A number of factors have contributed to a sharp increase in the number of publications related to disorders of sex development (DSD) in the past 5 years, namely: the establishment of a consensus in 2006 about nomenclature, investigations and the need to treat these patients in a multidisciplinary setting; increase of the knowledge base about genetic mechanisms of normal and abnormal sex development; critical appraisal about the timing and nature of genital surgery in patients with DSD. Herein, the authors present a comprehensive review with up-to-date data about the approach to the newborn with ambiguous genitalia as well as the diagnosis and management of the most common DSD.
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Patients with disorders of sexual development (DSDs) should be assessed and treated in a multidisciplinary clinic.
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Most patients with DSDs present early in life with genital ambiguity.
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A comprehensive assessment of infants with genital ambiguity allows proper gender assignment within a few days.
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DSD encompasses a wide range of diagnoses and clinical scenarios.
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The timing and nature of genital surgery remain controversial topics.
Introduction
The management of children with ambiguous genitalia remains controversial. Conditions associated with genital ambiguity lack a consistent terminology, and there is a variable approach to diagnosis and management. In 2006, a consensus statement was published in an attempt to standardize the nomenclature and approach, defining these conditions as disorders of sex development (DSDs). After a multidisciplinary meeting held in Chicago that included endocrinologists, surgeons, geneticists, psychologists, and representatives from advocacy groups, it was agreed on that traditional terms, such as intersex, true, and pseudohermaphroditism, and any expression that could give rise to an idea of a third gender should be abandoned. DSDs were categorized under 3 main subgroups according to karyotype (XX, XY, and sex chromosome for mosaic karyotypes). The consensus also acknowledged the integral role of psychosocial support and the management of these patients guided by a multidisciplinary team.
This consensus statement has been well accepted by the medical and patient community worldwide. Despite having diverse diagnoses under its umbrella, the DSD classification has allowed the subject to be addressed in a more scientific way with direct participation of patient support groups.
The embryologic development of the external genitalia (EG) is well understood. The fetal EG remains undifferentiated until 6 to 7 weeks’ gestation. The sex-determining region in the Y chromosome (SRY) is the main factor driving the development of the bipotential gonad into a testicle. The Sertoli cells secrete anti-Müllerian hormone (AMH), which in turn will inhibit the development of Müllerian structures (fallopian tubes, uterus, cervix, upper third of the vagina). Subsequently, Leydig cells produce testosterone, which binds to the nuclear androgen receptor to virilize the internal genitalia of the fetus. Testosterone is converted to dihydrotestosterone, a more potent androgen that stimulates the differentiation of the EG into male anatomy (development of the phallus into a penis, fusion of labioscrotal folds to form scrotum, and so forth) by acting on the androgen receptor. Most DSD conditions will result from inadequate androgen action (either excessive or insufficient) or gonadal dysfunction, which clinically will translate into either virilization of the female fetus or undermasculinization of the male one.
Classification
The current DSD classification follows the patients’ karyotype and 3 main groups are recognized: 46XY DSD, 46XX DSD, and sex chromosome DSD (mosaic karyotype, most commonly 45X/46XY). Further identification of the source of the problem (ie, gonad structure/function, androgen pathway, and receptor, and so forth) will lead to a specific diagnosis. The most common causes of DSD divided by karyotype are depicted in Table 1 .
| XX DSD | XY DSD | Sex Chromosome DSD | |
|---|---|---|---|
| Disorders of gonadal development |
|
|
|
| Disorders related to androgen synthesis or action | Androgen excess | Androgen action | |
| Androgen insensitivity syndrome | ||
| Androgen synthesis | ||
|
|
Most patients with DSDs present in the neonatal period with genital ambiguity. Clinical scenarios that should trigger evaluation for DSDs are overt genital ambiguity, virilized female EG (ie, enlarged clitoris, posterior labial fusion, and inguinal/labial mass), undervirilized male EG (bilateral undescended testicles, micropenis, association of hypospadias, and undescended testicles). Although the consensus advocates for a full DSD workup for patients with perineal hypospadias and bilateral descended testicles, the authors’ group has been moving away from that practice because a review of their own data showed that the large cohort of such patients with well-developed phallus and scrotum was uniformly assigned the male sex and found not to harbor any Müllerian structures. It is important to avoid using the term ambiguous genitalia and lengthy delays in sex assignment for such patients because this is a significant source of stress for parents.
A significant proportion (10%–20%) of patients can present later in life (childhood or even young adulthood) and for those, the absence of ambiguity is the rule. Reasons for the referral of female patients include palpable gonad within an inguinal hernia; absent, delayed, or incomplete puberty; virilization; and primary amenorrhea. In teenagers, breast development, gross cyclic hematuria, and sometimes simply infertility flag the possibility of DSD. In pediatric medicine, as karyotype has become more common, discordance between genital appearance and karyotype ordered for issues unrelated to gender assignment is another reason for referral to DSD clinics.
Approach to the newborn with genital ambiguity
History
Newborns with genital ambiguity should be evaluated on an urgent basis. The first challenge is to define which patients actually have ambiguous genitalia as opposed to minor genital abnormalities (eg, mild clitoral enlargement or isolated distal hypospadias) and, therefore, avoid overinvestigation. After identifying one of the scenarios listed in the previous section, the first step is to request an evaluation by an expert in DSD who works as part of a multidisciplinary team. Even before the first assessment is initiated, some general principles should be kept in mind: one should refrain from making comments or statements based on the appearance of the EG alone, every newborn infant should receive a male or female gender assignment after a thorough and timely investigation; a long-term care plan should be discussed in the setting of a multidisciplinary, holistic, patient-centered clinic using the best level of evidence available; family concerns should be addressed promptly, openly, and confidentially by professionals with the best communication skills, without withholding detailed information.
A detailed history should focus on a family history of DSD, parental consanguinity, unexplained infant deaths, maternal ingestion of drugs (particularly progestagens and steroids ), use of assisted reproductive technologies, and results of prenatal tests. A history of maternal virilization during pregnancy points toward the possibility of aromatase deficiency and, rarely, maternal androgen secreting tumors, such as luteomas. During the first interview, care should be taken to ascertain the degree of knowledge parents might already have about their baby’s condition and DSD. A careful perinatal history focused on the evidence of prematurity, intrauterine growth retardation, or other signs of placental insufficiency should also be obtained because an association of those conditions with undervirilization of the male genitalia has been described. Because the parents may not know details of a family history of DSD, it is important to ask about a history of hypospadias, amenorrhea, and infertility.
Physical Examination
Physical examination should initially focus on general findings and potentially life-threatening problems, like the presence of severe dehydration that can be associated with salt-wasting congenital adrenal hyperplasia (CAH), which usually happens after 1 to 2 weeks of life, followed by the inspection for signs of dysmorphic features or associated anomalies. The examination of the EG starts with the careful inspection of the phallic structure, noting length, breadth, and amount of erectile tissue; number of orifices in the perineum and their topography, rugation, pigmentation, and fusion of the labioscrotal folds; and the position and patency of the anus (girls with cloacal anomalies often have some degree of genital ambiguity). Asymmetry is also an important sign to look for because some DSD conditions, like ovotesticular DSD and mixed gonadal dysgenesis, will produce virilization on only one side of the genitalia.
Virilized female genitalia will usually exhibit variable degrees of clitoromegaly, pigmentation, and rugation of the labial skin and labial fusion; depending on the degree of virilization, only one opening other than the anus will be visible in the perineum representing an urogenital sinus (UGS). The Prader classification provides a useful standardization for such findings ranging from 1 (mild clitoromegaly) through to 5 (complete virilization with UGS opening up at the tip of the phallus) – Fig. 1 .
Male undervirilization is portrayed by variable degrees of hypospadias (urethral opening in the ventral aspect of the penile shaft), which can also be associated with bifid scrotum, penile ventral curvature, and penoscrotal transposition.
In either case, it is important to palpate the phallus for the presence of corpora (erectile tissue) and measure its stretched dorsal length, which can be compared with normalized data.
Even in patients with normal-appearing male genitalia, a penis shorter than 2.0 to 2.5 cm with a narrow breadth should be considered a micropenis and warrants further investigation.
Following the examination of the EG itself, palpation of gonads is a key step in the initial assessment. Gonads can be palpated within the scrotum or labioscrotal folds, inguinal canal, or nonpalpable. The status of the gonads on palpation bears a particularly important weight on the initial diagnostic thought process.
Diagnostic Tests
The most important initial diagnostic tests in the DSD workup are karyotype, pelvic ultrasound to evaluate the presence of Müllerian structures, and serum levels of sodium, potassium, and 17-hydroxyprogesterone (17-OHP) after day 3 of life. A thorough history and physical examination (especially gonad palpation ) coupled with the results of the aforementioned tests will allow patients to be situated within the DSD umbrella and receive a final diagnosis based on pathophysiology in most cases. Other serum biochemistry tests frequently used are androgens (testosterone, dihydrotesterone, androstenedione), cortisol, gonadotrophins, and AMH levels. In infants older than 3 to 6 months or if a defect of androgen production is suspected, it may be necessary to perform a stimulation test with human chorionic gonadotropin (hCG) to reliably estimate the gonadal production of androgens.
Pathology reports from gonadal biopsies or removal may be helpful in formulating a more complete diagnosis but such procedures are rarely performed in young newborns or infants right at the outset.
Despite the rapid incorporation of knowledge from genetic studies in recent years, particularly for 46XY DSD, genetic testing is currently not widely available and its ability to add benefit to the initial approach of ambiguous genitalia is uncertain. Nonetheless, increasing availability of such testing can be valuable for defining a molecular cause and supporting genetic counseling for families.
Classification
The current DSD classification follows the patients’ karyotype and 3 main groups are recognized: 46XY DSD, 46XX DSD, and sex chromosome DSD (mosaic karyotype, most commonly 45X/46XY). Further identification of the source of the problem (ie, gonad structure/function, androgen pathway, and receptor, and so forth) will lead to a specific diagnosis. The most common causes of DSD divided by karyotype are depicted in Table 1 .
| XX DSD | XY DSD | Sex Chromosome DSD | |
|---|---|---|---|
| Disorders of gonadal development |
|
|
|
| Disorders related to androgen synthesis or action | Androgen excess | Androgen action | |
| Androgen insensitivity syndrome | ||
| Androgen synthesis | ||
|
|
Most patients with DSDs present in the neonatal period with genital ambiguity. Clinical scenarios that should trigger evaluation for DSDs are overt genital ambiguity, virilized female EG (ie, enlarged clitoris, posterior labial fusion, and inguinal/labial mass), undervirilized male EG (bilateral undescended testicles, micropenis, association of hypospadias, and undescended testicles). Although the consensus advocates for a full DSD workup for patients with perineal hypospadias and bilateral descended testicles, the authors’ group has been moving away from that practice because a review of their own data showed that the large cohort of such patients with well-developed phallus and scrotum was uniformly assigned the male sex and found not to harbor any Müllerian structures. It is important to avoid using the term ambiguous genitalia and lengthy delays in sex assignment for such patients because this is a significant source of stress for parents.
A significant proportion (10%–20%) of patients can present later in life (childhood or even young adulthood) and for those, the absence of ambiguity is the rule. Reasons for the referral of female patients include palpable gonad within an inguinal hernia; absent, delayed, or incomplete puberty; virilization; and primary amenorrhea. In teenagers, breast development, gross cyclic hematuria, and sometimes simply infertility flag the possibility of DSD. In pediatric medicine, as karyotype has become more common, discordance between genital appearance and karyotype ordered for issues unrelated to gender assignment is another reason for referral to DSD clinics.
Approach to the newborn with genital ambiguity
History
Newborns with genital ambiguity should be evaluated on an urgent basis. The first challenge is to define which patients actually have ambiguous genitalia as opposed to minor genital abnormalities (eg, mild clitoral enlargement or isolated distal hypospadias) and, therefore, avoid overinvestigation. After identifying one of the scenarios listed in the previous section, the first step is to request an evaluation by an expert in DSD who works as part of a multidisciplinary team. Even before the first assessment is initiated, some general principles should be kept in mind: one should refrain from making comments or statements based on the appearance of the EG alone, every newborn infant should receive a male or female gender assignment after a thorough and timely investigation; a long-term care plan should be discussed in the setting of a multidisciplinary, holistic, patient-centered clinic using the best level of evidence available; family concerns should be addressed promptly, openly, and confidentially by professionals with the best communication skills, without withholding detailed information.
A detailed history should focus on a family history of DSD, parental consanguinity, unexplained infant deaths, maternal ingestion of drugs (particularly progestagens and steroids ), use of assisted reproductive technologies, and results of prenatal tests. A history of maternal virilization during pregnancy points toward the possibility of aromatase deficiency and, rarely, maternal androgen secreting tumors, such as luteomas. During the first interview, care should be taken to ascertain the degree of knowledge parents might already have about their baby’s condition and DSD. A careful perinatal history focused on the evidence of prematurity, intrauterine growth retardation, or other signs of placental insufficiency should also be obtained because an association of those conditions with undervirilization of the male genitalia has been described. Because the parents may not know details of a family history of DSD, it is important to ask about a history of hypospadias, amenorrhea, and infertility.
Physical Examination
Physical examination should initially focus on general findings and potentially life-threatening problems, like the presence of severe dehydration that can be associated with salt-wasting congenital adrenal hyperplasia (CAH), which usually happens after 1 to 2 weeks of life, followed by the inspection for signs of dysmorphic features or associated anomalies. The examination of the EG starts with the careful inspection of the phallic structure, noting length, breadth, and amount of erectile tissue; number of orifices in the perineum and their topography, rugation, pigmentation, and fusion of the labioscrotal folds; and the position and patency of the anus (girls with cloacal anomalies often have some degree of genital ambiguity). Asymmetry is also an important sign to look for because some DSD conditions, like ovotesticular DSD and mixed gonadal dysgenesis, will produce virilization on only one side of the genitalia.
Virilized female genitalia will usually exhibit variable degrees of clitoromegaly, pigmentation, and rugation of the labial skin and labial fusion; depending on the degree of virilization, only one opening other than the anus will be visible in the perineum representing an urogenital sinus (UGS). The Prader classification provides a useful standardization for such findings ranging from 1 (mild clitoromegaly) through to 5 (complete virilization with UGS opening up at the tip of the phallus) – Fig. 1 .
Male undervirilization is portrayed by variable degrees of hypospadias (urethral opening in the ventral aspect of the penile shaft), which can also be associated with bifid scrotum, penile ventral curvature, and penoscrotal transposition.
In either case, it is important to palpate the phallus for the presence of corpora (erectile tissue) and measure its stretched dorsal length, which can be compared with normalized data.
Even in patients with normal-appearing male genitalia, a penis shorter than 2.0 to 2.5 cm with a narrow breadth should be considered a micropenis and warrants further investigation.
Following the examination of the EG itself, palpation of gonads is a key step in the initial assessment. Gonads can be palpated within the scrotum or labioscrotal folds, inguinal canal, or nonpalpable. The status of the gonads on palpation bears a particularly important weight on the initial diagnostic thought process.
Diagnostic Tests
The most important initial diagnostic tests in the DSD workup are karyotype, pelvic ultrasound to evaluate the presence of Müllerian structures, and serum levels of sodium, potassium, and 17-hydroxyprogesterone (17-OHP) after day 3 of life. A thorough history and physical examination (especially gonad palpation ) coupled with the results of the aforementioned tests will allow patients to be situated within the DSD umbrella and receive a final diagnosis based on pathophysiology in most cases. Other serum biochemistry tests frequently used are androgens (testosterone, dihydrotesterone, androstenedione), cortisol, gonadotrophins, and AMH levels. In infants older than 3 to 6 months or if a defect of androgen production is suspected, it may be necessary to perform a stimulation test with human chorionic gonadotropin (hCG) to reliably estimate the gonadal production of androgens.
Pathology reports from gonadal biopsies or removal may be helpful in formulating a more complete diagnosis but such procedures are rarely performed in young newborns or infants right at the outset.
Despite the rapid incorporation of knowledge from genetic studies in recent years, particularly for 46XY DSD, genetic testing is currently not widely available and its ability to add benefit to the initial approach of ambiguous genitalia is uncertain. Nonetheless, increasing availability of such testing can be valuable for defining a molecular cause and supporting genetic counseling for families.
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