Levels of evidence (1a-4) and grades of recommendation (A-C) are defined at the end of the "Major Recommendations" field.
Background
The formerly called 'intersex disorders' were recently the subject of a consensus document in which it was decided that the term 'intersex' should be changed to 'disorders of sex development' (DSD).
DSD require a multidisciplinary approach to diagnosis and treatment, which should include geneticists, neonatologists, paediatric and adult endocrinologists, gynaecologists, psychologists, ethicists and social workers. Each team member should be specialised in DSD, and a team should have enough new patients to ensure experience.
The Neonatal Emergency
The first step is to recognize the possibility of DSD (see Table 4 in the original guideline document) and to refer the newborn baby immediately to a tertiary paediatric centre, fully equipped with neonatal, genetics, endocrinology and paediatric urology units. At the paediatric centre, the situation should be explained to the parents fully and kindly. Registering and naming the newborn should be delayed as long as necessary.
Choice of Laboratory Investigations
The following laboratory investigations are mandatory:
- Karyotype
- Plasma 17-hydroxyprogesterone assay
- Plasma electrolytes
- Ultrasonography to evaluate the presence of Müllerian duct structures
These investigations will provide evidence of congential adrenal hyperplasia (CAH), which is the most frequently occurring DSD. If this evidence is found, no further investigation is needed. If not, then the laboratory work-up should proceed further.
The human chorionic gonadotrophin (hCG) stimulation test is particularly helpful in differentiating the main syndromes of 46XYDSD by evaluating Leydig cell potential. When testosterone metabolism is evaluated, the presence or absence of metabolites will help to define the problem. An extended stimulation can help to define phallic growth potential and to induce testicular descent in some cases of associated cryptorchidism.
Gender Assignment
This is a very complicated task. It should take place after a definitive diagnosis has been made. The idea that an individual is sex-neutral at birth and that rearing determines gender development is no longer the standard approach. Instead, gender assignment decisions should be based upon:
- Age at presentation
- Fertility potential
- Size of the penis
- Presence of a functional vagina
- Endocrine function
- Malignancy potential
- Antenatal testosterone exposure
- General appearance
- Psychosocial well-being and a stable gender identity
Each patient presenting with DSD should be assigned a gender as quickly as a thorough diagnostic evaluation permits.
Role of the Paediatric Urologist
The role of the paediatric urologist can be divided into a diagnostic role and a therapeutic role (see Table below).
Table. Role of the Paediatric Urologist
Diagnostic role
- Clinical examination
- Ultrasound
- Genitography
- Cystoscopy
- Diagnostic laparoscopy
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Therapeutic role
- Masculinizing surgery
- Feminizing surgery
- Gonadectomy
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Diagnosis
Clinical Examination
A good clinical examination in a neonate presenting with ambiguous genitalia is important. As well as a good description of the ambiguous genitalia, some detailed information should be given on palpability and localization of the gonads. Information gathered by the various examinations described below should help the team to come to a final diagnosis.
Palpable gonad. It must be remembered that if it is possible to feel a gonad, it is almost certainly a testis; this clinical finding therefore virtually excludes 46XXDSD.
Medical photography can be useful but requires sensitivity and consent.
Phallus. The phallus should be measured. A cotton bud placed at the suprapubic base of the implant of the stretched phallus allows for a good measurement of phallic length.
Urogenital sinus opening. The opening of the urogenital sinus must be well evaluated. Is there only one opening visible? Can a hymenal ring be seen? What does the fusion of the labioscrotal folds look like; do the folds show rugae or some discolouration?
Investigations
Ultrasound can help to describe the palpated gonads or to detect non-palpated gonads. However, the sensitivity and specificity are not high. On ultrasound, the Müllerian structures can be evaluated. Is there a vagina? Are there some abdominal gonads? Is there a vaginal or utricular structure visible?
Genitography can provide some more information on the urogenital sinus. How low or how high is the confluence? Is there any duplication of the vagina? How does the urethra relate to the vagina?
General anaesthesia. In some cases, further examinations under general anaesthesia can be helpful. On cystoscopy, the urogenital sinus can be evaluated and the level of confluence between the bladder neck and the bladder. Cystoscopy can also be used to evaluate the vagina or utriculus, e.g., the presence of a cervix at the top of the vagina can be important information.
Laparoscopy is necessary to obtain a final diagnosis on the presence of impalpable gonads and on the presence of Müllerian structures. If indicated, a gonadal biopsy can be performed.
Management
It is clear that the timing of surgery is much more controversial than it used to be.
The rationale for early surgery includes:
- Beneficial effects of oestrogen on infant tissue
- Avoiding complications from anatomical anomalies
- Minimizing family distress
- Mitigating the risks of stigmatization and gender-identity confusion
However, adverse outcomes have led to recommendations to delay unnecessary surgery to an age when the patient can give informed consent. Surgery that alters appearance is not urgent. Early surgery should be reserved for those patients with high confluent urogenital tracts, girls with severely masculinized genitalia and boys with undervirilized genitals. Vaginoplasty should be delayed until puberty and milder forms of masculinization should not be treated surgically.
Feminizing Surgery
Clitororeduction. Reduction of an enlarged clitoris should be done with preservation of the neurovascular bundle. Clitoral surgery has been reported to have an adverse outcome on sexual function and clitoral surgery should therefore be limited to severely enlarged clitorises. Informed parental consent should be obtained. Although some techniques that conserve erectile tissue have been described, the long-term outcome is unknown.
Separation of the vagina and the urethra is preserved for high confluence anomalies. Many techniques for urogenital sinus repair have been described, but their outcome has not been evaluated prospectively.
Vaginoplasty should be performed during the teenage years. Every technique (self dilatation, skin or bowel substitution) has its specific advantages and disadvantages. All carry a potential for scarring that would require further surgery before sexual function was possible.
Aesthetic refinements. The goals of genital surgery are to maximize anatomy to allow sexual function and romantic partnering. Aesthetics are important in this perspective. The reconstruction of minor labiae from an enlarged clitoral hood is an example of aesthetic refinement.
Masculinizing Surgery
Hormone therapy early in life is advocated by many doctors. The level of evidence is low for restoration of normal penile size.
Hypospadias surgery. See the National Guideline Clearinghouse (NGC) summary of the EAU guideline, Hypospadias.
Excision of Müllerian structures. In the DSD patient assigned a male gender, Müllerian structures should be excised. There is no evidence about whether utricular cysts need to be excised.
Orchiopexy. See the NGC summary of the EAU guideline, Cryptorchidism.
Phalloplasty. The increasing experience of phalloplasty in the treatment of female to male transsexual patients has led to reports about the reliability and feasibility of this technique. It has therefore become available to treat severe penile inadequacy in DSD patients.
Aesthetic refinements. These include correction of penoscrotal transposition, scrotoplasty and insertion of testicular prostheses.
Gonadectomy. Germ cell malignancy only occurs in patients with DSD who have Y-chromosomal material. The highest risk is seen in patients with gonadal dysgenesis and in patients with partial androgen insensitivity with intra-abdominal gonads (Level of evidence: 2). Intra-abdominal gonads of high-risk patients should be removed at the time of diagnosis (Grade of recommendation: A).
Definitions:
Levels of Evidence
1a Evidence obtained from meta-analysis of randomized trials
1b Evidence obtained from at least one randomized trial
2a Evidence obtained from at least one well-designed controlled study without randomization
2b Evidence obtained from at least one other type of well-designed quasi-experimental study
3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports
4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities
Grades of Recommendation
- Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial
- Based on well-conducted clinical studies, but without randomized clinical studies
- Made despite the absence of directly applicable clinical studies of good quality
