elevated, but DHT is deficient.[10] Other disorders of androgen biosynthesis, including partial or mixed gonadal dysgenesis, may present similarly to 5α-RD2 deficiency, but careful hormonal evaluation (with or without AMH levels) will narrow the differential diagnosis. Accurate diagnosis is imperative because management and sex assignment strategies differ substantially among these conditions. While individuals with 5α-RD2 deficiency frequently transition to a male gender role during or after puberty, those with complete androgen insensitivity syndrome are typically reared as female. Therefore, a comprehensive diagnostic approach combining hormonal profiling, stimulation testing, and genetic sequencing is essential to guide appropriate medical, surgical, and psychosocial interventions.

The prognosis for individuals with 5α-RD2 deficiency is relatively favorable. Prostate cancer and benign prostatic hyperplasia have not been reported in these patients. Patients may have reduced facial and body hair but normal sebum production. Most men with a deficiency of 5α-RD2 are infertile. Contributing factors may include cryptorchidism, oligospermia, urethral strictures, and urethroscrotal fistulas. However, some individuals with 5α-RD2 deficiency are able to conceive with assisted reproduction technology.[10] The process of gender identity formation in individuals with 5α-RD2 deficiency is multifactorial and influenced by biological, psychological, and sociocultural factors. Although many affected individuals are assigned female at birth due to the ambiguous or feminized appearance of their external genitalia, a substantial proportion transition to a male gender role during or after puberty, following virilization. Longitudinal study findings suggest that exposure of the developing brain to androgens, particularly prenatal and pubertal testosterone, exerts a masculinizing effect on gender identity and psychosexual outcomes, regardless of external genital phenotype or rearing environment. The change in identity from female to male gender roles among individuals reared as female has been observed in multiple cohorts, although proportions vary. In the original Dominican kindred, 17 out of 18 individuals reared as female changed to a male gender role during or after puberty.[32] A Chinese series also showed almost all individuals changing their gender identity to male.[33] In contrast, results from a large French series reported female to male gender transition prevalence of 12.5%. Furthermore, findings from a large multicentric European study of DSDs demonstrated that gender role change occurred in approximately 13% of individuals with 5α-RD2 and 17β-HSD3 defects (commonly grouped under androgen synthetic defects). The desire to change to the male gender may depend on ethnic and cultural practices, religious context, and local gender norms, in addition to the degree of initial virilization, reflecting exposure to testosterone and DHT.[17][34][35]

The change in identity from female to male gender roles among individuals reared as female has been observed in multiple cohorts, although proportions vary. In the original Dominican kindred, 17 out of 18 individuals reared as female changed to a male gender role during or after puberty.[32] A Chinese series also showed almost all individuals changing their gender identity to male.[33] In contrast, results from a large French series reported female to male gender transition prevalence of 12.5%. Furthermore, findings from a large multicentric European study of DSDs demonstrated that gender role change occurred in approximately 13% of individuals with 5α-RD2 and 17β-HSD3 defects (commonly grouped under androgen synthetic defects). The desire to change to the male gender may depend on ethnic and cultural practices, religious context, and local gender norms, in addition to the degree of initial virilization, reflecting exposure to testosterone and DHT.[17][34][35] Nonetheless, neuroendocrinologic evidence supports the hypothesis that androgen imprinting of the brain contributes to male gender identity development. This hypothesis is supported by results from functional neuroimaging and behavioral studies showing masculinized neural and cognitive patterns in virilized individuals with 5α-RD2 deficiency who were reared as female and later transitioned to a male gender role. Given the complex interplay between biology and identity, early interdisciplinary counseling involving endocrinologists, psychologists, ethicists, and patient advocates is essential. Care teams should provide longitudinal psychosocial support, culturally sensitive guidance on gender development, and uphold the autonomy and preferences of the affected individual.[36]

The most salient complication associated with 5α-RD2 deficiency is discordance between chromosomal sex and phenotypic genital appearance. This ambiguity may lead to psychosocial stress, gender identity challenges, and complex decisions regarding sex assignment and surgical intervention. The phenotypic ambiguity of the external genitalia is the principal clinical manifestation, and its management carries both medical and ethical implications. Although undescended or ectopic testes are found in many affected individuals, the incidence of testicular cancer in patients with 5α-RD2 deficiency is not well-defined. No large-scale studies have demonstrated an elevated risk of testicular germ cell tumors in this population, although long-term surveillance data remain limited. Nevertheless, intra-abdominal testes, particularly in individuals reared as female, support consideration of prepubertal gonadectomy to prevent unwanted virilization and potentially mitigate the oncogenic risk.[16] Moreover, available studies evaluating bone health and mineralization in individuals with 5α-RD2 deficiency have reported normal bone mineral density as assessed by dual-energy x-ray absorptiometry.[17][37] Testosterone, even in the absence of conversion to DHT, is sufficient to maintain normative bone mass acquisition during adolescence and adulthood.[30] Individuals with a 46,XX karyotype who are homozygous for pathogenic mutations in the SRD5A2 gene represent a unique subset. These individuals are not affected by the genital ambiguity seen in individuals with 46,XY, and are typically reared as female. Limited evidence suggests a mild delay in menarche and reduced body hair. Nonetheless, ovarian function, fertility, and overall reproductive outcomes are typically preserved, with normal sexual function and fertility reported. These findings highlight tissue-specific roles of DHT and underscore the relatively limited impact of 5α-RD2 activity in female reproductive physiology.[38][39] In summary, the clinical course of 5α-RD2 deficiency is dominated by issues related to sexual development and gender identity; other systemic complications, such as bone demineralization and malignant neoplasms, appear to be minimal. Continued long-term follow-up studies are warranted to fully characterize the natural history and late-onset risks of this rare condition.[10]

Pediatric endocrinologists play a central role in coordinating interdisciplinary care. Additional referrals may be needed  at different stages of life, including: Neonatologists Geneticists Psychologists and psychiatrists Pediatric urologists and pediatric urologic surgeons Ethicists and legal counselors Fertility specialists

Early identification of 5α-RD2 deficiency and an interdisciplinary approach are critical to optimizing outcomes. A step-wise approach focused on empathetic and supportive care to families should be provided when their child is diagnosed. Although the condition is not life-threatening, it has significant implications for sex of rearing, gender identity, pubertal development, fertility potential, and long-term psychological well-being. Education should emphasize the genetic basis of the condition, typical presentation, and available management strategies, including hormonal therapy, surgical options, and psychosocial support. Clinicians must provide nondirective, culturally sensitive counseling, particularly regarding sex assignment and rearing decisions, which are highly individualized and should be made in collaboration with the family, psychologists, endocrinologists, and urologists. Deterrence focuses on: Avoiding premature or irreversible sex assignment or surgery in infancy without an appropriate diagnostic evaluation. Encouraging referrals for molecular genetic diagnosis whenever possible and providing genetic counseling to support informed decision-making regarding the sex of rearing. Emphasizing the importance of longitudinal interprofessional follow-up to support the patient's psychosocial adaptation and health needs over time. Effective care requires coordination among pediatric and adult endocrinologists, pediatric urologists, geneticists, mental health professionals, and primary care clinicians. Shared decision-making, based on current evidence and respect for family values, plays a central role in improving outcomes and minimizing long-term distress.

Deficiency of 5α-RD2 is a rare autosomal recessive disorder of sex development that typically presents in neonates with ambiguous genitalia, including a clitoris-like phallus, hypospadias, chordee, unfused or partially fused scrotum, undescended testis, and a persistent urogenital sinus. Lack of timely, comprehensive endocrine evaluation in neonates can result in delayed or inaccurate diagnosis, inappropriate sex assignment, and significant long-term psychosocial distress.[40] This condition necessitates a nuanced, patient-centered approach to care, underpinned by interprofessional collaboration across multiple disciplines. Early involvement of a healthcare team that includes neonatologists, pediatric endocrinologists, geneticists, pediatric surgeons, urologists, obstetricians, gynecologists, and nursing professionals is critical for optimal outcomes. As affected individuals age, mental health professionals, gender identity, and fertility specialists also play an essential role in providing ongoing counseling, especially for those who experience ambivalence regarding sex assignment or gender identity.[41]

Deficiency of 5α-RD2 is a rare autosomal recessive disorder of sex development that typically presents in neonates with ambiguous genitalia, including a clitoris-like phallus, hypospadias, chordee, unfused or partially fused scrotum, undescended testis, and a persistent urogenital sinus. Lack of timely, comprehensive endocrine evaluation in neonates can result in delayed or inaccurate diagnosis, inappropriate sex assignment, and significant long-term psychosocial distress.[40] This condition necessitates a nuanced, patient-centered approach to care, underpinned by interprofessional collaboration across multiple disciplines. Early involvement of a healthcare team that includes neonatologists, pediatric endocrinologists, geneticists, pediatric surgeons, urologists, obstetricians, gynecologists, and nursing professionals is critical for optimal outcomes. As affected individuals age, mental health professionals, gender identity, and fertility specialists also play an essential role in providing ongoing counseling, especially for those who experience ambivalence regarding sex assignment or gender identity.[41] To improve patient care, interprofessional teams must implement evidence-based diagnostic pathways and sex assignment protocols that integrate hormonal assays, genetic testing, and imaging studies and align with local legal and medical guidelines. Effective collaboration involves strategic, coordinated discussions among team members to develop individualized care plans that respect family preferences, cultural context, and emerging patient autonomy. Communication between specialties ensures that all aspects of the diagnosis—from endocrinologic evaluation to surgical planning and psychosocial support—are addressed in a timely and ethical manner.[30] Careful counseling for families, clear communication regarding long-term reproductive and gender identity–related implications, and well-documented care transitions contribute to reduced decisional regret and improved mental health outcomes. By promoting a collaborative team culture that values each discipline's expertise, interprofessional teams foster a supportive, inclusive, and ethically sound continuum of care. This cooperative model is essential not only for medical accuracy and surgical success but also for enhancing trust, patient satisfaction, and lifelong quality of care in individuals with 5α-RD2 deficiency.[2]