Hypospadias of Genetic Cause

A congenital malformation of the penis in which the urethral meatus opens on the ventral surface, from the glans to the perineum; the isolated form is, in most cases, multifactorial, and a minority results from variants in sex differentiation genes (AR, NR5A1, SRD5A2, HSD17B3, MAMLD1) or forms part of syndromes and 46,XY differences of sex development.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

Hypospadias is a congenital malformation of the penis in which the urethral meatus is displaced proximally onto the ventral surface: in mild cases on the glans itself, in more severe cases along the penile shaft, on the scrotum or on the perineum [17]. The prepuce is almost always incomplete on the ventral surface and forms a dorsal hood, a change that may be more visible than the position of the meatus; in some patients there is coexisting ventral curvature of the penis, which becomes more pronounced on erection and is more likely the more proximal the meatus [17]. Orphanet reserves the entity ORPHA:95706 for non-syndromic posterior hypospadias, defined by a penoscrotal, scrotal or perineal location of the meatus, frequently accompanied by curvature, bifid scrotum and, sometimes, micropenis [1].

This article covers isolated hypospadias in its genetic and clinical dimensions: the multifactorial form, which accounts for most patients; the monogenic forms with their own OMIM entries (HYSP1 due to variants in the androgen receptor gene, AR; HYSP2 due to variants in MAMLD1; HYSP3, an autosomal locus at 7q32.2-q36.1; HYSP4, susceptibility at Xp11.22) [2, 4, 6]; and the 46,XY differences of sex development (DSD) that present as apparently isolated hypospadias, in particular those associated with NR5A1, SRD5A2 and HSD17B3 [8, 16]. Some entities receive here only what is needed for diagnostic reasoning: the general approach to DSD, androgen insensitivity, 5α-reductase type 2 deficiency and 17β-hydroxysteroid dehydrogenase type 3 deficiency, 46,XY gonadal dysgenesis and NR5A1, congenital adrenal hyperplasia and the Smith-Lemli-Opitz, Opitz G/BBB and Mowat-Wilson syndromes and WT1-related Wilms tumour predisposition.

1.2. Anatomical classification

The classical system of the Oxford Desk Reference divides hypospadias into mild (glanular or coronal), moderate (penile) and severe (scrotal or perineal), with the caveat that curvature may mask the severity until it is released at the first operation [17]. The European Association of Urology (EAU) paediatric urology guideline, in its 2026 edition, uses three groups: distal-anterior (glans or distal shaft), intermediate-middle (penile) and proximal-posterior (penoscrotal, scrotal and perineal). The guideline adds that the classification should be revised after degloving of the skin, because the meatus may recede, and that severity also depends on penile length, the degree of curvature, the size and shape of the glans and the quality of the urethral plate [18]. In Dutch epidemiological studies, the anterior form accounts for 59% of cases, the middle form for 29% and the posterior form for 12% [23]; in a Swedish series of 676 phenotyped patients, 53% were glanular, 39% penile, 6% penoscrotal or perineal and 2% had only a cleft prepuce [24].

1.3. Milestones in understanding the aetiology

The case-control study of Stoll and colleagues, carried out in Alsace between 1979 and 1987, established the parameters that still guide counselling for the isolated form: a birth prevalence of 2.89 per 1000 boys, other malformations in 15.3% of cases, a recurrence risk of 17% for siblings and a heritability coefficient of 56.9% [25]. Reports of families with vertical transmission over several generations and of consanguineous families with several affected boys have suggested, since the 1970s, dominant and recessive monogenic forms [6]. Complex segregation analysis of 2005 Swedish pedigrees, with other cases in the family in 7%, pointed to a multifactorial cause in most and to monogenic effects in a small fraction of families [2, 24].

The search for genes began with the androgen axis. Batch and colleagues described, in 1993, two brothers with perineal hypospadias, a 46,XY karyotype, normal endocrinology, a qualitative androgen-binding defect and a point variant in AR; familial hypospadias was then included in the spectrum of partial androgen insensitivity [2]. Later studies in penile tissue from 40 patients and in cases of isolated perineal hypospadias showed that AR variants are a rare cause of the isolated form [2]. In 2006, Fukami and colleagues identified three nonsense variants in CXorf6, later designated MAMLD1, in four Japanese patients with penoscrotal hypospadias, and showed expression of the homologous mouse gene in fetal Sertoli and Leydig cells during the critical period of sex differentiation [5, 26]. The 2014 genome-wide association study, with 1006 surgically confirmed cases and 5486 Danish controls, replicated in 1972 cases and 1812 controls from Denmark, the Netherlands and Sweden, identified 18 genomic regions that together explain 9% of susceptibility [9]. Next-generation sequencing applied to cohorts with isolated hypospadias showed, from 2021 onwards, that a small fraction of patients, even with mild forms, have unrecognised monogenic DSD or underdiagnosed syndromes [16].

1.4. Nomenclature

The 2005 international consensus conference, published in 2006 under the auspices of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology, replaced the terms “intersex”, “male pseudohermaphroditism” and “undervirilisation of the XY male” with “46,XY DSD”; the term “differences of sex development” is now used alongside “disorders” [8, 27]. The 2016 update of the Global DSD consortium retained this nomenclature and reinforced the centrality of quality of life and the participation of patient associations [28]. The UK Society for Endocrinology has recommended, since 2021, the term “atypical genitalia” instead of “ambiguous”, because in most newborns the appearance is merely atypical and sex assignment is possible [20]. In Orphanet, the former entity “familial hypospadias” (ORPHA:440) is classified as obsolete, and severe hypospadias without a syndrome is coded as ORPHA:95706 [1].

2. Molecular Genetics and Pathophysiology

2.1. Embryology of the penile urethra and androgen dependence

Until about 12 weeks of gestation, the external genitalia are identical in both sexes: genital tubercle, urethral folds and labioscrotal swellings [29]. In the 46,XY fetus, the SRY gene triggers testicular differentiation at the end of the first trimester; Sertoli cells produce anti-Müllerian hormone, which causes regression of the Müllerian ducts, and Leydig cells produce testosterone, which stabilises the Wolffian ducts [29]. Masculinisation of the external genitalia, which begins at about 8 weeks, depends on dihydrotestosterone (DHT), formed from testosterone by 5α-reductase type 2 in the target tissues [17]. Fusion of the urethral folds in the midline, from proximal to distal, forms the penile urethra and the raphe; an interruption of this process leaves the meatus at a point proximal to the tip of the glans, and the ventral tissue distal to the meatus is represented by a urethral plate, by fibrous tissue causing curvature and by an incomplete prepuce [17, 18].

Hypospadias thus results from failure of a signalling pathway involving fetal androgen production (chorionic gonadotrophin/LH axis, Leydig cells, steroidogenic enzymes), its local conversion into DHT, action through the AR and a set of genital tubercle patterning genes. The systematic review by van der Zanden and colleagues, which selected 169 of 922 articles published up to 2011, found variants in WT1, NR5A1 (SF1), BMP4, BMP7, HOXA4, HOXB6, FGF8, FGFR2, AR, HSD3B2, SRD5A2, ATF3, MAMLD1, MID1 and BNC2, and associations with polymorphisms in FGF8, FGFR2, AR, HSD17B3, SRD5A2, ESR1, ESR2, ATF3, MAMLD1, DGKK, MID1, CYP1A1, GSTM1 and GSTT1; most investigators nevertheless considered that a single variant does not explain most cases of isolated hypospadias [30].

2.2. Genetic architecture of the isolated form

The genetic contribution to the isolated form is documented by familial aggregation studies. In the Danish cohort of 1,201,790 boys born between 1973 and 2005, with 5380 cases, the recurrence risk ratios were 50.8 (95% confidence interval, 95% CI, 34.2–75.5) for male twins, 11.6 (9.75–13.7) for first-degree relatives, 3.27 (2.47–4.34) for second-degree relatives and 1.33 (0.94–1.88) for third-degree relatives; the risk was the same for brothers and sons and the same through the paternal and maternal lines, which indicates a main role of genetic factors and not of the shared intrauterine environment [10]. The heritability coefficient was 56.9% in Alsace [25]. The sharp fall in risk between first- and second-degree relatives corresponds to the multifactorial threshold model, in which the risk for first-degree relatives approximates the square root of the population frequency and increases with the severity of the defect and with the number of affected relatives [31].

The genome-wide association study of Geller and colleagues identified 18 regions with independent association (P < 5 × 10⁻⁸), which together explain 9% of susceptibility; several contain genes with a role in embryonic development, such as HOXA4, IRX5, IRX6 and EYA1 [9]. Earlier, van der Zanden and colleagues had identified, in an association study with pooled DNA from 436 cases and 494 controls of European ancestry, replicated in a Dutch sample of 133 cases with their parents and in a Swedish series of 266 cases and 402 controls, two polymorphisms in DGKK (diacylglycerol kinase kappa, Xp11.22), rs1934179 and rs7063116, with allelic ORs of 2.2 to 3.9 in the three samples; DGKK expression in the prepuce was lower in carriers of the rs1934179 risk allele, and this locus defines the OMIM susceptibility entry HYSP4 (300856) [7]. A 2249-base-pair microdeletion in intron 6 of ESR1 (recorded as DEL_6_75504 in gnomAD), in almost complete linkage disequilibrium with a previously associated haplotype, was identified in Japanese and Italian boys and is associated with cryptorchidism and hypospadias; the deletion alters ESR1 expression in MCF-7 cells [32]. Interaction between genetic susceptibility and exposure to endocrine disruptors is one of the explanations proposed for the lack of replication of many genetic studies [18].

Exome sequencing of Chinese patients with hypospadias identified NR5A1, SRD5A2 and AR as the genes most frequently affected in severe forms and an excess of rare variants in ciliary dynein genes (DNAH5, DNAH8, DNAH9, DNAH11, DNAH17), present in 24% of cases, with a Dnah8-null mouse model that has reduced testosterone [33]. A cohort of 106 Chinese children studied as trios (92 trios), published in 2026, found an excess of de novo loss-of-function variants (2.2-fold; P = 0.001), mainly in ciliopathy genes (10.35-fold; P = 0.016), and proposed PRKCZ and HRNR as risk genes with functional validation [34]. These results are research findings: the contribution of ciliary genes has not been validated in European populations or incorporated into clinical panels.

2.3. Genes of monogenic causation

AR (androgen receptor; Xq12)

AR encodes a nuclear receptor that, when bound to testosterone or DHT, regulates the transcription of androgen-dependent genes; loss-of-function variants cause the androgen insensitivity spectrum, from the complete form (female phenotype) to partial forms with atypical or predominantly male genitalia and mild forms with infertility [3]. The predominantly male form of partial insensitivity may present as simple “isolated” hypospadias (glanular or penile) or severe (perineal) hypospadias, with a normal-sized penis and descended testes, or as severe hypospadias with micropenis and bifid scrotum [3]. OMIM classifies hypospadias due to AR variants as HYSP1 (300633), with two historical examples, p.Ile869Met and p.Pro546Ser (historical numbering, = NM_000044.6:c.2610T>G p.(Ile870Met) and NM_000044.6:c.1645C>T p.(Pro549Ser)) [35], described respectively in two brothers with perineal hypospadias and in a boy with distal hypospadias [2]. In a prospective French study of 292 Caucasian children with isolated hypospadias without micropenis or cryptorchidism and 345 controls, sequencing of AR exons 1 to 8 revealed five missense variants in nine patients (3%), five of them with anterior hypospadias; none was present in the controls, and three had previously been described only in men with isolated infertility [15]. The length of the CAG repeat tract in exon 1 modulates receptor activity; expansion above about 40 repeats causes spinal and bulbar muscular atrophy (Kennedy disease), and a Swedish report described a boy with severe hypospadias and 42 repeats, suggesting that hypospadias may be an underdiagnosed feature of this disease [3, 36]. Phenotypic variability with the same variant, between families and sometimes within them, is characteristic of partial insensitivity; part results from somatic mosaicism and part from modifier genes, such as FKBP52, which regulates AR transactivation and urethral morphogenesis in the mouse [3].

MAMLD1 (Xq28)

MAMLD1 encodes a protein with a mastermind-like domain, a transcriptional coactivator that activates the promoter of HES3, a non-canonical target of the Notch pathway, independently of NOTCH; it is expressed in fetal Sertoli and Leydig cells between embryonic days 12.5 and 14.5 in the mouse, and has been proposed to support fetal testosterone production [26, 37]. The gene lies about 80 kb centromeric to MTM1, and deletions spanning both genes have been described in boys with myotubular myopathy and genital anomalies; in a boy with myotubular myopathy and normal genitalia, the deletion began in intron 4 of MAMLD1 and preserved the preceding exons, including exon 3, which encodes more than 80% of the protein and was considered essential for male genital development [26]. The nonsense variants described by Fukami and colleagues were identified in four Japanese patients with penoscrotal hypospadias and apparently normal pituitary-gonadal hormone levels, were predicted to be targets of nonsense-mediated mRNA decay and markedly reduced transcripts in leucocytes [4]. Kalfa and colleagues found variants in 4 of 41 patients (9.7%) with isolated hypospadias of variable severity, including a CAG repeat expansion in a patient with subcoronal hypospadias [38]. A Chinese series of ten 46,XY patients with MAMLD1 variants and a review of 26 published cases showed hypospadias as the main phenotype (8 of 10 and all reviewed cases), usually severe, sometimes with micropenis, cryptorchidism or central precocious puberty, and with a generally normal endocrine assessment [19].

The causal role of MAMLD1 is debated. In a functional study of 108 46,XY patients with DSD, most of the nine variants identified behaved like the wild-type sequence in vitro, only the variant p.Leu210Ter (published designation, without a corresponding ClinVar record) showed loss of function in all assays, some variants are present in people without abnormalities, and the male Mamld1-knockout mouse has normal genitalia and reproduction [11]. Interpretation of a MAMLD1 missense variant in a boy with hypospadias therefore requires caution, and classification depends on functional and segregation evidence. Table 2.1 presents the variants of the OMIM entry with the historical nomenclature and the correspondence in the MANE transcript, confirmed in ClinVar; the historical numbering derives from a different isoform and differs by 73 codons from the MANE numbering [26, 35].

Table 2.1. MAMLD1 variants from OMIM entry 300120 normalised to the MANE Select transcript NM_005491.5.

Variants from later series, such as those of Kalfa (2008) and Li (2020), are cited in the numbering of the articles, which has not been converted [19, 38].

NR5A1 (steroidogenic factor 1; 9q33.3)

NR5A1 encodes steroidogenic factor 1 (SF-1), a nuclear receptor that binds DNA as a monomer and activates the transcription of steroidogenesis genes (CYP11A1, CYP11B, CYP21), AMH, STAR and NR0B1; it is essential for the development of the gonads and the adrenal cortex [39]. Heterozygous variants cause a spectrum: complete or partial 46,XY gonadal dysgenesis, 46,XY undervirilisation with penoscrotal hypospadias, curvature, microphallus or scrotal anomalies, vanishing testes and isolated male infertility; in 46,XX women, premature ovarian insufficiency and, rarely, testicular or ovotesticular DSD; adrenal insufficiency is rare [8, 40]. GeneReviews attributes 10–15% of non-syndromic 46,XY DSD to NR5A1 [8]. In a German series of 27 46,XY patients with severe undervirilisation without adrenal insufficiency, 5 (18.5%) had heterozygous NR5A1 variants [41]. The first description of a mild phenotype in a boy raised as male was that of a de novo variant NM_004959.5:c.1310T>A p.(Leu437Gln) in the ligand-binding domain, with partial activity in vitro, in a British patient with severe penoscrotal hypospadias, curvature, a small phallus and palpable testes; assessment showed a defect of androgen biosynthesis, a partial component of hypogonadotrophic hypogonadism in late childhood and a need for testosterone to induce puberty [42]. The same variant may present very differently within a family [39]. Inheritance is sex-limited autosomal dominant, with variants inherited from the mother (asymptomatic or with ovarian insufficiency) or from a mildly affected father, or arising de novo [8]. In isolated hypospadias, NR5A1 appears among the most frequent genes in French, American and Chinese series [16, 33, 43].

SRD5A2 and HSD17B3

5α-reductase type 2, encoded by SRD5A2, converts testosterone into DHT; biallelic variants cause an autosomal recessive 46,XY DSD whose phenotype at birth ranges from female to any degree of hypospadias and, rarely, isolated micropenis, with virilisation at puberty [8, 20]. The historical name “pseudovaginal perineoscrotal hypospadias” (OMIM 264600) shows the link with the subject of this article [12]. 17β-hydroxysteroid dehydrogenase type 3, encoded by HSD17B3, converts androstenedione into testosterone in the testis; the deficiency, autosomal recessive, produces female or atypical external genitalia with Wolffian structures present and virilisation at puberty, and the biochemical marker is a low testosterone/androstenedione ratio, especially after hCG stimulation [20, 44]. Some people with a partial androgen insensitivity phenotype have biallelic HSD17B3 variants, and in the French cohort with isolated hypospadias HSD17B3 was among the genes with likely pathogenic variants [3, 16].

Other genes and mechanisms

HSD3B2 (3β-hydroxysteroid dehydrogenase type 2) usually causes congenital adrenal hyperplasia with adrenal insufficiency and severe hypospadias with micropenis in boys, but in a Japanese and Vietnamese series of 62 patients with non-syndromic hypospadias homozygous variants were found as the only manifestation, and two of the seven patients with variants had changes in more than one gene, the first suggestion of oligogenicity in isolated hypospadias [8, 45]. The same series found variants in AR, BNC2 and SRD5A2 and a mosaic dicentric Y chromosome [45]. Genes of syndromes with hypospadias, such as MID1 (Opitz G/BBB syndrome) and RARA (retinoic acid pathway), and 18q deletions were identified by reverse phenotyping in children referred as having isolated hypospadias [16]. DSD genes with hypospadias and other anomalies, such as WT1, MYRF, GATA4 and ATRX, are listed in Table 6.1 [8, 43].

2.4. Placental and environmental factors

The most consistent association of hypospadias with non-genetic factors is with low birth weight, fetal growth restriction, maternal hypertension and pre-eclampsia, which points to placental insufficiency as a mechanism [18, 30]. Placental chorionic gonadotrophin stimulates fetal Leydig cells during the critical period, and a dysfunctional placenta may reduce testosterone production; in Alsace, the only associated factor was low placental weight [25]. 46,XY boys who are small for gestational age may have a partial androgen insensitivity phenotype without an AR variant, a situation for which the designation “XY DSD with fetal growth restriction, as yet unexplained” has been proposed [3].

Endocrine disruptors with oestrogenic or antiandrogenic activity can induce hypospadias in animal models, and it is uncertain whether usual human exposure reaches that effect [30]. The most direct human data come from diethylstilbestrol (DES): in the Dutch OMEGA cohort, 4 of 205 sons of women exposed to DES in utero had hypospadias, against 8 of 8729 sons of unexposed women (prevalence ratio 21.3; 95% CI 6.5–70.1), and a French study of 529 families found hypospadias without a molecular defect in a significant proportion of the grandsons of women treated with DES in pregnancy [46, 47]. In southern France, between 2009 and 2014, in 408 children with isolated hypospadias without variants in AR, SRD5A2 and MAMLD1 and 302 controls, estimated fetal exposure to endocrine disruptors in the genital differentiation window was 40.0% versus 17.6% (odds ratio, OR, 3.13; 95% CI 2.11–4.65), mainly to paints, solvents, detergents, pesticides and cosmetics, with more maternal (cleaning, hairdressing, beauty care, laboratory) and paternal occupational exposure, and more residence less than 3 km from industrial areas, incinerators and landfills [48]. These association studies are based on questionnaires and job-exposure matrices and do not prove causality.

Among drugs, valproate monotherapy in the first trimester was associated with hypospadias (adjusted OR 4.8; 95% CI 2.9–8.1) in the EUROCAT antiepileptic drug database, with 98,075 malformation records among 3.8 million births in 14 European countries between 1995 and 2005 [49]. Hormonal contraception used after conception was associated with the middle and posterior forms in a Dutch case-control study [23]. Pre-gestational and gestational maternal diabetes is associated with a higher risk [18]. In vitro fertilisation was associated with a small increase in risk in Sweden (OR 1.15) [14], but not in the OMEGA cohort (prevalence ratio 1.8; 95% CI 0.6–5.7) [46].

2.5. Aetiological heterogeneity by phenotype

The anterior and middle forms and the posterior forms appear to have different aetiological profiles. In the Dutch case-control study of 405 cases and 627 controls, family history was associated mainly with the anterior and middle forms, whereas twinning, primiparity, preterm birth and low weight for gestational age were associated mainly with the posterior form [23]. In a larger Dutch study (887 cases and 1005 controls), pre-eclampsia was associated with posterior hypospadias (adjusted OR 3.09; 95% CI 1.49–6.43), whether treated or not, and not with the other forms; chronic and gestational hypertension showed no association [50]. In practice, familial distal hypospadias tends to be polygenic, and proximal hypospadias, especially with other genital anomalies, concentrates the monogenic DSD and placental causes [18, 51].

3. Clinical Spectrum and Manifestations by System

3.1. Genital phenotype at birth

The diagnosis is made at birth in the great majority of boys; the exception is the megameatus intact prepuce variant, which is only recognised when the prepuce is retracted [18]. The full description includes the position, shape and width of the meatus; the presence of a distal atretic urethra and of division of the corpus spongiosum; the appearance of the preputial hood and of the scrotum; penile size; and curvature on erection [18]. Ventral curvature results from abnormal connective tissue, short ventral skin and, in severe forms, the urethral plate itself and disproportion between the corpora cavernosa; a curvature of 30 degrees or more is considered to warrant correction [18]. In posterior forms, the scrotum may be bifid, there may be penoscrotal transposition and the penis may be small; Orphanet includes micropenis in this description [1]. A glans width of less than 14 mm is an independent risk factor for surgical complications [18].

In the Alsace series, 80% of cases had a mild phenotype and more than 90% of these had no other malformations; associated malformations were more frequent in the severe forms [17, 25]. Overall, 15.3% of boys with hypospadias had other malformations, and among these renal and urinary anomalies were present in 37.0% [25].

3.2. Associated anomalies of the genitourinary tract

Congenital cryptorchidism accompanies hypospadias in 2% to 6.2% of cases, and acquired undescended testis, which arises after birth, in 1% to 14%, more in proximal hypospadias [18]. The combination of hypospadias with undescended testes is one of the classical signs of DSD [18]. The relationship with upper urinary tract anomalies (pelviureteric junction obstruction, renal agenesis, dysplasia or cystic disease) is contradictory in studies of hypospadias without a recognised syndrome [18]. In the Australian series of 50 children with complex hypospadias assessed between 2016 and 2024, 11% had renal anomalies and 19% proteinuria [52]. Dribbling and ballooning of the urethra suggest meatal stenosis [18].

3.3. Hypospadias as part of syndromes

Hypospadias is a sign of numerous chromosomal and monogenic syndromes. In Smith-Lemli-Opitz syndrome, hypospadias or cryptorchidism are present in 90–100% of boys, with genitalia sometimes atypical and a hypoplastic scrotum, growth delay, microcephaly, cleft palate (37–52%), heart disease (36–38%), Y-shaped syndactyly of the 2nd and 3rd toes (more than 95%) and postaxial polydactyly (about 50%) [17]. Opitz G/BBB syndrome combines hypertelorism, hypospadias, swallowing difficulties and developmental delay; laryngeal clefts and anteverted nares are specific to the X-linked form (MID1, Xp22) [17]. Mowat-Wilson syndrome (ZEB2) combines characteristic facies, severe intellectual disability, microcephaly, epilepsy, heart disease, corpus callosum anomalies and frequent hypospadias; hand-foot-genital syndrome (HOXA13) combines hypospadias with hypoplastic thumbs and short halluces [17]. WAGR syndrome (11p13 deletion) and Denys-Drash and Frasier syndromes (WT1) are accompanied by atypical genitalia, with a risk of Wilms tumour, nephropathy or gonadoblastoma [29]. Chromosomal causes include additional X chromosomes, XX male, triploidy, trisomies 13 and 18 and other anomalies visible on the karyotype, 9p24 deletions (DMRT1) and terminal 10q deletions [17, 29]. An 18q deletion was identified by panel coverage analysis in a child referred as having isolated hypospadias [16]. In Opitz G/BBB syndrome, severe hypospadias is associated with urinary anomalies, vesicoureteric reflux and hydronephrosis, and the boys also have cryptorchidism and bifid scrotum [53]. In Cornelia de Lange syndrome, hypospadias and micropenis are among the “other major systems” criteria, and genital hypoplasia (hypospadias, micropenis, hypoplasia of the labia majora) occurs in 57% of patients, cryptorchidism in 73% and vesicoureteric reflux in 40% [54]. Hypospadias also appears in descriptions of the 22q11.2 deletion (with unilateral or bilateral renal agenesis and cryptorchidism) [55], Wolf-Hirschhorn syndrome (with cryptorchidism and hypoplasia of the external genitalia) [56], 47,XYY syndrome (with cryptorchidism and hypogenitalism) [57], Silver-Russell syndrome (with cryptorchidism) [58] and thalidomide embryopathy (with cryptorchidism and testicular anomalies) [59]. In VACTERL association, anal atresia may be accompanied by hypospadias and bifid scrotum, and the differential diagnosis includes Opitz G/BBB syndrome and anophthalmia-oesophageal atresia-genital anomalies (AEG) syndrome, caused by de novo dominant variants in SOX2, with cryptorchidism and hypospadias in boys [60, 61]. Pallister-Hall syndrome (GLI3, autosomal dominant) combines hypothalamic hamartoblastoma, postaxial polydactyly, imperforate anus and hypospadias, with very variable expression, which justifies examining the parents [62]. Table 6.1 summarises the discriminating features.

3.4. Spectrum of monogenic forms

Patients with monogenic DSD and apparently isolated hypospadias are poorly distinguished by genital examination. In the French cohort of 284 children without undescended testis or micropenis, the proportion of likely pathogenic variants increased with severity, but was also present in the mild forms [16]. In partial androgen insensitivity with predominantly male genitalia, gynaecomastia at puberty and impaired spermatogenesis are the rule, and facial, body and axillary hair is often reduced [3]. In boys with MAMLD1 variants, hypospadias, almost always severe, was the main finding, with micropenis, cryptorchidism and, in one case, central precocious puberty [19]. In carriers of NR5A1 variants, the phenotype ranges from hypospadias with scrotal testes to gonadal dysgenesis, and adrenal insufficiency or progressive gonadal failure in adolescence may occur [8, 43]. In 5α-reductase 2 and 17β-HSD3 deficiencies, pubertal virilisation of a child raised as a girl, with primary amenorrhoea, a deep voice and absence of breast development (5α-reductase) or gynaecomastia (17β-HSD3), is the typical late presentation [29, 44].

3.5. Natural history without surgery

The natural history of untreated hypospadias is poorly documented [18]. Older studies in men with uncorrected hypospadias, mainly distal, described normal voiding, sexual function and satisfaction with penile appearance; more recent studies describe a spraying or deviated stream, urinary obstruction, curvature, pain on intercourse and dissatisfaction with genital appearance, and more than half of these men opted for correction in adulthood [18]. In a prospective controlled study, complications after primary tubularised incised plate urethroplasty were 2.5 times more frequent in adults than in children [18].

3.6. Treated disease: long-term outcome

After surgery in childhood, most adolescents and men report good sexual function and satisfaction; the severity of hypospadias and the number of operations are associated with poorer psychosexual well-being [18]. Obstructive uroflowmetry curves are frequent and mostly asymptomatic [18]. Patients report satisfaction with penile appearance similar to that of controls and higher than that attributed to them by parents and urologists; shorter penile length is associated with dissatisfaction, especially in proximal forms [18]. Long-term studies have high losses to follow-up and heterogeneous data, and specific quality-of-life instruments are lacking [18].

Swedish registry cohorts describe the lifelong health of people born with hypospadias, operated on or not, and allow comparison with brothers. In 2,165,255 men followed from 10 to 60 years of age, of whom 9714 had hypospadias, the risk of hypogonadism was three times higher (hazard ratio, HR, 3.27; 95% CI 2.33–4.59), more pronounced in the proximal form, with more delayed puberty (HR 1.49), type 2 diabetes (HR 1.57) and cardiovascular disease (HR 1.47), and mean height lower than that of brothers and of the population [63]. Men born between 1964 and 1998 with hypospadias were less likely to be biological fathers (adjusted HR 0.87; 95% CI 0.83–0.92), in the distal form (0.90) and especially in the proximal form (0.59; 95% CI 0.42–0.81), made more use of medically assisted reproduction and, when there was associated cryptorchidism, received more diagnoses of infertility [64]. The rate of dizygotic twins, used as an indicator of semen quality, did not differ in fathers with hypospadias who conceived without assistance, which does not exclude changes in the severe forms [65]. In the Swedish cohort born between 1964 and 2018, the risk of testicular cancer was double (HR 2.04; 95% CI 1.42–2.92), mainly in the proximal form, without clear familial coaggregation; there was an association with Wilms tumour in childhood and with bladder and urethral cancers, but not prostate cancer, with a low absolute risk [66]. In a cohort of almost 3 million people, including 16,890 with hypospadias, mortality was higher in early infancy (HR 2.07), in childhood (HR 1.77) and in adolescence and adulthood (HR 1.31), mainly in the proximal forms; in infants, the excess is largely explained by birth weight and associated malformations, and in adults by deaths from cardiovascular disease or diabetes (HR 3.20) and renal or urological disease (HR 5.16), with no increase in deaths from cancer, suicide or accidents [67].

In terms of neurodevelopment, among 9262 Swedish boys with hypospadias and 4936 brothers, a diagnosis of intellectual disability was three times more frequent (OR 3.2; 95% CI 2.8–3.8), and there was more autism spectrum disorder (OR 1.4), attention deficit hyperactivity disorder (OR 1.5) and behavioural disorders (OR 1.4); the brothers also had more autism spectrum disorder (OR 1.6), which suggests shared familial susceptibility [68]. In 4378 men with hypospadias born between 1969 and 1993, education, income and marriage did not differ from controls, but the probability of a disability pension was 39% higher [69]. Some of these associations reflect undiagnosed syndromes and DSD, and not the effect of isolated hypospadias [63].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

Ultrasound can identify severe hypospadias when there is marked curvature or atypical genitalia, and the combination with a male karyotype guides prenatal diagnosis [17]. Up to 20 weeks it may be difficult to determine fetal sex from the external genitalia [29]. A discrepancy between the chromosomal sex obtained by chorionic villus sampling or amniocentesis and the ultrasound or neonatal appearance is most frequently caused by maternal contamination of the sample, and only then by sample mix-up, true DSD or chimerism [29].

4.2. Newborn

Examination of the newborn identifies hypospadias and should distinguish, right at birth, the isolated form from a DSD; this distinction is a strong EAU recommendation [18]. Table 4.1 brings together the findings that indicate assessment for DSD according to the EAU, adapted from the American Academy of Pediatrics, and according to the UK Society for Endocrinology [18, 20].

Table 4.1. Hypospadias requiring assessment for a difference of sex development.

The external masculinisation score adds up the fusion of the labioscrotal folds, phallus size, meatal position and gonadal location, to a maximum of 12; in a systematic examination of 423 healthy term newborns, 412 (98%) scored 12, 10 scored 11 and only 1 scored less than 11 [20]. The external genitalia score describes the meatal position and the length of the genital tubercle in more detail and is gender-neutral [20].

The threshold for investigation is lower when there are malformations of other organs, dysmorphic features, metabolic disease, low birth weight or fetal growth restriction, or a family history of consanguinity, stillbirths, recurrent miscarriages, fertility problems, genital anomalies, hernias, delayed puberty, genital surgery, unexplained deaths or need for corticosteroid therapy [20]. The history includes questions about medication during pregnancy, in particular antiepileptic drugs, and about birth weight [17]. Examination looks for raised blood pressure and a renal mass (Wilms tumour), hypertelorism and swallowing or laryngeal abnormalities (Opitz G/BBB), cleft palate, postaxial polydactyly and syndactyly of the 2nd and 3rd toes (Smith-Lemli-Opitz), and genital and areolar pigmentation, which suggests ACTH (adrenocorticotrophic hormone) excess [17, 18].

4.3. Urgent situations

Any newborn with atypical genitalia is a diagnostic emergency, because a 46,XX girl with congenital adrenal hyperplasia may have fatal salt wasting; the EAU recommends (strong) not delaying diagnosis or treatment and referring to a centre with neonatology, endocrinology, paediatric urology and psychology [18]. Serum 17-hydroxyprogesterone is not reliable before 36 hours of life, and electrolytes only become abnormal in salt wasting from the fourth day, which justifies their serial measurement [20]. Boys with hypospadias and an NR5A1 variant may need surveillance for adrenal insufficiency [8, 43].

4.4. Childhood, adolescence and adulthood

Puberty is the second moment of recognition: gynaecomastia in a boy operated on for hypospadias suggests partial androgen insensitivity or 17β-HSD3 deficiency; virilisation of a child raised as a girl suggests 5α-reductase 2 or 17β-HSD3 deficiency; and delayed puberty or gonadal failure suggest NR5A1 or gonadal dysgenesis [3, 8, 29]. In adulthood, infertility, sexual dysfunction and late complications of surgery, including urethral stricture and recurrent curvature, prompt consultation [18, 64]. In an adolescent with pubertal delay or undervirilisation, a history of hypospadias repair, orchidopexy or gynaecomastia increases the probability of partial androgen insensitivity, a testosterone biosynthesis defect or mild testicular dysgenesis [20].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Principles

The diagnosis of hypospadias is clinical and has no formal criteria beyond the position of the meatus and the anatomical description [18]. The diagnostic problem is aetiological: to identify, without over-investigating the majority with an isolated distal form, the boys whose hypospadias is a manifestation of DSD, a syndrome or a chromosomal disorder [17, 20]. The Oxford Desk Reference recommends a stepwise approach, coordinated by a paediatric endocrinologist and a paediatric urologist, to avoid unnecessary invasive and costly investigations [17].

5.2. Isolated distal or middle hypospadias

In glanular or mid-shaft hypospadias, without undescended testis, micropenis, other malformations or family history, the Society for Endocrinology considers detailed endocrine or genetic investigation unnecessary [20]. The karyotype is not a routine test in isolated mild hypospadias [17]. As regards imaging, there is divergence: the Oxford Desk Reference (2017) indicates renal and urogenital ultrasound in all affected boys [17], whereas the EAU, in its 2026 edition, records contradictory data on urinary anomalies and the panel consensus is not to perform imaging in hypospadias [18]. The most recent guideline is the reference; ultrasound remains indicated when there are other malformations, suspicion of a syndrome or DSD, or urinary symptoms [18, 20].

Family history deserves attention even in mild forms: in a French multicentre study of 395 boys, 22.3% had relatives with hypospadias, almost always on the paternal side (59.1%, the father himself in 30.7%), and the familial forms had more genetic defects in AR, NR5A1, SRD5A2 and MAMLD1 (5.68% versus 1.63%; P = 0.048) [70]. Familial hypospadias of any degree is a criterion for DSD assessment in the United Kingdom [20].

5.3. First line when DSD is suspected

In all newborns with atypical genitalia or bilateral impalpable gonads, the first line defines the sex chromosomes, assesses the internal structures by pelvic ultrasound and excludes congenital adrenal hyperplasia due to 21-hydroxylase deficiency, the most frequent cause of a life-threatening situation associated with atypical genitalia [20]. It includes polymerase chain reaction or fluorescence in situ hybridisation with X and Y markers, with a result within two working days in specialist centres, blood glucose, 17-hydroxyprogesterone and serial electrolytes [20]. The Oxford Desk Reference adds a full karyotype with a search for mosaicism, serum testosterone and genomic microarray when there is no definitive endocrine diagnosis [29]. In congenital adrenal hyperplasia with high suspicion and a need for immediate corticosteroid therapy, serum and urine are stored beforehand for 17-hydroxyprogesterone, testosterone, androstenedione, renin activity and aldosterone [20].

In boys with atypical genitalia, a chromosomal anomaly is found in about 3% with isolated cryptorchidism, 7% with hypospadias and 13% with the combination of cryptorchidism and hypospadias, according to data cited by the Society for Endocrinology [20]. In 46,XY individuals, a complete investigation reveals an endocrine or genetic cause in at least a quarter of cases [20, 29].

5.4. Endocrine assessment

The endocrine assessment of a 46,XY boy with severe hypospadias or atypical genitalia measures gonadotrophins (LH and FSH), anti-Müllerian hormone (AMH), inhibin B, testosterone, androstenedione and DHT [20, 29]. Neonatal physiology conditions interpretation: “minipuberty” raises gonadotrophins and testosterone in the first weeks and months, and in the very young infant with an active axis and raised testosterone on serial samples the stimulation test may be dispensed with [20]. Serum AMH has a high predictive value for the testosterone response to human chorionic gonadotrophin (hCG) [20].

The hCG stimulation test identifies functioning Leydig cells and testosterone biosynthesis defects; it is invasive and should be done at a later stage, under the direction of the regional DSD centre [20]. UK protocols use intramuscular hCG 1000–1500 IU on three consecutive days, followed, in the prolonged version, by 1500 IU twice weekly for a further two weeks, useful in bilateral cryptorchidism or suspected hypogonadotrophic hypogonadism [20]. The testosterone response is normal when the value exceeds the upper limit of the prepubertal range or doubles the baseline; for androstenedione and DHT, the day-four sample, after hCG, is the most important, and in the prolonged test the day-22 sample should be stored for these measurements [20]. A poor testosterone response warrants assessment of adrenal function by a short tetracosactide test, especially in entities associated with adrenal insufficiency [20].

Table 5.1. Biochemical patterns in 46,XY DSD presenting with hypospadias.

Normal hormone values after birth do not prove that they were normal during the critical fetal period, and a normal androgen response in the infant does not prove normal sensitivity in utero [3]. Androgen sensitivity can be assessed by the effect of a short course of testosterone or topical DHT on the phallus, but there is no consensus on the androgen, dose, route, timing, duration or definition of response [20].

5.5. Genetic testing

The GeneReviews strategy begins with the chromosomal complement, by karyotype with enough cells to detect 45,X/46,XY mosaicism and fluorescence in situ hybridisation for SRY, or by chromosomal microarray, which defines the sex chromosome complement, the presence of SRY and deletions or duplications associated with DSD [8]. This is followed by a multigene DSD panel when the phenotype is suggestive, or by exome or genome sequencing when the phenotype does not point the way [8]. Laboratories have moved from gene-by-gene sequencing to high-throughput sequencing panels or to exome or genome sequencing with DSD gene filters; targeted panels have better coverage and fewer incidental findings, and the yield is below 50% in 46,XY DSD without a clear biochemical defect [20]. When biochemistry points to a specific steroidogenesis defect, single-gene analysis confirms most cases, and in 5α-reductase 2 deficiency molecular genetics is replacing detailed biochemistry [20]. The EAU considers next-generation sequencing and exome sequencing the emerging standard, with the caveat of the difficulty of proving causality of variants [18].

Table 5.2. Aetiological yield in hypospadias cohorts.

Comparison between these series is limited by different inclusion criteria, by the inclusion or not of variants of uncertain significance and by the proportion of severe forms. Two practical rules emerge: the yield increases with severity and with the presence of other genital anomalies, especially undescended testis [16, 51]; and even the mild isolated form may have a monogenic DSD with follow-up consequences, such as surveillance of adrenal function in NR5A1 or the risk of Wilms tumour in WT1 [16, 43]. The authors of the 2025 American study proposed an algorithm for proximal hypospadias that reduces the role of microarray, whose yield was low, and places exome or genome sequencing first-line when there are other congenital anomalies, recommending that genetic and endocrine assessment be considered in all infants with proximal hypospadias [51].

5.6. Limitations of tests and the report

A negative panel or exome does not exclude a genetic cause: most studies analyse mainly exonic variants, and regulatory variants, small structural changes, mosaicism and the polygenic contribution are missed [8, 16]. Copy number analysis from panel data detected an 18q deletion in the French cohort [16]. Somatic mosaicism may explain part of the variability of partial androgen insensitivity, and leucocyte DNA from the parents does not exclude germline mosaicism [3, 8]. The proportion of detectable variants in a gene is not equivalent to the clinical sensitivity of the test for hypospadias, which is low because most cases are multifactorial [9, 16].

The report should state the gene, the reference transcript with version (for example, AR NM_000044.6, MAMLD1 NM_005491.5, NR5A1 NM_004959.5, SRD5A2 NM_000348.4, HSD17B3 NM_000197.2), the variant in HGVS nomenclature, zygosity or hemizygosity and the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [35, 73]. Interpretation of a variant of uncertain significance in NR5A1 or MAMLD1 requires segregation studies, functional data and correlation with the phenotype; a variant of uncertain significance does not confirm the diagnosis, even when it guides surveillance [11, 74]. In the sex-limited inheritance of NR5A1, a carrier mother without signs or a father with a mild phenotype make the family history apparently negative [8].

5.7. Practical algorithm

Table 5.3. Stepwise investigation of hypospadias (synthesis of the EAU 2026 and Society for Endocrinology 2021 guidelines and of GeneReviews).

5.8. Prenatal and preimplantation diagnosis

When the causal variant has been identified in the family, prenatal diagnosis and preimplantation genetic testing are possible; the best time to discuss the risk is before pregnancy [8]. In the multifactorial form there is no prenatal test, and ultrasound detects, with limited sensitivity, only the severe forms [17]. Discussion of the use of these tests in a condition in which most forms can be corrected surgically is part of counselling, and perspectives may differ between professionals and between families [8].

6. Differential Diagnosis

6.1. Comparative table

The differential diagnosis of hypospadias has two levels: the anatomical, which distinguishes hypospadias from other penile anomalies, and the aetiological, which separates the isolated multifactorial form from DSD, syndromes and chromosomal disorders. Table 6.1 brings together the most relevant entities.

Table 6.1. Differential diagnosis of hypospadias.

Sources: [3, 8, 17, 18, 20, 29, 44, 49, 54, 55, 62].

6.2. Partial androgen insensitivity

Hypospadias due to an AR variant cannot be distinguished from other causes by genital examination, and AR variants associated with isolated hypospadias are rare [3]. In partial insensitivity, LH is raised with normal or raised testosterone; an X-linked family history is informative, but one third of cases result from de novo variants [20]. AR sequencing in an infant without a family history may be considered, but the probability of detecting a variant in the partial insensitivity phenotype is low and the predictive value of each variant for the phenotype is weak [3]. Newborns who are small for gestational age may have a similar phenotype without an AR variant [3].

6.3. Testosterone biosynthesis defects

17β-HSD3 deficiency has a phenotype very similar to that of 5α-reductase 2 deficiency: both have Wolffian internal genitalia and external genitalia almost always female or atypical, and both virilise at puberty; they are distinguished by the raised serum androstenedione in 17β-HSD3 deficiency [44]. In a Dutch national study, 12 of the 18 index cases of 17β-HSD3 deficiency had initially been diagnosed with androgen insensitivity, and the testosterone/androstenedione ratio after gonadotrophin stimulation was discriminating in all, without overlap with controls or with androgen insensitivity [44]. The Society for Endocrinology considers the reliability of a low ratio uncertain [20]. The minimum incidence in the Netherlands was 1:147,000, with a heterozygote frequency of 1:135, and at least four recurrent variants appear to be ancient, originating from founders [44]. In a consanguineous Arab community in Gaza, more than 60 affected people were identified [44].

6.4. MAMLD1, NR5A1 and other DSD with scrotal testes

Boys with severe hypospadias and symmetrical scrotal testes may have variants in NR5A1, AR, SRD5A2 or WT1, and their identification changes surveillance (adrenal function, Wilms tumour) [43]. MAMLD1 variants are associated with a normal endocrine assessment and absence of Müllerian structures, and their causal role is debated [11, 19].

6.5. Syndromes

The presence of developmental delay, dysmorphic features, malformations of other organs or growth restriction shifts the diagnosis towards syndromes and chromosomal disorders, which are investigated by microarray, exome or genome sequencing and by specific biochemical tests, such as 7-dehydrocholesterol [17, 51]. Reverse phenotyping after a DSD panel may reveal unrecognised syndromes, such as Opitz G/BBB due to MID1 [16].

7. Treatment and Risk Management Strategies

7.1. Organisation of care and recommendations

Isolated hypospadias is treated by paediatric urology or paediatric surgery; hypospadias with signs of DSD is assessed and followed by a multidisciplinary team with clinical genetics, paediatric endocrinology, paediatric urology, gynaecology, psychology and social work, in an experienced centre [8, 18]. The EAU recommendations for hypospadias are: differentiate isolated hypospadias from DSD at birth (strong); counsel caregivers about the functional and cosmetic value of surgery and the possible complications (strong); use the guideline algorithm to choose the technique (strong); correct curvature greater than 30 degrees (weak); and ensure long-term follow-up to detect urethral stricture, voiding dysfunction, recurrent curvature and ejaculatory changes and to assess satisfaction (strong) [18]. The guideline's summary of evidence grades the suggested age of 6–18 months as level 3, the treatment goals as 2b, the correlation between severity and complications, which are not limited to childhood, as 1a, and the usual preservation of sexual function as 2b [18].

7.2. Indications and goals of surgery

The surgical decision distinguishes functionally necessary procedures from cosmetically feasible ones, weighing voiding, sexual and reproductive function and appearance [18]. The indications are a proximal meatus that deflects the stream ventrally or makes it spray, meatal stenosis, ventral curvature, the preputial hood and penoscrotal transposition [18]. The goals are to correct the curvature, construct a neourethra of adequate calibre, bring the meatus to the glans and obtain acceptable skin cover and appearance; they require magnifying loupes, 6/0–7/0 absorbable synthetic sutures and bipolar cautery [18]. Because all techniques have complications, preoperative counselling of caregivers reduces decisional regret [18]. A child with hypospadias should not be circumcised before repair, because the prepuce may be needed for the reconstruction [17].

7.3. Age at surgery

The EAU indicates 6–18 months as the usual age for primary repair; age is not a risk factor for complications with the tubularised incised plate technique in prepubertal boys, and complications are 2.5 times more frequent in adults [18]. The Oxford Desk Reference (2017) mentioned repair between 12 months and 2 years or, after toilet training, between 3 and 4 years, and staged repair for moderate and severe forms [17]; the 2026 European guideline is the current reference. In a Finnish series of boys born between 1991 and 2003, the median age at first surgery was 1.3 years [75].

7.4. Preoperative hormone therapy

Androgen stimulation before surgery aims to increase penile length, glans size and local vascularity. The EAU considers the evidence inconclusive, limits the usual indication to proximal hypospadias, a small-appearing penis, a reduced glans circumference or a narrow urethral plate, mentions concern about negative effects on healing and bleeding and recommends stopping treatment one to two months before surgery; the guideline does not specify a drug, route or dose [18].

The systematic review and meta-analysis by Do and colleagues (32 studies, 1328 patients under 18 years of age, about a quarter randomised trials) showed that testosterone was the most used androgen (about 80% of arms), that the most frequent regimens were one intramuscular injection monthly for three months or daily application for two to three months, and that testosterone increased penile length by 9.34 mm (95% CI 6.71–11.97; I² 98.4%) and glans width by 3.26 mm (95% CI 2.50–4.02) [76]. With the homogeneous protocol of intramuscular testosterone 2 mg/kg once a month for three months, the increase in length was 10.24 mm; the response was greater in penises that were longer at baseline (an additional 0.52 mm for each baseline millimetre), which disadvantages precisely the patients with a smaller penis [76]. The overall complication rate did not differ (relative risk, RR, 1.08; 95% CI 0.75–1.54), but the risk of fistula was lower (RR 0.62; 95% CI 0.41–0.93) [76]. The 2026 network meta-analysis, restricted to six randomised trials with 715 patients and a search up to March 2026, confirmed a lower probability of urethrocutaneous fistula with androgen (OR 0.474; 95% CI 0.241–0.934), without statistical significance in the analysis restricted to distal hypospadias (OR 0.613; 95% CI 0.285–1.319) and without benefit for glans dehiscence or meatal stenosis; topical oestrogen did not reduce any complication [77].

Table 7.1. Preoperative hormonal stimulation regimens described in trials and series (off-label use; the guideline does not recommend a dose). Population: children with hypospadias before primary repair (under 18 years in the meta-analysis by Do and colleagues); no maximum dose defined in the source.

Short-term adverse effects of androgen therapy include pubic hair, pigmentation of the penile skin (35% in one series), pruritus and erythema (about one third with topical DHT), behavioural changes and aggressiveness, rare priapism and dose-dependent vomiting; the long-term concerns are acceleration of linear growth, increased bone turnover and the effect on puberty, and the available follow-up, of at most one year, has shown no significant effect on bone age [77]. The authors of the 2026 meta-analysis suggest assessing bone age before treatment and monitoring growth after stopping it [77].

No medicinal product has an approved indication for hypospadias. The US label for injectable testosterone enanthate indicates it for replacement therapy in primary or hypogonadotrophic male hypogonadism and in delayed puberty, without an indication or dose for infants, and warns that androgen therapy should be used very cautiously in children, only by specialists aware of its effect on bone maturation, with a radiograph of the hand and wrist every six months [79]. In Portugal, the SmPC of Testoviron Depot® (testosterone enanthate 250 mg/ml, solution for injection) indicates 250 mg intramuscularly every 2–3 weeks for induction and every 3–4 weeks for maintenance in adults, states that the product is not indicated in children and adolescents and warns of masculinisation, accelerated growth, bone maturation and premature epiphyseal closure with reduced final height [80]. Also authorised in Portugal are Sustenon® 250 mg/ml (testosterone esters), Nebido® 1000 mg/4 ml (testosterone undecanoate) and the gels Testogel® 50 mg/5 g and Testavan® 20 mg/g, none with a paediatric indication for hypospadias [80]. The dose of 2 mg/kg/month used in the trials corresponds, in a 10 kg infant, to 20 mg per month, outside the conditions of any label; the decision is shared with the family, with information on the adverse effects described.

Table 7.2. Regulatory status of the drugs used for preoperative stimulation.

7.5. Surgical technique

Correction of curvature follows a sequence: degloving of the penis and excision of the abnormal ventral connective tissue; assessment by artificial erection, preferably with a goniometer or an app, which are more accurate than visual estimation; and, if significant curvature persists, transection of the urethral plate in severe forms and correction of corporal disproportion [18]. Preservation of the plate without transection when it causes the curvature is associated with recurrent curvature in 20% and stricture in 17% [18]. Dorsal plication (including the Nesbit technique) shortens the penis and may reduce sensitivity; ventral lengthening by corporotomies, covered by tunica vaginalis or other tissues, does not have these effects and is associated with less recurrent curvature (5% versus 25%) [18]. Tubularised incised plate urethroplasty in proximal hypospadias had recurrent curvature in 26% [18].

Preservation of a well-vascularised urethral plate is the basis of the reconstruction [18]. A wide plate can be tubularised by the Thiersch-Duplay technique; a narrow plate can be incised in the midline and tubularised (Snodgrass-Orkiszewski technique, the treatment of choice in distal and middle forms), with an inlay graft of inner prepuce or buccal mucosa when the incision is deep; in proximal forms or with an inadequate plate, onlay urethroplasty with a preputial island flap is an option [18]. When the continuity of the plate cannot be maintained, single-stage techniques (Duckett tube and variants, Koyanagi-Hayashi) or two-stage or multistage repairs are used, the latter having become preferred because of less recurrent curvature [18]. Coverage of the neourethra with tunica vaginalis appears to have better results than dartos fascia, which should be used as a double layer; a penile tourniquet reduces operating time [18]. Glanuloplasty and skin reconstruction complete the operation; preputial reconstruction, where circumcision is not routine, does not increase fistulas or reoperations, with preputial dehiscence in 7–17% and secondary phimosis in 1.5%, and in minor variants it may be the only procedure [18].

Perioperatively, urine is drained by a transurethral stent or suprapubic catheter, and in the distal form drainage may be dispensed with; the type of stent and dressing and the duration have shown no influence on outcomes [18]. Prophylactic antibiotics did not reduce surgical site infection, urinary infection or late complications, especially in distal hypospadias [18]. Caudal block and penile nerve blocks give adequate analgesia and are not associated with more complications [18].

7.6. Outcomes and complications

Table 7.3. Outcomes of hypospadias surgery according to the EAU 2026.

Complications depend on severity, surgical history, the surgeon's experience and volume and the technique [18]. Recurrent curvature may require additional surgery with growth, in particular at puberty [18]. Reoperations have no definitive guideline and require individualised management according to the state of the urethral plate and tissues [18]. In the Australian series, surgical revision did not depend on the genetic or endocrine findings [52].

7.7. Management when hypospadias is part of a DSD

When hypospadias is part of a DSD, the sex of rearing should not be decided before expert assessment, and the choice in 46,XY DSD is based on the underlying diagnosis, expert opinion and the parents' beliefs [8]. Surgical decisions require detailed discussion of risks, benefits and limitations; many operations are not medically necessary, so postponing them to allow the person's own participation should be considered; procedures should favour function and avoid tissue removal and irreversible interventions [8]. In males, the options include hypospadias repair, orchidopexy, scrotoplasty and phalloplasty, and removal of Müllerian remnants may be considered; there are no controlled trials comparing techniques and no consensus on timing [8].

The Parliamentary Assembly of the Council of Europe adopted in 2017 a resolution calling for a ban on medically unnecessary “normalising” surgery and treatment without informed consent and for postponement of interventions that alter sex characteristics until the child can participate in the decision, except in cases of immediate risk to life [18]. The European Society for Paediatric Urology (ESPU) responded in an open letter that limiting surgery to emergencies does not correspond to the World Health Organization definition of health and that care should be organised in a patient- and family-centred model [18]. The EAU recommends (strong) a multidisciplinary approach and shared decision-making regarding gender assignment, genital surgery, in accordance with national legislation, and gonadectomy [18]. This divergence of perspectives concerns mainly DSD with atypical genitalia and less so isolated distal hypospadias, whose repair in childhood is the practice of the European guideline [18].

The risk of gonadal neoplasia varies with the entity (Table 7.4). Streak and non-functioning dysgenetic gonads should be removed because of the risk of gonadoblastoma; a dysgenetic gonad with some function may be brought down to the scrotum with surveillance, for which there is no guideline and one option is annual ultrasound [8]. Intra-abdominal gonads should be brought down or fixed to the wall to allow surveillance, self-examination and ultrasound-guided biopsy [18].

Table 7.4. Risk of gonadal neoplasia in DSD that may present with hypospadias (adapted from Looijenga, according to the EAU 2026).

Source: [18]. In the DSD-LIFE study, neoplastic lesions were found in 12% overall and in 36% in 46,XY gonadal dysgenesis; in disorders of testosterone biosynthesis and action, the risk of germ cell neoplasia in situ was 1–15% in childhood, with little tendency to invasive progression [18].

Testosterone has two roles in DSD with male sex of rearing: a short course in infancy for micropenis (stretched length below −2.5 standard deviations) and the induction and maintenance of puberty [8]. In partial insensitivity with atypical genitalia and choice of male sex, a therapeutic trial with pharmacological doses of androgen is recommended to predict the pubertal response, and phallic growth facilitates reconstruction; the efficacy of prolonged androgen therapy is difficult to predict and requires caution [3]. The pubertal gynaecomastia of partial insensitivity may require reduction mammoplasty [3]. 46,XY boys with a heterozygous NR5A1 variant may need management of adrenal insufficiency, and some retain testicular development that allows fertility, sometimes with medically assisted reproduction [8].

7.8. Clinical trials

Table 7.5. Trials and meta-analyses of preoperative hormone therapy.

Comparison between these analyses is indirect, and the included trials have a risk of bias (“some concerns” in all randomised trials and serious or critical risk in more than half of the non-randomised studies), high heterogeneity (I² above 98% for size outcomes) and different regimens [76]. The relative reduction in fistula should be read alongside the absolute rate, which ranges from 3–4% in the distal form with the incised plate technique to 12–19% in the proximal form [18]. The French oestrogen trial was negative, perhaps owing to lack of power, and has no results submitted to ClinicalTrials.gov [78]. The ClinicalTrials.gov search in October 2026 identified no ongoing phase 3 trials of drugs targeting hypospadias.

7.9. Developments in the last 12 months

Between November 2025 and October 2026, relevant results were published without any change in recommendations: the network meta-analysis of randomised trials on preoperative hormone therapy (published result, evidence from trials with risk of bias) [77]; trio sequencing of 106 Chinese children with an excess of de novo variants in ciliary genes (human research study, without clinical validation) [34]; a Chinese study of 34 patients with severe hypospadias and correlation between variants, associated malformations and adrenal precursors [72]; a multidisciplinary preoperative checklist for complex hypospadias in Australia [52]; and, in 2025, the Swedish mortality cohort and the American study of endocrine and genetic assessment of proximal hypospadias [51, 67]. The 2026 edition of the European paediatric urology guideline maintains the age of 6–18 months and the position on hormone therapy [18]. There are no recent regulatory authorisations or opinions for hypospadias therapies.

7.10. Prevention, pregnancy and transition

Valproate monotherapy in the first trimester is associated with hypospadias (adjusted OR 4.8) and other malformations [49]. Occupational and environmental exposure to endocrine disruptors has been associated with hypospadias in association studies, without proof of causality [30, 48]. Transition to adult care should ensure follow-up of late complications (urethral stricture, curvature, ejaculatory changes) and of fertility and, in DSD, review of the diagnosis and access to adult teams [18, 20].

8. Reproductive Options and Family Counselling

8.1. Isolated multifactorial hypospadias

In isolated hypospadias without an identified cause, counselling is based on empirical risks. The Alsace study estimated the recurrence risk for the brothers of an affected boy at 17% (about 1 in 6) [25]. In the Danish cohort, the recurrence risk ratio for first-degree relatives was 11.6, the same for brothers and for sons, and fell to 3.27 for second-degree and 1.33 for third-degree relatives; transmission was similar through the paternal and maternal lines [10]. The risk ratio multiplies the frequency in the population; with a population frequency between about 19 per 10,000 births (EUROCAT) and 8 per 1000 boys (Sweden), a relative risk close to 12 corresponds to an absolute risk of a few percentage points for a brother or son, consistent with the 2–5% predicted by the multifactorial model for most common congenital defects [10, 13, 14, 31]. The risk increases with the number of affected relatives and with severity, according to the multifactorial model, and is low for more distant relatives [31, 81]. In families, hypospadias occurs more frequently than was thought (22.3% in a French series) and mainly on the paternal side, and the familial forms tend to be anterior and middle [23, 70]. There are reports of dominant transmission over several generations (HYSP3, Finnish family linked to 7q32.2-q36.1) and of recessive inheritance in consanguineous families [6, 17].

8.2. Monogenic forms

In partial androgen insensitivity (AR, X-linked recessive), the mother of an affected boy may be a carrier; one third of variants arise de novo [20]. If the mother is a carrier, each 46,XY child has a 50% chance of inheriting the variant and each 46,XX child has a 50% chance of being a carrier; expressivity varies between families and, sometimes, between brothers [3]. The same logic applies to MAMLD1, with the caveat of its debated causal role: in the Fukami family, two maternal half-brothers shared the variant and the mother was heterozygous [11, 26].

In NR5A1 (sex-limited autosomal dominant), the variant may have been inherited from the mother, usually without signs or with primary ovarian insufficiency, or from a father with a mild phenotype, or may have arisen de novo; testing of the parents is recommended [8]. If a parent is a carrier, each sibling has a 50% chance of inheriting the variant; 46,XY carrier siblings will have manifestations and 46,XX sisters generally not, although some develop primary ovarian insufficiency [8]. If the variant is not present in the leucocyte DNA of either parent, the risk to siblings is low, but higher than that of the population, because of the possibility of germline mosaicism [8]. A man with an NR5A1 variant and preserved fertility, sometimes with medically assisted reproduction, transmits the variant to 50% of his offspring [8].

In 5α-reductase 2 and 17β-HSD3 deficiencies (autosomal recessive), the parents are obligate carriers, each sibling has a 25% chance of being affected and only 46,XY individuals manifest DSD; consanguinity increases the probability [8, 44].

8.3. Prenatal and preimplantation diagnosis

Once the family variant is known, prenatal and preimplantation diagnosis are possible [8]. In isolated multifactorial hypospadias there is no prenatal test, and ultrasound detects only severe forms with curvature or atypical genitalia [17]. When there is no molecular diagnosis, GeneReviews suggests considering DNA banking of the proband, because technology and knowledge of the genes will evolve [8].

8.4. Counselling of children, adolescents and adults

Information should be given to the parents from the first contact and revisited over time, with respect, confidentiality and active participation of the family in decisions [8]. Counselling of adolescents and young adults with hypospadias should address sexual function, fertility, which is reduced on average and especially in proximal forms and with cryptorchidism, and the recurrence risk in offspring [10, 18, 64]. The sex of rearing may not coincide with gender identity, which the person defines over time; about 3% of people with DSD change gender after puberty, and gender dysphoria is more frequent in people raised as female with 5α-reductase 2 or 17β-HSD3 deficiency [8, 18].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence in Europe

The EUROCAT registry study, with 23 European registries between 2001 and 2010, counted 10,929 cases in 5,871,855 births, a total prevalence of 18.61 per 10,000 births (the EAU gives a range of 5.1 to 36.8 between registries), with no significant time trend, except an increase in the anterior and posterior forms and a decrease in unspecified forms, and no association with maternal age [13, 18]. The variation between registries mainly reflects differences in ascertainment [13]. In Sweden, the incidence among the 1,948,591 boys born between 1973 and 2009 was about 4.5 per 1000 male live births until 1990 and rose to about 8 per 1000 in the following decade, in mild and severe forms, without explanation by known risk factors and without exclusion of changes in registry classification [14]. In Alsace, between 1979 and 1987, the birth prevalence was 2.89 per 1000 boys [25]; the figure of 6.4 per 1000 male live births that the Oxford Desk Reference attributes to this study does not match the original publication [17, 25]. Orphanet estimates the birth prevalence of non-syndromic posterior hypospadias in Europe at 19.25 per 100,000 [1]. None of these values corresponds to the fraction attributable to MAMLD1 or to any other gene [37].

9.2. Worldwide variation

Springer's review, with about 90 million births studied between 1910 and 2013, found mean prevalences of 19.9 per 10,000 in Europe (1–464), 34.2 in North America (6–129.8), 5.2 in South America (2.8–110), 0.6–69 in Asia, 5.9 in Africa (1.9–110) and 17.1–34.8 in Australia, with extreme heterogeneity, no standardised definition and contradictory trends [82]. These values measure different things (malformation registries, surgical series, questionnaires) and are not comparable with one another. In Sweden, boys with parents born in Asia (OR 1.45) or continental Europe (OR 1.41) were at higher risk [14]; in a Swedish surgical series, 22% of patients were of non-Swedish origin, one third of these from the Middle East [24]. In the sources consulted there are no prevalence estimates for Portugal or Brazil; the Portuguese registry is part of EUROCAT, but the values per registry are not given in the abstract consulted [13].

9.3. Founder populations and monogenic entities

17β-HSD3 deficiency has ancient variants of founder origin scattered across Europe, a minimum incidence of 1:147,000 in the Netherlands and a high concentration in a consanguineous Arab community in Gaza [44]. Androgen insensitivity had, in the Netherlands, a minimum incidence of 1:99,000 [3]. The original MAMLD1 variants were described in Japanese patients, and later MAMLD1 series come mainly from East Asia [5, 19]. Most of the recently published trio and exome sequencing studies come from China, which limits extrapolation to European and American populations [33, 34, 72].

9.4. Groups at increased risk

The risk is higher in boys with low birth weight or small for gestational age (OR 4.34 in Sweden), twins (OR 1.8), those born after in vitro fertilisation (OR 1.15) [14], sons of mothers with pre-eclampsia (posterior form) [50], diabetes [18] or obesity [23], those exposed to valproate [49] and sons of women exposed to DES [46].

9.5. European networks and patient associations

The European reference network eUROGEN (rare and complex urogenital diseases) has an area of expertise dedicated to posterior hypospadias (area 1.6) and another to complex genital reconstruction in DSD (area 1.1) [21]. Endo-ERN (rare endocrine conditions) includes main thematic group 7, sex development and maturation [22]. The dsd-LIFE consortium and Endo-ERN itself promote patient participation in research and registries [18]. The association Hypospadias UK (https://www.hypospadiasuk.co.uk/) supports families with hypospadias, and AISSG supports people with androgen insensitivity [17]. International projects such as DSDnet and the I-DSD registry involve individuals and patient groups [20].

10. Illustrative Clinical Case

Romano and colleagues, at an Italian children's hospital, described a 4-month-old infant referred for a severe genital malformation [74]. Examination showed micropenis, complete bifid scrotum, perineal hypospadias and complete penoscrotal transposition, with a GMS score (glans, meatus, shaft) of G2M4S4; both gonads were palpable at the emergence of the labioscrotal folds and the stretched penile length was 2.6 cm (Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC11825467/figure/F1/) [74]. The karyotype was 46,XY, hormones were within normal values and ultrasound showed both testes in the scrotum, symmetrical and of equal size [74]. A 19-gene DSD panel by next-generation sequencing identified a heterozygous missense variant in NR5A1, classified as of uncertain significance; the article does not give the HGVS nomenclature [74].

After multidisciplinary counselling, repair was performed in three stages [74]. At 11 months, degloving down to the penoscrotal junction and artificial erection revealed curvature greater than 60 degrees, corrected by multiple transverse corporotomies of the ventral tunica albuginea, with lengthening of the shaft by 1.2 cm, coverage with a dartos flap and preputioplasty (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC11825467/figure/F2/) [74]. Six months later, a 3 × 1.5 cm dorsal inner preputial flap was transposed to the ventral surface, between the meatus and the tip of the glans; six months later still, the neourethra was tubularised by the Duplay technique in three layers, with glanuloplasty and urinary diversion by urethral catheter and suprapubic cystostomy for 14 days [74]. At 18 months of follow-up, recovery had been uneventful and the genital appearance was satisfactory (Figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC11825467/figure/F3/) [74].

The case illustrates three points of this article. First, the combination of perineal hypospadias, micropenis and bifid scrotum meets the EAU and Society for Endocrinology criteria for DSD assessment, even with scrotal testes and normal hormones [18, 20]. Second, the NR5A1 variant is of uncertain significance and does not establish the cause; its value lies in justifying segregation studies in the parents, surveillance of adrenal and gonadal function and counselling on fertility, as the authors emphasise [8, 74]. Third, the multistage surgical approach, with ventral lengthening by corporotomies for severe curvature, corresponds to the options that the EAU considers preferable in severe proximal hypospadias, but the outcome at 18 months gives no information on late complications, which require follow-up until after puberty [18, 75].

11. Prognosis and Long-term Follow-up

11.1. Prognosis

The functional prognosis of operated distal hypospadias is good: 85–90% success with the first operation, complications below 10% with the tubularised incised plate technique and sexual function usually preserved [18]. In proximal hypospadias, complications range from 14% to 68%, and cumulative reoperation in a Finnish series was 51.8% at 15 years, higher in severe forms; half of the problems arose in the first three months and the other half over the years [18, 75]. Complications are not limited to childhood (level of evidence 1a) [18].

In terms of general health, Swedish registries show, in men born with hypospadias, more hypogonadism, delayed puberty, type 2 diabetes and cardiovascular disease, fewer biological children, double the risk of testicular cancer and slightly higher relative mortality, with low absolute mortality; the effects are more marked in proximal forms [63, 64, 66, 67]. These data describe associations in registry cohorts that include patients with undiagnosed DSD and syndromes, and do not by themselves justify specific screening programmes outside the guidelines [63]. In DSD, the prognosis depends on the entity, including gonadal function, tumour risk and gender identity [8, 18].

11.2. Surveillance

Table 11.1. Surveillance after the diagnosis and repair of hypospadias.

12. Summary and Concluding Remarks

Hypospadias has a prevalence of about 19 per 10,000 births in European malformation registries and of 4.5 to 8 per 1000 boys in the Swedish national registry, and the isolated form, mainly distal, results from the sum of many variants of small effect, placental factors and environmental exposures [9, 13, 14, 30]. Familial aggregation is strong, with a relative risk of about 12 for brothers and sons and an empirical risk of 17% for brothers in the classic French series [10, 25].

A minority has a monogenic cause: variants in AR (partial androgen insensitivity), in NR5A1, in the testosterone metabolism genes (SRD5A2, HSD17B3, HSD3B2) and, with a debated causal role, in MAMLD1, as well as syndromes and chromosomal disorders [11, 15, 16]. The yield of panels in isolated hypospadias is about 5%, and increases in proximal forms and when there is undescended testis, micropenis or other anomalies [16, 51]. European and British guidelines guide investigation: no systematic investigation in isolated distal or middle hypospadias; assessment for DSD in perineal or familial hypospadias, or with micropenis, bifid scrotum or undescended testes [18, 20].

Treatment is surgical, preferably between 6 and 18 months, with a technique adapted to severity and staged repair in severe proximal forms [18]. Preoperative hormone therapy increases the size of the penis and glans and reduces fistulas in trials with risk of bias, is used off-label and should be stopped one to two months before surgery [18, 76, 77]. Complications and reoperations are frequent in proximal forms and occur into adulthood, which requires prolonged follow-up and organised transition [18, 75]. Swedish cohorts associate hypospadias with hypogonadism, reduced fertility, testicular cancer and cardiometabolic disease in adulthood, mainly in proximal forms [63, 64, 66]. When hypospadias is part of a DSD, the molecular diagnosis guides adrenal and gonadal surveillance, tumour risk and counselling, and decisions about genital surgery are made by the team together with the family [8, 18].

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