Approach
The initial management of a neonate with atypical genitalia is a social and clinical emergency. The local team has a key role in coordinating the initial assessment and investigations, managing a clinical emergency, and supporting parents. It is important there is early discussion with a more specialist multidisciplinary team (MDT) if at all possible.
Management of a neonate with atypical genitalia should involve an MDT of pediatric subspecialists, including an endocrinologist, a neonatologist, a urologic surgeon, a radiologist, clinical psychologist, and a specialist nurse.[7] The core MDT should have links with a wider team, including specialists from genetics, biochemistry, relevant adult medical specialties, such as gynecology and endocrinology, social services, and if possible a clinical ethics forum.[7] Ongoing communication and support for the family is crucial, as well as communication with the primary care physician.[7][18][29]
The following principles should guide the management of a neonate with atypical genitalia:[1][2][7][19][30][31]
Sex assignment. This should be undertaken by a specialist differences of sex development (DSD) MDT. The child is referred to as "baby," not boy or girl. The family is encouraged to delay naming the baby until the sex has been assigned.
The baby should be managed at a center with multidisciplinary expertise in the evaluation of neonates with atypical genitalia. In some situations, care at a local hospital may be appropriate, with early consultation with a specialized MDT in a regional center.
The needs, background, culture, and expectations of the parents must be understood and respected. It is important that parents are kept fully informed throughout the investigative process by the clinical team. Regular clear communication and information updates are important.
When a neonate is identified as having atypical genitalia, psychological support should be provided for the family, particularly where there has been a delay in sex assignment.
Sex assignment
The specialist DSD MDT must take into account many factors when considering sex assignment, including:
Underlying diagnosis if known
Appearance of the external genitalia
Surgical reconstructive options
Need for hormonal replacement therapy
Potential for future fertility
Culture and preferences of the family
Exposure of high levels of testosterone on brain development
Potential for future sexual function
Potential future gender identity.
Sex chromosome DSD
Gonadal dysgenesis
Sex assignment is based on likelihood of fertility, degree of virilization, presumed gonad function in puberty based on hormonal tests, and risk of gonadal malignancy.
If the patient is raised female, surgical separation of the urethral and vaginal openings may be required. Clitoral reduction may be indicated in cases of severe virilization. Bilateral gonadectomy is usually undertaken before puberty to avoid virilization during puberty and to eliminate the risk of gonadal malignancy. Exogenous estrogen will be needed at puberty to allow pubertal development. Further genitoplasty in adolescence may be required.
If raised male, surgical correction of hypospadias or chordee is usually required. Testosterone replacement may be required at puberty if there is gonadal failure or if bilateral gonadectomy has previously been undertaken.
45,X/46,XY mixed gonadal dysgenesis
Sex assignment can be challenging, as the phenotype is variable. Factors that should be considered include future prospects of fertility, genital appearance, size of phallus, presumed testicular function in puberty based on hormonal tests, gonadal development, and malignancy risk (see section on sex assignment above). The risk of gonadal malignancy is highest in mixed gonadal dysgenesis when there is Y chromosomal material in those with an intra-abdominal (undescended) gonad.
For individuals assigned male, hypospadias or chordee, if present, may require surgical correction. Testes are at increased risk of malignancy. Testes present in the scrotum should be monitored clinically and, if there are concerns, a biopsy may be required. A streak ovary, if present, should be removed because of the risk of malignant change. If there is gonadal failure, testosterone replacement will be required at puberty. Müllerian structures should be removed in individuals raised male.[1]
For individuals assigned female, surgery may be an option, although the timing of surgery needs to be individualized. Gonadectomy may be indicated to prevent gonadal malignancy and to avoid risk of virilization during puberty.[32] Estrogen will be needed at puberty for pubertal development. Further genitoplasty in adolescence may be necessary. Those with a uterus will need treatment with cyclic progesterone once breakthrough bleeding occurs.
46,XX DSD
Congenital adrenal hyperplasia (CAH) secondary to 21 hydroxylase deficiency[33]
These individuals are typically assigned a female sex, as fertility is preserved in CAH. Surgical management is sometimes required.
Glucocorticoids (usually hydrocortisone) are typically required to replace cortisol. If there is salt wasting, fludrocortisone is required to replace aldosterone, and salt supplements may be required in the first 1 to 2 years of life and then discontinued. Corticosteroid treatment is commenced as soon as the diagnosis is confirmed and is continued lifelong.
Separation of the urethral and vaginal openings may be required. Clitoral reduction may be indicated in cases of severe virilization. Further genitoplasty in adolescence may be necessary. More recently, some centers opt to not undertake genital surgery until the affected individual is old enough to make an informed decision about whether to proceed with surgical intervention.
46,XY DSD
Testosterone biosynthetic defects
Neonates are usually (but not always) assigned a male sex, which has the potential to preserve future fertility. However, debate continues as to the optimal strategy for sex assignment, gonadectomy, and surgical intervention. Many factors are considered by the MDT before a final decision is made.[34]
Individuals with defects that are common to the adrenal gland and the testes may have deficiencies of glucocorticoids and/or mineralocorticoids. Treatment with glucocorticoids and/or mineralocorticoids in these patients is commenced as soon as the diagnosis is confirmed and continued lifelong.
If hypospadias or chordee is present, surgical correction is usually required. Gonadectomy may be considered if the neonate is assigned female sex.
Testosterone replacement may be required at puberty, particularly if there is evidence of gonadal failure or poor virilization.
5 alpha-reductase deficiency
Individuals with 5 alpha-reductase deficiency have a high degree of phenotypic variability and have been raised male or female. Debate continues as to the optimal strategy for sex assignment, gonadectomy, and surgical intervention. A decision regarding sex of rearing will involve an MDT discussion with the parents and will be informed by age at diagnosis, degree of virilization, and other factors (see section on sex assignment above). If an early diagnosis is made, some favor male sex assignment as the penis and scrotum are likely to respond to exogenous dihydrotestosterone. If hypospadias or chordee is present, surgical correction is usually required.
If raised male, affected individuals may not need hormonal replacement in puberty as further virilization may occur spontaneously. 5 alpha-reductase converts testosterone into dihydrotestosterone in the peripheral tissues, including the genital skin, and the rise in testosterone levels at the onset of puberty may be sufficient to induce the development of secondary sexual characteristics, either through low-level expression of 5 alpha-reductase or via alternative pathways.
If raised female, bilateral gonadectomy may be considered.[34]
Partial androgen insensitivity
Some individuals are raised male, although in those with severe partial androgen insensitivity adequate virilization at puberty will not occur and female sex of rearing may be more appropriate.[34]
If raised male, surgical correction of hypospadias or chordee is usually required. Testosterone replacement may be needed at puberty, particularly if testosterone levels remain low. The response to exogenous testosterone is variable.
If raised female, surgical separation of the urethral and vaginal openings may be required. Clitoral reduction may be indicated in cases of severe virilization. Bilateral gonadectomy is considered before puberty to avoid further virilization at puberty and because of the risk of malignant change in the gonad (particularly if it is outside the scrotum). If gonads are removed, exogenous estrogen will be needed at puberty for pubertal development. Further genitoplasty in adolescence may be required. Removal of gonads will mean the individual will be infertile, so the decision for female sex assignment needs to be considered carefully.
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