Ambiguous Genitalia

Ambiguous genitalia, Disorders of Sex Development (DSD)

1. What every clinician should know

Disorders of sex development (DSD) are congenital conditions where there is an inconsistency between chromosomal, gonadal, and/or anatomic sex and includes individuals with ambiguous genitalia, the situation in which the genital appearance does not permit an accurate declaration of gender. Prevalence may approach 1% when minor variations are included, while only 0.1% to 0.2% of births are ambiguous enough to warrant investigation, and only a small portion of these require additional evaluation for gender assignment.

Assessment is needed when there is (1) overt genital ambiguity; (2) a female phenotype with an enlarged clitoris, a palpable labial mass, posterior labial fusion, or inguinal hernia(e); (3) male phenotype with: tertiary hypospadias, bilateral cryptorchidism; (4) genital/karyotype discordance; or (5) a family history of DSD.

When genital ambiguity is present it is crucial to assess and document the genital appearance, phallic size, position of urethral meatus, the presence of a urogenital opening, the extent to which the labioscrotal folds are fused (degree of fusion, presence of rugae, degree of pigmentation), the presence/absence of palpable gonads, and the presence/absence of genital asymmetry.

Ambiguous genitalia, one presentation of DSD, involves external genitalia that are neither fully differentiated as male or female. DSD is defined as a discrepancy between external genital development, gonadal and chromosomal sex and is estimated to occur in approximately one in 4500 births. Ambiguous genitalia include a spectrum ranging from mildly virilized female genitalia with clitoromegaly and/or posterior labial fusion to essentially male genitalia with hypospadias and a unilateral gonad. One or two palpable gonads may occur in a phenotypic female.

The most common form of DSD results from an autosomal recessive gene mutation in one of the enzymes responsible for adrenal steroidogenesis resulting in congenital adrenal hyperplasia (CAH). CAH also has diminished capacity for adrenal cortisol production and carries the risk of adrenal insufficiency in the neonate.

Newborns may present with ambiguous genitalia, which may not permit a sex assignment at birth. Evaluation should begin as soon as genital ambiguity is recognized as the underlying cause may be associated with life-threatening adrenal insufficiency. The genital phenotype must be carefully documented and verified as consistent or inconsistent with the spectrum of development between male and female. Often, infants can be categorized as an excessively virilized female or an undermasculinized male.

Initial testing includes karyotype, and because of the risk of adrenal insufficiency also includes measurement of serum electrolytes, 17-hydroxyprogesterone, cortisol, and ACTH. Transabdominal ultrasound should also be obtained to characterize the internal reproductive anatomy (gonads, uterus, and vagina). Results provide for classification as an guide toward an etiologic diagnosis of 46,XX DSD, 46,XY DSD, or sex chromosome DSD.

Management may involve hormonal replacement and surgery. Because outcome-based guidelines are lacking and the ideal management for any infant with ambiguous genitalia is unknown, decisions made by a multidisciplinary team are highly recommended. Both physical (embryonic) and psychosexual (sexual identity) development must be considered. The physical development is directed by genes and hormones, progresses in a predictable sequence, and is relatively well understood. Psychosexual development, consisting of three components: gender identity, gender role, and sexual orientation, is influenced by environment, is poorly understood, and occurs in an unpredictable sequence.

2. Diagnosis and differential diagnosis

Initial assessment includes physical examination focusing on external genitalia, karyotype, and imaging of internal genitalia.

Initial testing can be based on symmetry/asymmetry of genitalia and presence of palpable gonad(s).

• Symmetrical genitalia without palpable gonads

• Need to evaluate for CAH

• Obtain adrenal steroids: 17-hydroxyprogesterone, androstenedione, ACTH, deoxycortisol, testosterone, renin, and electrolytes

• Asymmetrical and/or palpable gonad(s)

• Focus on male reproductive system hormones

• Testosterone (T), LH, FSH, androstenedione, Müllerian-inhibiting substance (MIS), inhibin B

Diagnosis and initial studies

A diagnosis of DSD should be considered in those who have clitoromegaly (>9 mm in length). Examples of clitoromegaly, including two photos of newborns with other findings of genital ambiguity, and an example of extension of the clitoris and prepuntial skin between the labia are given in Figure 1, Figure 2, and Figure 3. Also consider this in those with posterior labial fusion (anogenital ratio: anus to posterior fourchette distance ÷ anal-clitoral base distance of >0.5 suggests virilization). Figure 4 includes sketches indicating the measurement of the anogenital ratio.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

A diagnosis should also be considered in those with palpable gonads in labioscrotal folds, micropenis (length < 2.5 cm at term) and hypospadias: hypospadias with bifid scrotum or only one or no palpable gonad(s). Figure 5, Figure 6, Figure 7, and Figure 8 show four examples of hypospadias, including distal at the juncture of the glands and phallic shaft, midshaft and two with perineal hypospadias, one in a newborn and also one showing the urethral opening in an older infant. The initial evaluation includes a karyotype to determine whether there is virilization of a 46,XX infant, undervirilization of a 46,XY infant, or an abnormal sex chromosome pattern. Because of the risk of adrenal insufficiency, electrolytes should be monitored until the diagnosis has been established.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Diagnostic categories and specific diagnoses

The multidisciplinary team may consist of obstetricians and urologists particularly those with experience in diagnosis and surgery for DSD, pediatric endocrinologists, psychologists (particularly those with experience with psychosexual issues), geneticists, and other available health caregivers with a background in DSD.

46,XX DSD

While the most common etiology is CAH, the differential diagnosis includes gestational hyperandrogenism, multisystem congenital anomalies, and ovotesticular DSD (formerly called true hermaphroditism), and testicular DSD such as occurs when there is a translocation of the sex determining region of Y (SRY) to an autosome.

CAH-21α-hydroxylase (CYP21A2)

The most common may involve mineralocorticoid deficiency with life-threatening salt-wasting. CYP21A2 and 11β-hydroxylase deficiency (11β-OH) can be evaluated with a 17-OH progesterone level. 11β-OH and 3β-hydroxysteroid dehydrogenase (3β-HSD) deficiency are evaluated using cortisol, dehydroepiandrosterone (DHEA), ACTH, 17-hydroxypregnenolone, and 11-desoxycortisol levels.

Gestational hyperandrogenism

This is caused by maternal androgen excess, including placental aromatase deficiency, and maternal theca-lutein cysts or luteomas as well as some synthetic progestational agents. 19-Nortestosterone derivatives, norethindrone, ethisterone, norethynodrel, and C-21-steroid medroxyprogesterone acetate, when used for habitual abortions, have been associated with clitoromegaly. There may be a history of maternal virilization during pregnancy. SRY translocation, SOX9 duplication, and ovotesticular DSD are assessed using MIH, inhibin B, and hCG stimulation for testosterone response.

Disordered genitalia

In 46,XX infants, this includes persistent cloaca (cloacal malformation) an extreme form of anorectal malformation in female infants in which there is incomplete separation of the urinary tract, genital tract, and hindgut.

46,XX sex reversal

This may occur with SRY translocation, SOX9 duplication, or idiopathically and generally does not present with ambiguous genitalia, but with male genitalia.

46,XY DSD

There are multiple causes including testicular dysgenesis, defects of androgen synthesis, and abnormal response to androgens including receptor defects. These may involve mutations impacting SRY function and rarer causes of CAH resulting in lack of normal virilization of the male fetus. Laboratory assessment includes assessment of testicular function including: 17-OH progesterone, androstenedione, LH, FSH, T, MIS, inhibin B, and dihydrotestosterone (DHT). Assessment between 6 weeks and 6 months of age may be preferable because of an active hypothalamic pituitary gonadal axis activity at this age. Assessment of 3β-HSD, StAR protein deficiency, and 17β-hydroxylase deficiency includes measurement of DHEA, deoxycorticosterone, and 17-hydroxypregnenolone.

General etiologic categories of 46,XY DSD

Gonadal dysgenesis

The degree of genital ambiguity is a consequence of extent and timing of the gonadal dysgenesis ranging from completely female external genitalia to normal male external genitalia with absent testes. Müllerian and Wolffian ducts may be fully regressed or developed to varying amounts. Low or undetectable MIH or inhibin B is consistent with lack of functioning testicular tissue; hCG-stimulation testing is a useful test to assess Leydig cell androgen biosynthetic capacity. Gene mutations such as DAX-1 duplication and SF-1 mutations can cause gonadal dysgenesis.

Androgen synthesis defects

Incomplete virilization may be a consequence of mutations in genes involved in androgen synthesis and include 17alpha hydroxylase deficiency; 17β-hydroxysteroid dehydrogenase type 3, and 5α-reductase type 2 deficiencies. In 17alpha hydroxylase deficiency cortisol, productions are also impaired and CAH is present. In 17β-hydroxysteroid dehydrogenase type 3 deficiency, testosterone levels are low and androstenedione are elevated, a profile which become more accentuated after hCG stimulation testing. The 5α-reductase type 2 enzyme is active in androgen-sensitive tissues and permits the conversion of T to DHT; mutations in 5α-reductase result in an hCG stimulated T:DHT ratio of >10:1. Mutations of steroidogenic genes that impair both testicular and adrenal cortical steroid synthesis include side-chain cleavage defects including StAR protein defect, 3β-hydroxysteroid dehydrogenase deficiency, and 17β- hydroxylase/17,20 lyase deficiency; all compromise cortisol production and the former also compromises mineralocorticoid synthesis, a reason to monitor electrolytes among 46,DSD patients.

Abnormal response to androgen, other testicular hormones, and endocrine disruptors

The phenotype of the androgen insensitivity (androgen receptor [AR] defects) syndromes (AIS) range from female genitalia with labial testes to male genitalia with hypospadias. Hormone profiles include elevated baseline and stimulated testosterone values along with modest elevation in gonadotropins. While the definitive diagnosis is based on AR mutations, responsiveness of genital growth to exogenous androgen may be helpful. Mutations of the MIH gene or MIH receptor gene may result in persistence of Müllerian duct derivatives in otherwise normally developed males. Patients present with male genitalia; testes may be cryptorchid and the uterus may be palpable within the inguinal canal. While endocrine disruptors have been suggested as a cause of abnormal male genital differentiation, particularly hypospadias, this has not been convincingly demonstrated.

Sex chromosome DSD

This category includes conditions that occur alongside something other than the usual 46,XX or 46,XY karyotype, of which many do not present with genital ambiguity. Those conditions that may present with ambiguity include the category referred to as ovotesticular DSD (true hepmaphrditism) and mixed gonadal dysgenesis, a condition that frequently manifests with an asymmetry of internal and/or external genitalia. While the diagnosis is generally made by documenting the presence of ovarian and testicular tissue on surgical biopsy the presence of ovarian tissue may be assessed during the first 2 months of life by measuring inhibin A levels.

General developmental defects beyond gene or hormone defects impacting genital differentiation

Genitalia that do not conform to the typical female or male pattern resulting from abnormal embryonic development may be associated with other physical anomalies and may not be caused by hormonal abnormalities. Such disordered genital anatomy occurs with cloacal extrophy which may involve multiple cloacal anomalies, cloacal anomaly or ano-rectal anomalies. This type of caudal field defect may involve displacing the genitalia anteriorly giving the appearance of virilization. Cloacal extrophy commonly involves a split in the genital tubercle, so the penis/clitoris is often split.

Assessment during infancy to predict gonadal competence at and after puberty

Potential gonadal function, the determination of the integrity of the hypothalamic-pituitary-gonadal axis can be accomplished through determination of LH, FSH, testosterone, inhibin B and MIS levels in the male and LH, FSH, estradiol in females. It is important to determine, when possible, the potential for testicular function if the sex of rearing is male and conversely to determine potential for ovarian function when female. Because ovarian follicular function involves both ova maturation and estrogen secretion, when there is evidence of inadequate of estrogen production, follicular development will also likely to be compromised. There is an age window in which it may be possible during infancy to assess ovarian function that is generally felt to be between 6 weeks and 3 months of age. In males, this window is felt to occur between 6 weeks and 6 months.

Assessment needed for evaluation and before female reconstructive surgery

Assessment of anatomy in 46,XX DSD patients with ovaries: In addition to the description of the external genitalia, visualization with ultrasound is used to determine the presence of a uterus, ovaries and to assess the size of the adrenal glands. Clitoral hypertrophy must be described along a spectrum from just beyond normal size and configuration to severe hypertrophy with a phallic “urethra” terminating at the tip of the glands. The degree of labial fusion from mild to complete masculinization with fused hemi-scrota must be described. Any labia minora should be described as they are usually absent with significant virilization. Any labial tissue is commonly anteriorly displaced from where the vaginal orifice would be. Since the urethra and vagina usually share a distal common channel exiting on the perineum, the location of the confluence from low, near the perineum, to high (near the bladder neck) needs to be described. Cystoscopy remains the best way to identify the level of urethrovaginal confluence and measure the distance from bladder neck to vaginal confluence and the distance below to the perineal meatus and assess vaginal size. This study is best if done before the genitoplasty.

Assessment of anatomy in 46,XY DSD or other DSD patients who have testes

The extent of masculinization of the male genitalia includes description of the penis length, impression of corpora development based on palpation, extent of fusion of the labiourethral folds, presence or absence of chordee, extent of fusion of the labioscrotal folds to form a scrotum, and presence, size, and location of testis(es). Visualization of internal structures is often of limited value in the patients with primarily male development. However, it is important to determine whether there is development of Müllerian structures as part of the etiologic evaluation, as well as for surgical planning.

3. Management

Management depends on the etiology, presence of hormone deficiencies, need for surgery, and whether sex assignment must be made.

Initial therapy in cases of adrenal insufficiency and adrenal hormone replacement therapy

Most crucial is the determination of the presence of salt-wasting CAH that may result in an adrenal crisis, which typically develops between 5 to 10 days of life and presents with hyponatremia, hyperkalemia, shock, vomiting, hypoglycemia, and cardiovascular collapse. This should be monitored by serum and urinary electrolytes at least daily until the diagnosis is established. Abnormal findings include increased urinary sodium and particularly hyperkalemia from a free flowing blood sample. If abnormalities are present, glucocorticoid (hydrocortisone at 50 to 100 mg/m2) should be given as an initial IV dosage, followed by a similar total daily dosage given every 6 hours IV or as a continuous infusion. Fluid and electrolytes are also needed to correct electrolyte disturbance when present. An IV bolus of normal saline, not hypotonic saline, of 20 mL/kg should be given followed by maintenance fluids of D5 NS. For severe hypoglycemia, 2 to 4 mg/kg of 10% glucose should also be given as an IV bolus. For CAH patients, “stress-dose” steroid replacement is required before surgery.

Sex steroid therapy and gonadal hormone replacement therapy

In patients with normal adrenal function, hormone replacement is based on the determination of the integrity of the hypothalamic-pituitary-gonadal axis. Therapy is usually not indicated until puberty except when a limited course of androgen therapy can be used to stimulate penile growth in the infant/child. If fertility is an issue, both the parents and, at an appropriate age, the patient, must be aware of current assisted fertility methods.

Among males, the potential for both testosterone secretion and seminiferous tubule function regarding sperm production is important. Normal but detectible LH, FSH, and T levels for age during infancy suggest that androgen therapy at an appropriate pubertal age may not be necessary. Among those with the possibility of unresponsiveness to androgen and those with penis size below the range for age, short-term testosterone therapy may be given to determine responsiveness or to stimulate penis growth. Regimens of 25 or 50 mg of depot testosterone preparations have been used monthly for 3 months. Further, inhibin B and MIS suggest potential for germ cell maturation particularly when reasonable testicular volume is present and increase the likelihood for future spermatogenesis.

Among females, assessment may involve factors to determine whether the patient has potential for fertility, is a candidate for ART, or lacks anatomical structures that preclude pregnancy. Gonadal evaluation aims to determine the presence and extent of ovarian differentiation. Gonadotropin levels during infancy, childhood (particularly FSH), and at pubertal age may be helpful. Visualization techniques, if ovarian tissue is detectible, may suggest the presence of follicles of cysts.

A regimen to stimulate pubertal development should be planned for those with evidence of gonadal failure beginning around the age of puberty. For female development, initial regimens such as are used for hypogonadism are appropriate using estrogen with addition of progesterone if indicated, while for males, a pubertal induction regimen with testosterone is appropriate.

A simple protocol to stimulate puberty in females is to use the lowest available form of estrogen; conjugated estrogens (Premarin) are commonly used, beginning with the smallest available dosage and progressively increasing doses at intervals of 4 to 6 months.

Testosterone can be administered to boys transdermally as a gel or patch, or by depot injection, which is most commonly used. The beginning dosage ranges from 50 to 75 mg. every 4 weeks; the dosage is gradually increased at 4- to 6-month intervals. Frequency of injection can be increased to every 2 to 3 weeks or quantity increased for the q 4 week injection until adult dosages are reached. The adult dosage is 100 mg week given at 1-, 2- , 3-, or 4-week intervals.

Psychological care

The impact of the initial dialogue with the parents cannot be overemphasized. It is crucial that appropriate information be given, within the context that genitalia are sometimes over- or under-developed and that after testing more information will be available. Background information about the bipotential nature of genital structures and gonads together with a description of how sexual development typically proceeds as a complete male or female and description of how ambiguity may occur. Parents should be reassured that a team will work with them, inform them of all information that is learned, and discuss with them options for treatment, including sex assignment if needed. If so, it should be emphasized that a decision will be made, with their input and agreement, regarding whether assigning as a male or female is most appropriate.

Full disclosure regarding new information and opinions should continue with counseling sessions successively, together with assessment of adjustment, implementing appropriate therapy as need for both the patient and parents. At an appropriate age, as judged by the patient’s maturity, the focus for providing information and counseling should shift from parents exclusively, to parents and patient to the patient exclusively. It is clear that acceptance and support by parents is a key factor in the adjustment of the patient. Psychological counseling must involve discussion of fertility, the potential for parenthood, and the likelihood of the germ cells coming from the patient. If the latter is unlikely, discussion of options from a young age make them much more acceptable.

Feminizing surgery

There is little evidence to support or refute the historical position that early surgery to “normalize” the genitalia is beneficial psychologically for the child. The family should always be made aware of the pros and cons of both surgery and no surgery. The role of the pediatric urologist/surgeon together with the multidisciplinary team is to help the family make informed decisions without dictating the need for surgery. Genital surgery most commonly involves the 46,XX child with CAH. These children have varying degrees of virilization, resulting in a number of anatomical issues.

Based on anatomic variations, surgical reconstruction may involve three main areas:

• Clitoroplasty

• Labioplasty

• Vaginoplasty

Controversies regarding genitoplasty involve the timing or age of surgery including the position that a single stage clitoro-vagino-labioplasty should be performed during early infancy to take advantage of an increased pliability of genital tissue. The 2005 consensus statement notes that there is “inadequate evidence currently in relation to establishment of functional anatomy to abandon the practice of early separation of the vagina and urethra.

Other controversises include the recommendation for early clitoroplasty and labioplasty with delay of vaginoplasty until adolescence because of the high risk of vaginal stenosis with early surgery, the delay of all surgery until after puberty, the need for clitoroplasty regardless of the extent of clitoromegaly, the potential for sensory loss of the genital structures, the risk of subsequent vaginal stenosis and other need for revisional surgery after early vaginoplasty, and the fact that the steps in feminizing genitoplasty are the same regardless of the child’s age.

It is currently possible to achieve nearly normal cosmetic results, while years of follow-up are required to judge achievement of sufficient vaginal caliber and sufficient clitoral and vaginal sensations to provide for normal pleasurable intercourse and orgasm.

Surgical procedures

Clitoroplasty

A ventral incision avoids manipulation of the innervation and vascular supply. Tunics that contain neurovascular bundles are left intact. If erectile tissue is to be excised, it is accomplished by entering the corporal bodies ventrally away from the neurovasculature. The inner mucosal surface of the clitoral foreskin is preserved for both sensation and should be used to create a clitoral hood.

Labioplasty

Clitoral skin remaining after creation of a clitoral hood is used to create labia minora. Midline division of phallic skin is divided into equal flaps which are moved inferiorly on either side of the clitoris and vagina to make a near normal appearance of the external genitalia. Labia majora, which are displaced anteriorly, are moved inferiorly so that the vagina is to exit between them. A Y-V plasty of the labia majora is required to complete this.

Vaginoplasty

Using partial or total urogenital mobilization techniques, the urogenital complex (sinus, urethra, vagina, and bladder) is mobilized toward the perineum. Thereby, the vagina reaches the perineum without having to separate the vagina from the urinary tract, generally avoiding the complication of urethrovaginal fistula. This mobilized urogenital tissue can be used to create a mucosal lined vestibule, an anterior or posterior vaginal wall. This urogenital tissue retains innervations, is not hair bearing as skin flaps and vaginal stenosis is less likely to develop.

Masculinizing surgery

Masculinizing surgery involves penile surgery ranging from hypospadias repair to penile construction, construction or completion of the scrotum, and placement of the testes into the scrotum.

The goals of reconstructive penile surgery are to straighten the penis, and to move the urethra from wherever it lies to the tip of the penis. This sometimes can be done in one step, but not infrequency, it will take more than one step depending on available skin, and extent of curvature of the penis (chordee) is marked or overall marked ambiguity. It is ideal to perform surgery from 6 to 12 months of age.

The goal is for full correction of the genitalia before two years of age. Most male surgery should be performed early well before pubertal age. Problems of male reconstructive surgery include development of fistulas and persistent chordee. Successful reconstruction may not result in a fully normal penis of normal size and the constructed urethra is not surrounded by corpus spongiosa.

Sex assignment decisions

Bases for gender assignment – most likely adult gender identify, specific diagnosis when known, genital appearance, and surgical options – potential for satisfactory sexual activity, fertility – potential with ovarian or testicular tissue containing germ cells, cultural aspects (cultural pressures, family dynamics, and social circumstances) are of prime importance – deference should be given to psychosocial factors when outcome is unpredictable. Should avoid the perception that gender is completely established at birth.

Recognize an impact of androgen exposure upon the fetal CNS regarding sexual identity, although the effect of this cannot be reliably predicted. Decision should be based upon internal and external genital phenotype and developmental potential.

• A penis <2 SDs or clitoris >2 SDs in not necessarily a criteria for reassignment or surgery.

• The importance of sex chromosome (XX or XY) should be deemphasized.

  Sexual development is directed by genes, which may be translocated.

  Sex reversal should be recognized and not stigmatized.

• Assignment recommendations

  Female for complete AIS, LH receptor defect/Leydig cell agenesis, and generally for 46,XX CAH

• While female assignment is recommended for all 46, XX CAH, recent evidence suggests that those with fully virilized male external genitalia do well when raised male

  Male for 5α-reductase and 17β-HSD deficiency based on outcome data gender identification and self-reassignment to male

Care is multidisciplinary to address medical, surgical, genetic, psychological, and social issues. This care should be ongoing involving the indicated caregivers based on current and long-term needs.

4. Complications

Consequences of DSD may impact physical, social, and psychological health during childhood dependent upon the specific diagnosis. Those forms that are a consequence of sex steroid synthesis that involve the adrenal glands (CAH) include medical and surgical treatment.

The medical treatment of glucocorticoid insufficiency and mineralocorticoid excess or insufficiency

During infancy and childhood, the goal of glucocorticoid therapy is to provide adequate exogenous glucocorticoid continually to avoid insufficiency and provide for normal metabolism, growth and development while keeping the dosages below the level that will produce glucocorticoid excess including growth suppression. Adjustment of this therapy is necessary during puberty. Once adulthood is reached, changes are dosages or dosing equivalents change little in individuals with good health.

Regarding surgical therapy in virilized 46,XX patients, complications may develop even in the most experienced hands. Recent reports have shown that adult sexual dysfunction is relatively common (>40%) in 46,XX patients who received genital surgery as children. In addition, it has been noted that additional genital surgeries are often needed.

Psychological and social problems may result from lack of counseling. Ongoing informative and supportive counseling is needed from the neonatal period, with transitioning of the counseling from the parents to the patient as is possible. Full disclosure to parents with planned disclosure to the patient is associated with improved outcome. Psychological support should also involve recurrent assessment to identify vulnerability to maladaptive coping. After childhood, focus of counseling should primarily be upon relationships rather that sexual activity and function.

5. Prognosis and outcome

Assessment of outcome for DSD patients regarding all aspects from gender identity, quality of life, and results of treatment are not available until at least 15 to 20 years after birth. Because of the dramatic changes of approach, particularly regarding genital surgery, such studies are often outdated before they can be completed. Nevertheless, the improved technical aspects of surgery and clarification of neuroanatomy should improve functional outcome. The approach to outcome studies must be multidisciplinary and consider quality of life, gender identity, body image, and potential sexual function (sexual sensation and satisfaction involving orgasm, lubrication, and pain-free intercourse), as well as surgical results related to continence, appearance and size of genitalia, especially the vagina and penis.

Exteriorization of the vagina is possible in nearly all girls with CAH. While most caretakers and families agree with early surgery, the need for this has been questioned by some. Parents should be made aware that many vaginoplasties done in early infancy will require another repair in late adolescence. Whether early or late vaginoplasty (or a combination of both) using current techniques will result in the best long-term outcome remains unclear. The most important factor affecting surgical results is the expertise of the surgical team. It seems clear that the more complex patients should be referred to “Centers of Excellence.” To optimize long-term results, long-term support with skilled endocrinologic and psychologic care is mandatory.

Care of the child with DSD, particularly those with ambiguous genitalia, must be individualized based upon external and internal reproductive system anatomy. There is a greater potential for fertility now using assisted reproductive technique when germ cells are present. When parents receive an objective, realistic, and complete assessment of their child’s condition and participate in decisions, outcome can be expected to be good. This assessment must be periodically updated by a medical team representative providing new data including interpretations of outcome data and discussion of differing opinions.

The long-term reality is significant issues will likely persist for the lifetime for the individual but that parents can make a major impact in ability of the patient to adapt and in quality of life issues. No single specific plan/approach/set of guidelines are applicable to all individuals. Continuing psychological care is critical. It is also important to disassociate sex assignment from the psychosocial domains of sexual identity (gender role and sexual orientation).

Standard of care: (1) a clear decision leading to a sexual assignment for all, (2) avoid assignment before expert evaluation involving a multidisciplinary team, (3) recognition that a secure assumption of a gender assigned depends upon parents who are fully satisfied with the decision, (4) confidentiality, attention to family, and patient concerns with open communication with the family and patient, (5) family, and eventually patient, involvement in all decision making, and (6) utilization of team approach to management as needed over time, together with care to inform parents, and patient, whenever new information is identified.

6. What's the evidence?

Houk, CP, Levitsky, LL. “Evaluation of the infant with ambiguous genitalia”.

Houk, CP, Levitsky, LL. “Management of the infant with ambiguous genitalia”.

Houk, CP, Lee, PA. “Intersexed States: Diagnosis and Management.”. Endocrine and Metabolic Clinics of North America. vol. 34. 2005. pp. 791-810.

Lee, PA, Houk, CP, Ahmed, SF, Hughes, IA. “Consensus Statement on Management of Intersex Disorders.”. Pediatrics.. vol. 118. 2006. pp. e488-500.

Lee, PA, Witchel, SW, Rogol, AD, Houk, C, Kappy, MS, Allen, DB, Geffner, ME. “Disorders of Sex Development”. Pediatric Practice Endocrinology. 2010. pp. 299-320.

Witchel, SS, Lee, PA, Sperling, M. “Ambiguous genitalia.”. Pediatric Endocrinology,. 2008. pp. 127-164.

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