Ambiguous genitalia constitutes an emergency – both a social and medical emergency. Medical emergency in the sense that if the underlying cause leads to adrenal insufficiency, the outcome could be fatal. It is a social emergency when the child is assigned a gender not in consonance with his genetic sex or future reproductive/sexual function. It is important to review the process of gonadal differentiation and genital development when confronted with a patient presenting with ambiguous genitalia. There has been a lot of advances as far as genetic control of all the processes in DSDs is concerned which can readily be accessed with modern technology.

Diagnosis of Ambiguous Genitalia
The diagnosis of the cause of ambiguous genitalia involves the basic process of history, physical examination, and investigations.

History dates back to the perinatal period with inquiries for symptoms of maternal virilization or maternal medication use in pregnancy suggestive of an exogenous (maternal) source of androgen. A detailed family history should be obtained to include: unexplained neonatal deaths, consanguinity, and infertility. Early neonatal death in a male sibling is suggestive of a salt-wasting form of congenital adrenal hyperplasia. Families may not share the diagnosis of DSD with relatives but may disclose issues of infertility. Parental consanguinity increases the risk of autosomal recessive disorders such as CAH, testosterone biosynthetic defects, Leydig cell hypoplasia, and 5-alpha reductase deficiency.

On physical examination it is important to assess for features suggestive of a dysmorphic syndrome . General evaluation of health should include assessment for dehydration, although salt-wasting crises with CAH generally occur between the 4th and 15th day of life. Examination of the external genitalia cannot provide a diagnosis, nor determine gender assignment, but it can provide evidence to exclude some diagnosis (ie, with a palpable labioscrotal gonad, CAH in a female infant is unlikely) and is one factor that will be considered in gender assignment.

Attention should be focused on phallic size, symmetry of the external genitalia, fusion of labioscrotal folds, rugosity of labioscrotal folds, presence of a persistent urogenital sinus, presence of a vaginal opening, and position of the urethral meatus.. One of the important features to assess on examination is the presence or absence of unilateral or bilateral palpable gonads. Gonads may need to be milked down into the labioscrotal folds, and a careful examination sweeping from the internal ring along the inguinal canal is necessary . Gonads that are bilaterally palpable are generally testes.

The phallus should be measured for both length and width of the corporal bodies, from the base to the tip of the glans. The full-term newborn penis should measure at least 2 cm and is usually 3.5 +/- 0.4 cm a phallus less than 2.3 to 3.6 cm is consistent with a micropenis. Clitoral size in term newborns ranges from 2.0 to 8.5 mm in length, with width from 2.0 to 6.0 mm. A single opening on the perineum may suggest a persistent urogenital sinus; imaging such as a genitogram is required to determine the level of the confluence relative to the perineum. Fusion of the labioscrotal folds is evident if the distance measured from the anus to the posterior fourchette is more than 50% of the distance measured from the anus to the phallus (clitoris). In hypospadius patients, it is important to assess the location of the urethral meatus along the ventral aspect of the penile shaft and the degree of chordee. Hyperpigmentation of the genital skin and nipples may reflect the excess ACTH (adrenocorticotropic hormone) and proopiomelanocortin in infants with CAH.

Laboratory investigations
Some investigations are applied to all individuals with DSD to assist with diagnosis, others are more specifically ordered based on results of earlier testing and physical examination. All patients with ambiguous genitalia require chromosomal analysis on peripheral blood. Initial rapid testing is available using fluorescence in situ hybridization for X and Y chromosomes (DX1 for X, sex determining region Y [SRY] for Y) but careful assessment of the full karyotype must be performed for definitive assessment especially to rule out mosaicism. Ultrasound imaging of the internal genital tract to assess for the presence of a uterus and intra-abdominal or inguinal gonads is a useful initial step. A genitogram of the urogenital sinus, to determine presence of vagina, impression of cervix, and length of confluence (high or low urogenital sinus) is helpful especially in planning for future surgery. Gonadotropins, testosterone, and ihydrotestosterone are part of initial investigations.

CAH is both the most common cause of ambiguous genitalia in the newborn, with a Philippine incidence based on newborn screening of 1: 8,500.All babies born with ambiguous genitalia is presumed to have CAH unless proven otherwise .Basal 17 hydroxyprogesterone will be elevated in the most common form of CAH- the 21 Hydroxylase deficiency, but may not be significantly elevated until 48 hours following birth.

Salt-losing form of CAH will have hyponatremia, hyperkalemia, and dehydration , therefore,serum and urine electrolytes, renin, and aldosterone are important additional testing.

Treatment
Since results of laboratory tests may not be available immediately, focus on gender of rearing should be made during the waiting period. Ideally, management should consist of a pediatric surgeon or pediatric urologist expert on urogenital reconstructive surgery, psychologist, psychiatrist, social worker, pediatric endocrinologist and a neonatologist (pediatrician in the older age group). Parents need to participate in discussions and decision making for sex of rearing and surgical intervention.

Once a specific diagnosis is confirmed, decision making and therapy can be guided accordingly. Appropriate sex of rearing is based on specific pathophysiology, prognosis for spontaneous pubertal development, capacity for sexual activity and orgasm, and fertility potential.

For patients with CAH, mainstay of medical therapy consist of glucocorticoid (Hydrocortisone) and mineralocorticoid (Fluodrocortisone) initially at suppressive doses for a few weeks aiming towards normal physiologic dose. Surgery depends on the extent of ambiguity and should be done as soon as feasible. Psychological and genetic counseling and support are essential aspects of management.

A neonate with CAH due to 21-Hydroxylase enzyme deficieny presenting with adrenal crisis on the 7th day of life.