Hypospadias: Pathogenesis, diagnosis, and evaluation

INTRODUCTION — Hypospadias is a congenital anomaly of the male urethra, foreskin, and penis that results in abnormal ventral placement of the urethral opening. The location of the displaced urethral meatus may range anywhere within the glans, the shaft of penis, the scrotum, or perineum (picture 1).

The pathogenesis, diagnosis, and evaluation of hypospadias will be reviewed here. The management and outcome of hypospadias are discussed separately. (See "Hypospadias: Management and outcome".)

EMBRYOLOGY

Normal development — The external genitalia in the two sexes develop from common genital tubercle, swellings, and folds and are indistinguishable until seven to eight weeks gestation (figure 1). At the seventh and eighth week of gestation, the external genitalia consist of the bipotential genital tubercle and genital swellings. At 8 and 9 weeks gestation, sexual differentiation begins resulting in either male or female external genitalia [1,2]. In the male fetus, penile development includes androgen-independent morphological events, similar to those observed in the development of female external genitalia, and androgen-dependent events, which differentiate the developing penis from the clitoris [3].

●Androgen-independent events, which occur in both male and female fetuses, include:

•Development of the genital tubercle

•Formation of the genital folds

•In males, swelling and canalization of urethral plate to form the urethral groove [3]

•In females, swelling and canalization of the vestibular plate to form the vestibular groove [4]

•Formation of the corporal bodies and glans [2,5].

●In the male fetus, androgen-dependent events result in proximal to distal fusion of the urethral groove forming the tubular urethra (picture 2 and figure 2) [5]. The glandular urethra is formed by a complex process of direct canalization and mesenchymal confluence ventral to the urethra. The final step in penile development is circumferential development of the foreskin that ultimately covers the entire glans by 17 weeks gestation [6]. This is in contrast to the foreskin in the clitoris that does not fuse and remains only on the dorsal aspect of the human glans clitoris [5,7]. The penis continues to elongate under the influence of androgens [2].

The lack of appropriate androgenic stimulation results in the female external genital phenotype, classified as disorders of sexual development. (See 'Cryptorchidism' below.)

Hypospadias — In patients with hypospadias, the urethral folds fail to completely or partially close, and the foreskin does not fuse onto the ventral aspect of the penis resulting in the dorsal hooded foreskin commonly seen in patients with hypospadias (picture 3). The extent of this fusion failure determines the position of the urethral opening. In most cases, it remains unknown what causes the arrest of normal penile development.

Penile curvature occurs normally during development and resolves by the end of urethral formation (picture 2). Penile curvature is often associated with an ectopic urethral meatus (hypospadias) but can also occur in the setting of normal glandular and penile shaft urethra, so called chordee without hypospadias.

ANATOMY — Surgical correction of hypospadias requires understanding of the anatomy of both the normal and hypospadiac penis particularly penile innervation [8].

Normal — The penis in the uncircumcised male consists of the penile shaft and the distally located glans with the coronal sulcus (rim of the glans) covered by the foreskin (figure 3). The structural components include the corpus spongiosum, which contains the urethra, and the paired corpora cavernosa (erectile bodies). The corpus spongiosum lies ventral to the corporal bodies. The corpora cavernosa structures are covered by the thick, elastic tunica albuginea. The dorsal penile nerve lies on top of Buck's fascia, which circumferentially envelops the corpus spongiosum and cavernosa.

Sensation of the penile shaft, glans, and anterior urethra is primarily derived from the dorsal penile nerves. The neurovascular bundles lie in the 11 and 1 o'clock positions with branches extending longitudinally from 11 to 7 o'clock and 1 to 5 o'clock along the surface of the tunica albuginea, enclosing the corpora cavernosa, and terminating in the glans. No nerve fibers are found at the 12 o'clock position in either the normal or hypospadiac penis [9].

Hypospadias — Hypospadias is defined as a combination of any or all of the following associated penile anomalies [10]:

●Ectopic urethral meatus

●Penile curvature (chordee)

●Ventral foreskin deficiency with incomplete foreskin closure around the glans, leading to the appearance of a dorsal hooded prepuce

Classification — Hypospadias is classified into the following categories based on the appearance of the foreskin, urethral location, and the presence and degree of penile curvature (table 1 and picture 1):

●Forme fruste of hypospadias (incomplete or partial presence of hypospadias (picture 4).

●Standard hypospadias – Ectopic urethral meatus that is accompanied by a classic dorsal hooded foreskin without fusion of the foreskin to the scrotum with a normal penile length, normal glans size (≥14 mm at maximal diameter), and variable penile curvature (picture 3 and picture 1).

●Severe hypospadias – Ectopic urethral meatus located in the scrotum or perineum and/or an abnormally small glans size (<14 mm at maximal diameter) and severe curvature (picture 5).

●Less common variants, including chordee without hypospadias and megameatus with a normal appearing foreskin (picture 6 and picture 7).

Forme fruste (incomplete or partial presence) of hypospadias — Forme fruste of hypospadias (incomplete or partial presence of hypospadias) seen in approximately 10 percent of case is characterized by clinically insignificant meatal abnormalities, occasionally asymmetric foreskin, and no penile curvature. The urethral defect is typically manifested as a blind ending urethral pit (picture 4) or a slightly ectopic urethral meatus (picture 3), which is usually located 1 to 2 mm from the normal terminal position of the urethral meatus on the ventral tip of the glans penis. These patients do not have any impairment of voiding or sexual function, and surgical reconstruction is rarely required.

In most patients, the foreskin is only slightly deficient on the ventral aspect. However, circumcision may be difficult to perform with the foreskin asymmetry due to the inability to properly place either a Plastibell or Gomco device over the glans and have sufficient foreskin to complete the circumcision. In these patients, circumcision, should it be desired by the family/caregiver, is delayed until a freehand circumcision can be safely performed in the operating room.

A less common variation is a normally positioned urethral meatus with incomplete fusion or separation of the glans with a bridge of ventral skin. These patients may also have a dorsal hooded foreskin. However, there are no voiding issues with this variant, and reconstruction of the glans is of questionable benefit (picture 8).

Standard hypospadias — Standard hypospadias is the most common form of hypospadias and occurs in approximately 65 percent of cases. It is characterized by an ectopic urethral meatus that is accompanied by a classic dorsal hooded foreskin without fusion of the foreskin to the scrotum, and a penis and glans of normal length and size, and curvature that varies from none to mild or moderate (picture 1 and picture 3).

Standard hypospadias is further subdivided by the location of the ectopic urethral meatus [11]. The severity of hypospadias increases as the position of the displaced urinary meatus increases from the normal position at the tip of the glans and with increasing penile curvature.

●Distal – The most common location for an ectopic urethral meatus is at the proximal glans, coronal margin, or just below the coronal margin, which has been described in the literature as distal hypospadias or mild hypospadias [11]. Patients with distal standard hypospadias typically have a normal-size penis and glans, and dorsal hooded foreskin due to deficient ventral foreskin with or without mild penile curvature. Distal to the ectopic meatus, a pit or web of tissue is frequently present between the ectopic urethral meatus and the often distal urethral pit. Patients with this type of hypospadias may have a deflection in their urinary stream downward secondary to this web of tissue. In addition, a common observation is that the asymmetric foreskin gives the appearance that the infant is neither circumcised nor uncircumcised.

●Proximal – The more severe variant of standard hypospadias occurs when the urethral meatus is proximally located along the penile shaft, at the penoscrotal junction or within the scrotum. These patients often have moderate amounts of penile curvature. They have a normal size penis and glans, and a classic dorsal hooded foreskin without fusion of the foreskin to the scrotum, which distinguishes them from patients with the more severe hypospadias variant.

Severe hypospadias — Severe hypospadias (approximately 20 percent of cases) is characterized by an ectopic urethral meatus located in the scrotum or perineum, and/or an abnormally small glans (<14 mm at maximal diameter), and severe penile curvature, often associated with a ventral penile foreskin tethering (referred to as short urethral plate) or fusion of the foreskin to the scrotum (picture 9). There is often associated penoscrotal transposition (where the scrotum inserts above the penis and the penis is abnormally located well below the scrotum) (picture 5). (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

Other uncommon variants — Other uncommon variants of hypospadias occur in approximately 5 percent of cases and include:

●Hypospadias with intact foreskin (megameatus intact prepuce) – In this uncommon variant (approximately 5 percent of cases), the foreskin is normal, and the urethral abnormality only becomes apparent during or after circumcision when the glans of the penis is visualized. Patients with this form of hypospadias typically have an abnormally large urethral meatal opening at the coronal margin, referred to as megameatus intact prepuce (picture 7). The clinician and family/caregiver should be aware that the hypospadias is not caused by the circumcision and can be repaired whether the circumcision is completed or aborted. As a result, we would recommend the circumcision be completed.

●Chordee with normal urethral meatus – Patients with this variation of hypospadias have a normal glans and normal terminal urethral meatus but with atretic urethral spongiosum manifested by a thin urethra on the penile shaft resulting in penile curvature (picture 6).

PATHOGENESIS — In most cases of hypospadias, the cause is unknown. Genetic defects and environmental exposures may play a role.

Risk factors — Reported risk factors include the following [11-16]:

●Advanced maternal age

●Preexisting maternal diabetes mellitus

●Gestational age before 37 weeks

●History of paternal hypospadias

●Prenatal exposure to smoking and pesticides

●Placental insufficiency (low placental weight and pathology)

●Prematurity

●Fetal growth restriction

●In-vitro fertilization

Proposed mechanism — The proposed mechanism for the pathogenesis of hypospadias is disruption of the androgenic stimulation required for the development of the normal male external genitalia. Both genetic and environmental factors that negatively affect androgenic stimulation have been associated with hypospadias, suggesting that in some cases, the etiology is multifactorial [12,13,17,18].

●Genetic defects — Support of a genetic component includes:

•Pathologic gene variants that affect androgen metabolism and estrogen and androgen response (eg, androgen receptor and disruption of estrogen receptors) have been associated with hypospadias [19-29].

Genome-wide association studies using single nucleotide peptide (SNP) microarrays have shown an association between variants in development genes and hypospadias [30-32]. These include the HOXA4 (MIM *142953), IRX5 (MIM *606195), IRX6 (MIM *606196), EYA1 (MIM *601653), and DGKK (MIM *300837) genes. DGKK is expressed in preputial skin and encodes a human type II diacylglycerol kinase, which plays an important role in signal transduction. Changes in the genes activating transcription factor 3 (ATF3), CXORF6, (MIM *300120) and the zinc finger-box gene 1 (ZEB1) (MIM *189909) have also been associated with an increased risk of hypospadias [22,23,27].

•Well known genetic syndromes are associated with hypospadias. These include:

-Denys-Drash syndrome – Renal insufficiency, male pseudohermaphroditism, and Wilms tumor (see "Presentation, diagnosis, and staging of Wilms tumor", section on 'Denys-Drash syndrome')

-WAGR syndrome – Wilms tumor, aniridia, genitourinary malformations, and mental retardation (see "Presentation, diagnosis, and staging of Wilms tumor", section on 'WAGR syndrome')

-Opitz syndrome –Ocular hypertelorism, asymmetry of the skull, and laryngoesophageal defects (see "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'Opitz G/BBB syndrome')

•Positive family history of hypospadias has been reported in approximately 20 percent of cases [11,33].

•The incidence of hypospadias is increased in consanguineous families [34].

●Environmental exposures — In observational studies, hypospadias has been associated with prenatal exposure to endocrine disruptors such as maternal progestin, diethylstilbestrol, and polybrominated diphenyl ethers (contained in paints, solvents, adhesives, pesticides, cosmetics, and industrial chemicals) which may affect androgenic stimulation [12,13,35-37]. In contrast, a study using data from the National Birth Defects Prevention study found that maternal high dietary intake of phytoestrogens (plant constituents with estrogenic properties) was associated with a decreased risk of hypospadias [38].

INCIDENCE — Hypospadias is one of the most common congenital anomalies, with an incidence that varies from 0.3 to 0.7 percent in live male births [7,39-46].

The incidence varies with ethnicity, as illustrated by a population-based study from the state of Washington that showed hypospadias was more prevalent in male infants born to White mothers compared with male infants of Black mothers (odds ratio [OR] 0.67, 95% CI 0.51-0.89) and Hispanic mothers (OR 0.46, 95% CI 0.37-0.58) [12].

In population surveys, the incidence of hypospadias appears to have increased since the 1970s [40-42,44,47]. Improved surveillance and detection may account for some of the increased incidence. Increased exposure to environmental contaminants or drugs that disrupt androgenic stimulation during embryologic development also may contribute to the increased reported incidence.

DIAGNOSIS — The diagnosis of hypospadias is generally made during the newborn genital examination (picture 1). (See 'Physical examination' below.)

Physical findings consistent with the diagnosis include:

●Abnormal foreskin resulting in an incomplete closure around the glans leading to the appearance of a dorsal hooded prepuce.

●Abnormal penile curvature (chordee).

●The appearance of "two urethral openings;" the first in the normal position at the end of the glans, which is usually a blind ending urethral pit, and the second, the abnormally located true urethral meatus (picture 1 and picture 4 and picture 3). The location of the displaced urethra is anterior/distal (glans and corona) in 40 to 50 percent, middle (penile shaft) in 25 to 30 percent, and posterior/proximal (scrotum and perineum) in 20 percent of cases [46,48].

INITIAL EVALUATION — Once a concern for hypospadias has been identified, the initial evaluation includes a focused history, close examination of the genitalia, and identification of other congenital anomalies.

History — History should determine whether there is a family history of hypospadias, or any maternal or infant risk factors. (See 'Risk factors' above.)

Physical examination — The physical examination focuses on identifying other associated anomalies and the genital examination that determines the presence and degree of hypospadias.

●Other congenital anomalies ‒ The presence of other congenital anomalies may indicate an underlying syndrome, for which further evaluation may be warranted. (See 'Presence of other organ anomalies' below.)

Examples, albeit rare, include:

•Aniridia associated with Wilms tumor. (See "Presentation, diagnosis, and staging of Wilms tumor", section on 'WAGR syndrome'.)

•Hand-foot-mouth anomalies typical of Hox 11 mutations.

•Ocular telorism, asymmetry of the skull and laryngoesophageal defects are associated with Opitz G/BBB syndrome. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'Opitz G/BBB syndrome'.)

•Cryptophthalmos and cutaneous syndactyly are features of Fraser syndrome that is also associated with genitourinary anomalies. (See "Renal hypodysplasia", section on 'Genetic disorders'.)

Other findings that have been associated with hypospadias include ear tags/deformities, digit abnormalities, cardiac anomalies, club feet, spinal abnormalities, and imperforate anus. Males with severe hypospadias are more likely to have to have other non-genital anomalies [49]. These patients are at increased risk for an underlying genetic condition and endocrine dysfunction including disorders of sex development [50-52]. (See 'Severe hypospadias' above and 'Cryptorchidism' below.)

●Genital examination — A comprehensive genital examination is imperative to distinguish clinically significant hypospadias that requires urologic referral for possible correction from benign forms, which have no impact on voiding and sexual function and for which no further intervention is needed (table 1). (See "Hypospadias: Management and outcome", section on 'Urologic referral' and 'Classification' above.)

The key aspect of the genital examination is direct visualization of the penis and glans, hence adequate lighting is obligatory. The examination includes:

•Assessment of the stretched penile length, which should be 2.5 to 3.5 cm in a full term male (figure 4). To measure the penile length, the glans penis is held with the thumb and forefinger and the penis is fully stretched until point of increased resistance is reached. The measurement is taken using a ruler or caliper from the pubic ramus (making sure the suprapubic fat pad is depressed) to the distal tip of the glans penis over the dorsal side.

•Assessment regarding any evidence of penile curvature, and if so, the degree of curvature. The severity of curvature is classified by the assessment of the curvature when the penis is fully erected as follows:

-Normal – No curvature to 15 degrees

-Mild – 15 to 30 degrees

-Moderate – < 30 to 75 degrees

-Severe – >75 degrees

•Assessment of the foreskin to ensure complete and circumferential development of the foreskin without any ventral asymmetry or deficiency.

-If the foreskin is normally circumferential, it is unlikely that a significant hypospadias requiring surgery is present. As a result, it is not necessary to retract the foreskin, which in the neonate is typically adherent to the glans. In addition, the terminal meatus may be seen through the tiny opening in the normal newborn foreskin.

-If the foreskin is not properly formed, the presence of an ectopic urethral meatus along the ventral shaft of the penis should be sought after and identified.

•Determination of the presence of both testicles in the normal dependent position in the scrotum.

In cases where the genital examination is abnormal, further evaluation is performed to detect the presence and location of the testes, and for those with severe hypospadias (ectopic urethra at the scrotum or perineum), the presence of penoscrotal transposition and the severity of the foreskin defect. (See 'Severe hypospadias' above and 'Cryptorchidism' below.)

Renal imaging — Because the external genitalia (after eight weeks gestation) forms well after the critical stages of renal development (seven weeks) and arises from different embryologic structures [53], associated upper genitourinary tract anomalies are not more frequent in patients with isolated hypospadias than the general population [54-57]. As a result, imaging studies to detect upper tract abnormalities are not routinely recommended with the exception of patients with febrile or symptomatic urinary tract infection.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for hypospadias is very limited. However, circumcision injuries, which are infrequent, may be initially confused with hypospadias, but close examination differentiates them from hypospadias. These include meatal stenosis with ventral urethral meatal scarring, and foreskin abnormalities due to impaired circumcision (inadequate separation of the inner prepuce from the glans and inadequate skin removal). (See "Complications of circumcision", section on 'Surgical complications'.)

Urethral duplication is an extremely rare anomaly that can mimic hypospadias (picture 10). In this condition, both meatuses are open and neither are a pit with a blind ending. The ectopic meatus is typically the functional urethra and the other is an accessory second urethra. Pediatric urologic expertise usually distinguish this unusual finding from hypospadias.

ADDITIONAL EVALUATION FOR SELECT PATIENTS

Cryptorchidism — The risk of disorders of sex development (DSD) is increased in males with cryptorchidism (one or both testicles undescended) and hypospadias. This combination of findings is most likely due to abnormal cellular and hormonal signaling that interrupts normal genital development. Cryptorchidism is present in approximately 10 percent of patients with hypospadias, and increases in patients with severe hypospadias (eg, scrotal or perineal urethral meatus) [58,59].

In one case series of 114 boys with severe hypospadias, 22 boys had 26 nonscrotal testes, of which two were due to primary cryptorchidism, 16 due to acquired cryptorchidism, and eight due to retractile testes [58]. (See "Undescended testes (cryptorchidism) in children: Clinical features and evaluation", section on 'Evaluation'.)

Evaluation — The following evaluation, which is discussed in detail separately, is performed in patients with hypospadias in whom a DSD is suspected (see "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Initial laboratory testing' and "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Imaging'):

●Pelvic ultrasound to evaluate internal genitalia, such as the presence or absence of the uterus.

●Karyotype to determine the presence of a normal chromosome component, the presence of the Y chromosome, and to place the infant into one of three diagnostic categories that guide further evaluation for DSD. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)", section on 'Sex chromosome analysis'.)

•XX virilization

•XY undervirilization

•Mixed sex chromosome pattern, such as mixed gonadal dysgenesis XY/XO (picture 9)

●In the presence of bilateral nonpalpable testes, serum electrolytes as a screen for salt-wasting forms of congenital adrenal hyperplasia (CAH), one of the causes of DSD, is indicated. Some forms of CAH may be associated with adrenal crisis and are characterized by hyponatremia and hyperkalemia. (See "Causes of primary adrenal insufficiency in children", section on 'Congenital adrenal hyperplasia'.)

Severe hypospadias — For patients with severe hypospadias with or without cryptorchidism, we evaluate for both DSD and pathogenic genetic variants, as these patients are at increased risk for both DSD and other genetic disorders [11,49,60]. We evaluate for DSD as previously discussed (see 'Evaluation' above) and for genetic variants with karyotype, chromosomal microarray, and/or whole exome sequencing. In one case series, nine of 60 males with severe hypospadias (15 percent) were diagnosed with a DSD [49]. In another case series of 14 males with 46, XY karyotype, severe hypospadias, and bilaterally descended testes, eight (57 percent) had a pathogenic genetic variant that changed management [60].

Presence of other organ anomalies — As noted above, patients with hypospadias who have other organ system anomalies (eg, congenital cardiac disease, imperforate anus, limb malformations, or cleft lip) require kidney and bladder imaging with ultrasonography because they are at risk for upper tract abnormalities.

In cases where there are multiple congenital anomalies, further evaluation is warranted to detect an underlying syndrome or genetic defect and is discussed separately. (See "Congenital anomalies: Approach to evaluation".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Hypospadias (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition and anatomy ‒ Hypospadias is a congenital anomaly of the male urethra that results in abnormal ventral placement of the urethral opening and is associated with abnormal foreskin development and penile curvature. (See 'Anatomy' above.)

●Classification ‒ Hypospadias is classified into the following categories based on the appearance of the foreskin, urethral location, and the presence and degree of penile curvature (table 1 and picture 1). (See 'Classification' above.)

•Forme fruste of hypospadias (10 percent of cases) – Incomplete or partial presence of hypospadias (picture 4). (See 'Forme fruste (incomplete or partial presence) of hypospadias' above.)

•Standard hypospadias (65 percent of cases) – Ectopic urethral meatus that is accompanied by a classic dorsal hooded foreskin without fusion of the foreskin to the scrotum with a normal penile length, normal glans size (≥14 mm at maximal diameter), and variable penile curvature (picture 3 and picture 1). (See 'Standard hypospadias' above.)

•Severe hypospadias (20 percent of cases) – Ectopic urethral meatus located in the scrotum or perineum and/or an abnormally small glans size (<14 mm at maximal diameter) and severe curvature (picture 5). (See 'Severe hypospadias' above.)

•Less common variants (5 percent of cases), including chordee without hypospadias and megameatus with a normal appearing foreskin (picture 6 and picture 7). (See 'Other uncommon variants' above.)

●Incidence ‒ Hypospadias is one of the most common congenital anomalies with an incidence that varies from 0.3 to 0.7 percent in live male births. (See 'Incidence' above.)

●Pathogenesis ‒ In most cases, the pathogenesis remains unknown but is thought to be caused by disruption of the androgenic stimulation required for the development of the normal male external genitalia with both associated genetic and environmental factors (figure 1 and picture 2). (See 'Embryology' above and 'Pathogenesis' above.)

●Diagnosis ‒ The diagnosis of hypospadias is generally made during the newborn examination. The following physical findings are consistent with the diagnosis (see 'Diagnosis' above):

•Abnormal foreskin resulting in an incomplete closure around the glans leading to the appearance of a dorsal hooded prepuce

•Abnormal penile curvature (chordee)

•Ectopic urethral meatus or blind ending urethral pit

●Initial evaluation ‒ The initial evaluation focuses on identifying other associated anomalies. A comprehensive genital examination is imperative to distinguish clinically significant hypospadias that requires urologic referral for possible correction from benign forms, which have no impact on voiding and sexual function and for which no further intervention is needed. (See 'Initial evaluation' above and 'Classification' above.)

The genital examination encompasses:

•Measurement of the stretched penile length

•Assessment of penile curvature

•Assessment of the foreskin

•Determination of the presence of both testicles in the normal scrotal position

●Differential diagnosis ‒ The differential diagnosis for hypospadias is very limited. However, circumcision injuries, which are infrequent, may be initially confused with hypospadias, but close examination differentiates them from hypospadias. (See 'Differential diagnosis' above.)

●Further evaluation ‒ Additional evaluation is required for the following select patients:

•Cryptorchidism and hypospadias – These patients are at-risk for disorders of sex development (DSD). The evaluation includes pelvic ultrasound, karyotype, and serum electrolytes. (See 'Cryptorchidism' above.)

•Severe (scrotal or perineal) hypospadias – These patients are at risk for pathogenic genetic variants of hypospadias as well as DSD. They require chromosomal microarray and/or whole exome sequencing for other genetic variants in addition to pelvic ultrasound, karyotype, and serum electrolytes. (See 'Severe hypospadias' above.)

•Patients with other anomalies – These patients are at-risk for upper track anomalies and a renal and bladder ultrasonography is used for evaluation. In cases where there are multiple major congenital anomalies, further evaluation to detect an underlying syndrome or genetic defect is performed. (See 'Presence of other organ anomalies' above.)