Sumber: http://www.mayoclinic.

com/health/ambiguo us-genitalia/ds00668/dsection=causes Causes

By Mayo Clinic staff Ambiguous genitalia occurs when something goes wrong during pregnancy to interrupt or disturb the fetus' developing sex organs. How sex organs form in the womb A baby's genetic sex is established at conception, based on the 23rd pair of chromosomes. The mother's egg contains an X chromosome, and the father's sperm contains either an X or a Y chromosome. A baby who inherits the X chromosome from the father is a genetic female (two X chromosomes). A baby who inherits the Y chromosome from the father is a genetic male (one X and one Y chromosome). Male and female sex organs develop from the same tissue. Whether this tissue becomes male organs or female organs depends on the chromosomes. In males, a region on the Y chromosome triggers the development of testicles, which produce male hormones. The presence or absence of male hormones controls the development of the sex organs. Male genitals develop in response to male hormones from the fetal testicles. In a fetus without a Y chromosome without the effects of male hormones the genitals develop as female. How ambiguous genitalia occurs A disruption of the steps that determine sex can result in a mismatch between the external genitals and the internal sex organs or the chromosomal sex (XX or XY). A lack or deficiency of male hormones in a genetic male fetus can cause ambiguous genitalia, while exposure to male hormones during development results in ambiguous genitalia in a genetic female. Mutations in certain genes can influence fetal sex development and cause ambiguous genitalia. Chromosomal abnormalities, such as a missing sex chromosome or an extra one, also can cause ambiguous genitalia. In some cases, the conditions may seem to happen by chance. Possible causes in genetic females Causes of ambiguous genitalia in a genetic female may include:

Congenital adrenal hyperplasia. Certain forms of this genetic condition cause the adrenal glands to make excess male hormones (androgens). Prenatal exposure to male hormones. Certain drugs that contain male hormones or that stimulate production of the male hormones in a pregnant woman can cause developing female genitals to become more masculine. Examples include progesterone, which is a medication sometimes taken in the early stages of pregnancy,

and anabolic steroids. A developing baby may also be exposed to excess male hormones if the mother has a disease or condition that causes hormone imbalance. Tumors. Rarely, a tumor in the mother can produce male hormones.

Possible causes in genetic males Causes of ambiguous genitalia in a genetic male may include:

Impaired testicle development. This may be due to genetic abnormalities or unknown causes. Congenital adrenal hyperplasia. Certain forms of this genetic condition can impair production of male hormones. Androgen insensitivity syndrome. In this condition, developing genital tissues don't respond normally to male hormones. Abnormalities with testes or testosterone. Various abnormalities can interfere with the testes' activity. This may include structural problems with the testes, problems with production of the male hormone testosterone or problems with cellular receptors that respond to testosterone. 5a-reductase deficiency. This enzyme defect impairs normal male hormone production.

Tests and diagnosis

By Mayo Clinic staff Ambiguous genitalia is usually diagnosed at birth or shortly after. Doctors and nurses who help with your delivery may notice the signs of ambiguous genitalia in your newborn. Determining the cause of ambiguous genitalia If your baby is born with ambiguous genitalia, the doctors will work to determine the underlying cause of the disorder. The cause helps guide treatment and decisions about the baby's gender. Your doctor will likely begin by asking questions about your family and medical history and will do a physical exam to check for testes and evaluate the infant's genitalia. Your medical team will likely recommend the following tests and procedures:

Blood tests to measure hormone levels Blood tests to analyze chromosomes and determine the genetic sex (XX or XY) Ultrasound of the pelvis and abdomen to check for undescended testes, uterus and vagina X-ray studies using a contrast dye to help clarify anatomy In certain cases, minimally invasive surgery may be necessary to collect a tissue sample of your newborn's reproductive organs

Determining the gender Using the information gathered from these tests, your doctor may suggest an appropriate gender for the baby. The suggestion will be based on the genetic sex, anatomy, and future reproductive and sexual potential. Usually, a family can make a decision within a few days

after the birth. Parents should be aware that as the child grows up, he or she may make a different decision about gender identification.

Sumber: http://www.pediatricsurgerymd.org/AM/Template.cfm?Section=List_Of_Conditions&TEMPLATE=/C M/ContentDisplay.cfm&ContentID=1313

Ambiguous Genitalia
Ambiguous genitalia refers to a condition of the genitals in which there is a question about whether the sex of the child is male or female. Proper male or female assignment to a newborn with ambiguous genitalia should be expeditious and timely, but it is crucial that it be proper and accurate. Proper gender assignment should entail an approach that includes, but is not limited to, input from pediatric endocrinology, surgery, urology, psychiatry, and radiology consultants and the parents. When an appropriate sex assignment has been made, it is possible to proceed with an operation procedure in a timely fashion, if one is required. EMBRYOLOGY Normal sexual development during gestation requires a coordination among the following factors: the correct chromosome number and type, proper movement of germ cells to form the ovaries and testes, appropriate hormone production by the ovary or testes, and proper response by the tissues that develop from the secreted hormones. A problem in any one of these steps can result in the development of a child with ambiguous genitalia (those genitalia that appear to be a cross between male and female). Humans normally have 46 chromosomes and have two sex chromosomes. Boys have an X and a Y chromosome and girls have two X chromosomes and no Y chromosome. During development all humans have what is called a gonad that can develop into either a testis and thus a male or into an ovary and thus a female. The developmental path depends on whether a Y chromosome is present or not. In the absence of the Y chromosome the path of development is automatically directed torward a girl. The presence of the Y chromosome changes the path of development towards a boy. The Y chromosome of the male leads to formation of a testis, and the SRY antigens (sex-determining region of the Y chromosome) is what initiates this change of the primitive gonad into a testis. Although the SRY antigens can be found on all male cells, the only cells that have receptors for SRY antigens are those that eventually form the testis. SRY antigens binding to these tissues are responsible for the change into a testis. Once the testes are formed they begin to produce m u llerian inhibitory substance, which causes M u llerian ducts (the ducts that from the tubes and uterus in a female) to disappear. The testicle then starts to produce testosterone. Testosterone stimulates the development of the wolffian duct system which forms the structures of the male such as the vas deferens, seminal vesicles, and epididymis. In addition, testosterone is transformed to dihydrotestosterone which is responsible for the development of the external genitalia (penis and scrotum) in the male.

In the absence of the Y chromosome and the SRY antigens, the primitive gonad develops into an ovary. Female development of the M u llerian duct system (the uterus and upper part of the vagina) and external genitalia (vagina, clitoris, and vulva) thus occurs. The normal female is not exposed to M u llerian inhibitory substance so that the M u llerian ducts do not disappear and instead go on to form the fallopian tubes, uterus, cervix, and upper portion of the vagina. Simultaneously, in the absence of testosterone, the male wolffian ducts disappear. The clitoris, labia minora, labia majora, and lower vagina develop when testosterone and dihydrotestosterone are not present. DIAGNOSTIC EVALUATION There are four types of ambiguous genitalia: female pseudohermaphroditism, male pseudohermaphroditism, true hermaphroditism, and gonadal dysgenesis.

Initial evaluation of the newborn with ambiguous genitalia. During the initial evaluation of an infant with ambiguous genitalia, it is often possible to differentiate these four entities accurately by noting the symmetry of the gonads: Are one or both gonads in or absent from the scrotum? Preliminary analysis of the chromosomes is performed. This generally permits appropriate gender assignment by determining whether a child carries an XX chromosome (girl) or an XY chromosome (boy). If the gonads are different on opposite sides (asymmetric) in a karyotypic female (XX) this frequently indicates a true hermaphrodite. The child has both a testis and an ovary. If a boy has asymmetric gonads, ie. both an ovary and a testis, this usually indicates the presence of a condition called mixed gonadal dysgenesis. It should be determined initially if other family members have a history of ambiguous genitalia, whether female relatives died in infancy suggestive of a disease called congenital adrenal hyperplasia, or whether there is infertility in the family. A detailed evaluation of drug ingestion during pregnancy is important, especially for androgenic agents such as pro-gesterone. Urinary mineralocorticoid and glucocorticoid steroid measurements and serum electrolyte (blood chemicals) levels should be obtained since some of the ambiguous genitalia problems may lead to steroid and electrolyte problems. Pelvic ultrasound, endoscopy (using a scope to look inside the body), and contrast genitography (a type of X-ray study where dye is injected into a possible vagina if one is present) are performed to clarify the status of the internal genital structures and to show the vaginal entrance. Occasionally, laparoscopy is required for sex identification, particularly with true hermaphrodites. Laparoscopy allows the doctor to look inside the body and directly see whether there are ovaries present.

Figure. 79-3 Retrograde genitogram in a patient with congenital adrenal hyperplasia. This procedure is performed with a catheter (plastic tube) inserted just inside the perineal opening (the opening between the legs) with the balloon inflated. Note that the vagina (V) joins the urethra very close to the perineum and far away from the bladder (B). In general, most infants with ambiguous genitalia are best reconstructed as females because of the practicality of surgical reconstruction based on the size of the phallus. Although there is a great deal of discussion of the subject, it is likely that regardless of genotype (chromosome number, XX or XY), if an inadequate phallus cannot be corrected surgically, the patient will fare better in the female gender role. The matter of testosterone imprinting on the brain requires careful consideration and more research than is available at present. Genetic males with severe penoscrotal hypospadias (a type of condition where the opening to the penis is not in the correct anatomic location) and bilateral undescended testes (the testes are not in the scrotum but may be in the abdomen) frequently may be reconstructed successfully, however, so they usually are reared as males. SPECIFIC DISORDERS Female Pseudohermaphroditism (Adrenogenital Syndrome) Infants with congenital adrenal hyperplasia have 46 chromosomes with two X sex chromosomes , so they should be girls. However, they are missing one of three enzymes which serve to process normal steroids into the sex hormones. If one of the enzymes is missing, too much of the steroids will become testosterone. As a result, the external genitalia will be masculinized: they will look more like a male. The common enzymes that are missing are 21-hydroxylase, 11-hydroxylase, and 3-hydroxysteroid dehydrogenase. How masculine they will look is variable. There may be mild clitoral enlargement alone at one extreme and complete masculinization with a normal-appearing but small penis with the urethra at the end of the penis. The vagina may enter into the urethra way up inside instead of coming out onto the perineum between the legs. This common tube of the vagina and the urethra is called a urogenital sinus. During normal development the genital, urinary and intestinal structures empty into a common cavity and then split apart into separate structures. All three structures emptying into a common cavity is called a cloaca. If only the urinary and genital structures

share a common opening, it is called a urogenital sinus. Normally this structure would have gone on to form the normal openings for the urinary tract and the vagina. All of these children are reared as females and should have normal fertility because they have normal internal genitalia (ovaries, vagina and uterus). Surgical treatment is designed to correct the appearance of and functional deformities of the external genitalia, primarily the enlargement of the clitoris and the malformation of the vaginal entrance. In the usual form of this malformation, surgery is usually performed at 3 to 6 months of age. In infants with the very masculinized form of congenital adrenal hyperplasia in which the vagina inserts up high into the urethra, surgery is delayed until at least 2 years of age so that a pull-through of the vagina to the perineum can be performed safely. This may be corrected at an earlier age with what is called a posterior sagittal approach or a total urogenital sinus mobilization technique. One of the additional problems with the adrenogenital syndrome which can cause them to be sick as newborns is that some of the steroids that control the chemicals in the blood (electrolytes) and blood pressure may be low. The two types of steroids, that are problematic are called mineralocorticoids and glucocorticoids. Each of these types does different things. Patients with a low glucocorticoid steroids require cortisol replacement (a type of steroid). Additionally, patients with mineralocorticoid deficiency require fludrocortisone acetate replacement. Mixed Gonadal Dysgenesis The syndrome of mixed gonadal dysgenesis is associated with dysgenetic (abnormal) gonads and persistent Mullerian structures. Most commonly, there is a streak gonad like an ovary on one side with Mullerian structures (uterus, tube, vagina) and a testis on the opposite side with a vas and epididymis. In general, these individuals have mixed chromosomes: 45 chromosomes with only one X chromosome in some cells and 46 chromosomes with XY sex chromosomes in others. Half of these individuals eventually develop malignancy in their gonads. Gonadoblastoma is the most common malignancy overall, but seminoma and dysgerminoma may occur in the streak gonad. For this reason, removal of the streak gonad is recommended in all patients with mixed gonadal dysgenesis early in childhood. Surgical reconstruction is similar to that for congenital adrenal hyperplasia. Those with adequate male genitalia may be raised as males with careful surveillance of the scrotally placed testis. Male Pseudohermaphroditism Male pseudohermaphroditism occurs in infants with 48 chromosomes and XY sex chromosomes, but deficient masculinization of their external genitalia. This disorder used to be called testicular feminization syndrome, but it is best referred to as androgen insensitivity syndrome, which is more descriptive of the problem. This condition can result from inadequate testosterone production, inability to convert testosterone to dihydrotestosterone, Mullerian inhibitory factor (MIF) deficiency, and most commonly, inability of the external genitalia to respond to testosterone or dihydrotestosterone. The sex of rearing is dependent on whether the genitalia looks more like a female or male. In many of these children, the diagnosis is made at the time of routine inguinal hernia repair in a child that has female genitalia, but also has gonads that can be felt within the groin. Given the risk of eventual malignant degeneration to gonadoblastoma or seminoma of the intra-abdominal gonads, removal is required. There is some discussion as to whether this is best done at the time of discovery or whether the gonads should be removed at puberty because these gonads can induce breast development. The best answer to this question

probably is based on determination of urinary steroid levels because individuals with high androgen levels probably should have early gonadectomy to prevent masculinization during puberty. The current opinion is that it is probably best to perform gonadectomy (gonad removal) early in these patients. Occasionally a patient does not present until puberty with amenorrhea (never develops menses). Under these circumstances, when the diagnosis is confirmed, bilateral gonadectomy and vaginal reconstruction should be performed if needed. All patients with androgen insensitivity syndrome have a short vagina because the upper two thirds of the vagina are not produced if a Y chromosome is present. Some can be treated with vaginal dilation. However, to produce a functionally adequate vaginal cavity most require vaginal augmentation with the large intestine. Although most of these individuals do not have clitoral enlargement, a few require an operation to make that clitoris smaller. True Hermaphroditism The rarest form of ambiguous genitalia is true hermaphroditism. These patients have normal male and female gonadal tissue with an ovary on one side and a testis on the other or a combination of an ovary and testis on one or both sides. Streak ovaries are common. Of these patients, 80% have 46, XX chromosomes, and others have a mixture of different chromosomes. Most of these children have an inadequate penis and are raised as females. In these patients, the testis and the testicular portion of the ovotestis should be removed, leaving the ovarian tissue in place. The surgical goals of reconstruction are similar to those for children with other forms of ambiguous genitalia. When the phallus is adequate for the male gender role, all ovarian and Mullerian structures are removed. Occasionally, testosterone treatment is needed for these patients. After puberty, a testicular prosthesis may be inserted into the scrotum in individuals to be raised as males. SURGICAL RECONSTRUCTION The timing of surgical reconstruction for patients with ambiguous genitalia represents a balance between the desirability of early reconstruction and the technical limitations imposed by the small size and delicacy of the structures involved. The earlier reconstruction can be performed safely, the better. One of the most common considerations has to do with the enlarged clitoris. Because the clitoris is essential for normal female sexual function, all procedures are designed to preserve all or part of the clitoris with its nerve supply. Surgery ranges from putting the clitoris under the pubic symphysis (pelvic bone) to a procedure in which just the end of the clitoris is preserved with its nerves and blood supply and the middle part is partially or completely removed. The latter procedure may be necessary to allow the clitoris to be placed underneath the symphysis bone in patients with an extremely large clitoris. Experienced evaluation of each individual patient determines the best approach to this problem. Either way, long-term functional evaluations are needed to indicate which is the preferred approach to this problem.

A. Cutback vaginoplasty where the skin which is covering the opening to the vagina is divided along the dashed line. B. Completed cutback vaginoplasty with the vagina opening now seen. The clitoris is being operated upon to push it back up under the pelvic bone so that it does not protrude as much. The figure above describes one approach to fixing the vagina as it is commonly seen in congenital adrenal hyperplasia with minimal to moderate masculinization. When the vagina joins the urethera way up inside, more substantial operations are required. PENILE AGENESIS Penile agenesis is a rare problem in which the urethral opening may lie in front of the rectum on the perineum or be located in front of the scrotum or pubic symphysis. The testes and scrotum are usually normal, although the testes may be undescended. Because penile reconstruction is not feasible, raising the child as a female appears to be the most practical approach. It is best to remove the testes in infancy to reduce androgen imprinting and masculinization, and a vagina should be constructed from the scrotal skin or intestine. Use of the sigmoid colon may be a desirable approach. Estrogen administration should be initiated at 10 to 12 years of age to promote breast development and development of female sex characteristics.

Sumber: http://adc.bmj.com/content/89/5/401.full

Early assessment of ambiguous genitalia

1. A L Ogilvy-Stuart1, 2. C E Brain2

+ Author Affiliations 1. 2.
1 2

Neonatal Unit, Rosie Hospital, Addenbrookes NHS Trust, Cambridge CB2 2SW, UK Dept of Paediatric Endocrinology, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK

1. Correspondence to: Dr A L Ogilvy-Stuart Neonatal Unit, Rosie Hospital, Addenbrookes NHS Trust, Cambridge CB2 2SW, UK; amanda.ogilvy-stuart@addenbrookes.nhs.uk

ambiguous genitalia intersex AMH, anti-Mllerian hormone CAH, congenital adrenal hyperplasia DHEA, dehydroepiandrosterone DHEAS, dehydroepiandrosterone sulphate DHT, dihydrotestosterone EUA, examination under anaesthesia hCG, human chorionic gonadotrophin StAR, steroidogenic acute regulatory protein

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A multidisciplinary problem To discover that there is uncertainty about the sex of ones newborn baby is devastating and often incomprehensible for most parents. It is paramount that clear explanations and investigations are commenced promptly, and that no attempt is made to guess the sex of the baby. Extreme sensitivity is required, and ideally the baby should be managed in a tertiary centre by a multidisciplinary team including a paediatric endocrinologist and a paediatric urologist. Early involvement of a clinical psychologist with experience in this field should be mandatory. Other professionals including geneticists and gynaecologists may also become involved. There must be access to specialist laboratory facilities and experienced radiologists. The incidence of genital ambiguity that results in the childs sex being uncertain is 1 per 4500,1 although some degree of male undervirilisation, or female virilisation may be present in as many as 2% of live births.2 Parents require reassurance that either a male or female gender will definitely be assigned. However the outcome of some of the investigations may take some weeks, and registration of the childs birth should be deferred until gender has been assigned. This may require communication with the Registrar of Births, and a skilled clinical psychologist will help the parents in deciding what to tell family and friends in the interim. It is also helpful (if appropriate) to reassure the parents that their child is otherwise healthy. While not all intersex conditions are apparent at birth (for example, complete androgen insensitivity may only become apparent in a child with a testis within an inguinal hernia, or at

puberty with primary amenorrhoea and lack of androgen hair), only those presenting with genital ambiguity at birth will be considered in this article. An understanding of sex determination and differentiation is essential to direct appropriate investigations and to establish a diagnosis. Genetic sex is determined from the moment of conception and determines the differentiation of the gonad. The differentiation of the gonad in turn determines the development of both the internal genital tracts and the external genitalia and thus phenotypic sex, which occurs later in development (from about 56 weeks of gestation). Both male and female genitalia differentiate from the same structures along the urogenital ridge. At about 4 weeks after fertilisation, primordial germ cells migrate from the yolk sac wall to the urogenital ridge that develops from the mesonephros. The urogenital ridge also contains the cells that are the precursors for follicular or Sertoli cells and steroid producing theca and Leydig cells. The indifferent gonads form on the genital ridges. The development of the fetal adrenals and gonads occur in parallel, as before migration, the potential steroidogenic cells of both originate from the mesonephros. There are many genes and transcription factors that are expressed in both tissues (for example, SF1 and DAX1), and hence mutations in these genes may affect both adrenal and gonadal development (fig 1). In addition, WT1 is expressed in the kidney and gonad, hence the association of Wilms tumour and gonadal dysgenesis in Denys-Drash syndrome, for example.

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Figure 1

Normal sexual differentiation. SRY, sex determining region on Y chromosome; TDF, testis determining factor; AMH, anti-Mllerian hormone; T, testosterone; DHT, dihydrotestosterone; WT1, Wilms tumour suppressor gene; SF1, steroidogenic factor 1; SOX9, SRY-like HMG-box; Wnt4, Wnt=a group of secreted signalling molecules that regulate cell to cell interactions during embryogenesis; DAX1, DSS-AHC critical region on the X chromosome. The undifferentiated gonad is capable of developing into either an ovary or a testis. The theory that the default programme generates an ovary is probably not correct, although the exact role of ovarian determining genes in humans is unclear at present. In contrast, testicular development is an active process, requiring expression of the primary testis determining gene SRY, and other testis forming genes such as SOX9. Transcription factors such as SF1 and WT1 are also required for development of the undifferentiated gonad, as well as for the activation of the other male pathway genes required for testis development and the consequent development of male internal and external genitalia.3 DAX1 and Wnt 4 are two genes that may act to antagonise testis development. Overexpression of DAX1 (through duplication of Xp21) and Wnt4 (through duplication of 1p35), have been associated with impaired gonadal development and undervirilisation in a small number of karyotypic 46 XY males. Mutations or duplications in the various genes responsible for gonadal differentiation and the subsequent development of the internal and external genital phenotype genes may be responsible for gonadal dysgenesis and in some cases complete sex reversal (table 1).
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Table 1

Consequences of mutations/deletions and duplications/translocations of genes involved in gonadal differentiation Wnt4 is also expressed in the Mllerian ducts and in the absence of anti-Mllerian hormone (AMH) (also known as Mllerian inhibiting substance) and testosterone, Mllerian structures develop, while the Wolffian ducts involute.4 AMH promotes regression of Mllerian structures and as the only source of AMH in the fetus is the testes, the absence of a uterus in a baby with ambiguous genitalia is evidence that there has been functional testicular tissue (Sertoli cell) present. Testosterone produced from Leydig cells promotes differentiation of the Wolffian ducts and hence the internal male genitalia (vas deferens, epididymis, and seminal vesicles).

Testosterone is converted to dihydrotestosterone [DHT] by the enzyme 5-reductase. DHT masculinises the external genitalia from about 6 weeks gestation, and the degree of masculinisation is determined by the amount of fetal androgen present (irrespective of source) and the ability of the tissues to respond to the androgens. Defects in any part of this pathway (including gene mutations and chromosomal abnormalities (for example, 46XY/46XX, 45X/46XY), inappropriate hormone levels, or endorgan unresponsiveness) may result in genital ambiguity, with undervirilisation of an XY individual, virilisation of an XX individual, or the very rare true hermaphrodite (an individual with both ovarian tissue with primary follicles and testicular tissue with seminiferous tubules which may be in separate gonads or ovotestes).
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CLINICAL ASSESSMENT OF AMBIGUOUS GENITALIA

History

The history should include details of the pregnancy, in particular the use of any drugs (table 2) that may cause virilisation of a female fetus and details of any previous neonatal deaths (which might point to an undiagnosed adrenal crisis). A history of maternal virilisation may suggest a maternal androgen secreting tumour or aromatase deficiency. A detailed family history should be taken, including whether the parents are consanguineous (which would increase the probability of an autosomal recessive condition) or if there is a history of genital ambiguity in other family members (for example, an X-linked recessive condition such as androgen insensitivity).
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Table 2

Disorders of sex differentiation

Examination

The general physical examination should determine whether there are any dysmorphic features and the general health of the baby. A number of syndromes are associated with ambiguous genitalia, for example, Smith-Lemli-Opitz syndrome (characterised by hypocholesterolaemia and elevated 7-dehydrocholesterol levels, and resulting from mutations affecting 7-dehydrocholesterol reductase), Robinow syndrome, Denys-Drash syndrome, and Beckwith-Wiedemann syndrome. Mid-line defects may point towards a hypothalamicpituitary cause for micropenis and cryptorchidism. Hypoglycaemia may indicate cortisol deficiency secondary to hypothalamic-pituitary or adrenocortical insufficiency. The state of hydration and blood pressure should be assessed as various forms of congenital adrenal hyperplasia (CAH) can be associated with differing degrees of salt loss, varying degrees of virilisation in girls or undervirilisation in boys, or hypertension (table 3). Although the cardiovascular collapse with salt loss and hyperkalaemia in congenital adrenal hyperplasia

does not usually occur until between the 4th to 15th day of life and so will not be apparent at birth in a well neonate, it should be anticipated until CAH has been excluded. Jaundice (both conjugated and unconjugated) may be caused by concomitant thyroid hormone or cortisol deficiency. The urine should be checked for protein as a screen for any associated renal anomaly (for example, Denys-Drash/Frasier syndromes).
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Table 3

Forms of CAH causing genital ambiguity in the newborn

Examination of external genitalia and Prader staging

Examination of the external genitalia determines whether gonads are palpable and the degree of virilisation or Prader stage. Prader stages IV describe increasing virilisation from a phenotypic female with mild cliteromegaly (stage I) to a phenotypic male with glandular hypospadias (stage V) (fig 2).

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Figure 2

Differential virilisation of the external genitalia using the staging system of Prader, from normal female (left) to normal male (right). Sagittal (upper panel) and perineal (lower panel) views shown. If both gonads are palpable they are likely to be testes (or ovotestes) which may be normal or dysgenetic. Flat finger palpation from the internal ring milking down into the labial scrotal folds may detect the presence of a gonad. They may be situated high in the inguinal canal so careful examination is required. A unilateral palpable gonad may be a testis, ovotestis, or rarely an ovary within an inguinal hernia. Congenital adrenal hyperplasia must be excluded in a phenotypically male baby with bilateral undescended testes.

The length of the phallus should be determined. The normal term newborn penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.02.5 cm, although this does vary slightly depending on ethnic origin.5 Chordee should be noted as this may decrease the apparent length of the phallus and the penis may be buried in some cases. The presence of hypospadias and the position of the urethral meatus should be determined. The urine may be coming from more than one orifice. The degree of fusion and rugosity of the labioscrotal folds should be noted and the presence or absence of a separate vaginal opening determined. Hyperpigmentation, especially of the genital skin and nipples occurs in the presence of excessive ACTH and pro-opiomelanocortin and may be apparent in babies with CAH. The gestation of the baby can cause confusionin preterm girls the clitoris and labia minora are relatively prominent and in boys, the testes are usually undescended until about 34 weeks gestation.
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INVESTIGATIONS
Initial investigations ascertain whether the child is an undervirilised male or a virilised female and from these a differential diagnosis can be established and subsequent investigations planned (fig 3). The principal aims of the initial investigations are to determine the most appropriate sex of rearing and in a genetic female, to exclude CAH and avert a salt losing crisis. Rarer forms of CAH (steroidogenic acute regulatory protein (StAR) deficiency, 3 hydroxysteroid dehydrogenase deficiency) may also present with an adrenal crisis in undervirilised males.

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Figure 3

Investigation flow plan for assessment of ambiguous genitalia.

Karyotype

As the differential diagnosis and a number of subsequent investigations will depend on the genetic sex, an urgent karyotype should be sent. Rapid FISH studies using probes specific for the X (DX1) and Y (SRY) chromosomes can provide useful information, although a full karyotype is required for confirmation and exclusion of mosaicism. The latter may be tissue specific and may not be apparent from blood, but only from skin or gonadal biopsies. In cases with a mosaic karyotype, for example, XO/XY or XX/XY, the gonads are often different. This may involve one being a streak gonad and the other a testis or ovotestis, or two ovotestes with different ovarian and testicular components.
Determination of internal anatomy

As with the external genitalia, the degree of virilisation of the internal genital tracts is defined by Prader stages IV (fig 2). The anatomy of the vagina or a urogenital sinus and uterus may be determined by ultrasound, and if necessary, further delineation by EUA/cystoscopy or urogenital sinogram. Ultrasound is also useful in excluding associated renal anomalies, particularly if Denys-Drash syndrome is suspected or proven. It may also be used to visualise the adrenal glands. Ultrasound may also locate inguinal gonads, although it is not sensitive for intra-abdominal gonads. Ultrasound sensitivity and accuracy depend on probe resolution; an experienced ultrasonographer is required. Identification of the gonads may require magnetic resonance imaging (MRI) or laparoscopy. These latter investigations are also useful for determining the anatomy of the internal genitalia, and gonadal and genital skin biopsies can be performed at the time of laparoscopy.
Testosterone response to human chorionic gonadotrophin (hCG)

To determine whether functioning Leydig cells are present (that is, capable of producing testosterone in response to LH), an hCG stimulation test is undertaken. This is also used to delineate a block in testosterone biosynthesis from androstenedione (17-hydroxysteroid dehydrogenase deficiency) or conversion of testosterone to DHT (5-reductase deficiency). There are a variety of protocols for the hCG test, but essentially it involves taking baseline samples for testosterone and its precursors dehydroepiandrosterone (DHEA) (or DHEA sulphate (DHEAS)) and androstenedione and its metabolite (DHT). One to three intramuscular injections of high dose hCG (5001500 IU) are given at 24 hour intervals and repeat androgen samples are taken at 72 hours or 24 hours after the last injection. The neonatal gonad is more active than at any time in childhood until puberty, reaching a peak at about a 68 weeks of age. A balance needs to be reached between performing the hCG test when the gonad is normally most active (testosterone secretion normally rises in the fourth week of life, peaking at 13 months68) and proceeding with the investigations as promptly as possible. While some would advocate that this test is deferred beyond 2 weeks of age, this may not be necessary. In the newborn period an increase in testosterone, reaching adult male levels, would normally be expected after hCG.

The hCG test can be extended to a three week test if the three day hCG test is inconclusive. The same dose of hCG is administered twice weekly for three weeks and testosterone, DHT, and androstenedione samples taken 24 hours after the last hCG injection. The clinical response in terms of testicular descent and change in the size of the phallus and frequency of erections should be documented. Photographs pre- and post-hCG, may be helpful.
Anti-Mllerian hormone (AMH) and inhibin B levels

While hCG stimulation tests the function of the Leydig cells, both AMH and inhibin B are secreted by the Sertoli cells. Inhibin B is detectable for the first six months, rising again at puberty. AMH levels are high in human male serum postnatally for several years before declining during the peripubertal period, but AMH is undetectable in female serum until the onset of puberty. AMH may prove to be a more sensitive marker for the presence of testicular tissue than serum testosterone levels, both before and after the neonatal androgen surge, and, consequently, may obviate the need for hCG stimulation in the evaluation of certain intersex disorders.9 Similarly, basal inhibin B has been shown to predict the testosterone response to hCG in boys, and therefore may give reliable information about both the presence and function of the testes. Furthermore, inhibin B levels have been shown to demonstrate specific alterations in patients with genital ambiguity which may aid the differential diagnosis of male undervirilisation.10 However, these assays are not routinely available in the UK.
Assessment of gonadotrophins

Assessment of the gonadotrophins may give useful information. Raised basal gonadotrophins are consistent with primary gonadal failure. The gonadotrophin response to GnRH is difficult to interpret in the prepubertal child unless exaggerated, which is consistent with gonadal failure but adds little to the basal levels alone. Pituitary failure would give a flat response but is not diagnostic, and hypothalamic abnormalities such as Kallmanns syndrome are not excluded by a normal response The optimal time to assess this is within the first six months of life when there is a gonadal surge in both sexes (girls greater than boys), and the axis is hence maximally responsive.
Assessment of adrenal function Urine steroid profile

Output of adrenal steroids will be low in adrenal insufficiency. In CAH specific ratios of metabolites will be altered, depending on the level of the enzyme block.
Synacthen test

A standard short Synacthen test is useful in the following situations:

Suspected CAH where a peak 17-hydroxyprogesterone (17-OHP) of 100200 nmol/l is suggestive of 21-hydroxylase deficiency. (Higher reference ranges for preterm infants.) Suspected CAH to assess adrenal cortical reserve (measurement of cortisol levels).

The dose of Synacthen is dependent on local protocol (example 36 g/kg or a standard dose of 62.5 g intravenously or intramuscularly). Cortisol and 17-OHP levels are normally

measured at 0 and 30 minutes only as the 60 minute value does not usually contribute further. A normal basal value, or even a normal stimulated response does not exclude the evolution of adrenal insufficiency, and may need to be repeated depending on clinical suspicion. A basal ACTH level may be helpful, but in most laboratories the turnaround time is slower than for cortisol.
Skin and gonadal biopsies

Genital skin biopsies (24 mm) performed at the time of examination under anaesthesia (EUA) or genitoplasty are useful to establish cell lines for androgen receptor binding assays and analysis of 5-reductase activity. The cell line is also a source of genomic DNA and RNA and/or subsequent molecular and functional studies. Karyotype analysis for the presence of mosaicism may be indicated. Gonadal biopsies are essential when considering diagnostic categories such as dysgenesis and true hermaphroditism. A detailed histopathological report is essential. As special treatment of the samples may be required, prior discussion with the pathologist or genetics laboratory should take place.
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INTERPRETATION OF RESULTS
Genital ambiguity with a 46XX karyotype indicates a virilised female

The female fetus with ovaries and normal internal genitalia has been exposed to excessive testosterone, and hence dihydrotestosterone (by conversion of testosterone by 5-reductase) which virilises the external genitalia. The androgens may be derived from the fetal adrenal gland (CAH and placental aromatase deficiency), fetal gonad (the testis or ovotestis in true hermaphroditism), or rarely, exogenously via transplacental passage from the mother (adrenal or ovarian tumours). Absence of palpable gonads in association with otherwise apparently male genitalia should always alert one to the possibility of a virilised female. By far the commonest cause of this is CAH. Of the enzyme defects that cause virilisation in female fetuses, 21-hydroxylase deficiency is the most frequent (accounting for 9095%, UK incidence 1/1520 000). Diagnosis is made on a raised serum 17-hydroxyprogesterone level. This level may be increased in the first 48 hours in normal babies, and may be significantly increased in sick and preterm babies in the absence of CAH. The other enzyme defects that can cause virilisation of female fetuses are 11-hydroxylase deficiency (where the 11-deoxycortisol levels will be increased) and less commonly 3-hydroxysteroid dehydrogenase deficiency (diagnosed by raised 17-hydroxypregnenolone and dehydroepiandrosterone) (table 3). If CAH is confirmed, the electrolytes need to be watched closely as salt wasting occurs in 70% of cases of 21-hydroxylase deficiency, usually between days 4 and 15. Mineralocorticoid deficiency induces a rise in serum potassium levels (usually the first sign of salt wasting) and sodium levels fall. Urinary sodium levels will be inappropriately high. Further confirmatory tests for CAH are DHEA, androstenedione, testosterone, ACTH, and plasma renin activity, all of which may be increased. From day 3 of life, the ratio of urinary steroid metabolites will be altered depending on the site of the block, and is very helpful in the diagnosis of 21-OHD and the rarer forms of CAH. A skilled ultrasound examination will show normal internal genitalia, but an EUA may be required to confirm the presence of

normal Mllerian structures, and to show the level of entry of the vagina into the urogenital sinus, in the case of a single perineal opening. The excessive androgen may be gonadal in originusually from an ovotestis or testis in a true hermaphrodite. While the commonest karyotype of the true hermaphrodite is 46XX (70.6%), the next commonest karyotype is a chromosomal mosaicism containing a Y chromosome (usually 46XX/46XY) (20.2%).11 It is important to check fibroblast and/or gonadal genotype in these babies, which may contain a mosaic cell line. Transplacental transfer of androgen may rarely occur if the mother has an androgen secreting tumour (she may be virilised as a result) or from drugs given during pregnancy. Placental aromatase deficiency, by inhibiting the conversion of androgens to oestrogens, may cause virilisation of a female fetus, and in addition, maternal virilisation occurs from placental transfer of the excessive fetal androgens.12 Table 2 lists conditions that cause virilisation of a female fetus.
Genital ambiguity with a 46XY karyotype indicates an undervirilised male

This is a genetically XY male with two testes, but whose genital tract fails to differentiate normally. There are numerous presentations of genital anomaly, from apparently normal female (Prader I) with a palpable gonad through to an apparently normal male with hypospadias (Prader V). The three main diagnostic categories are: testicular dysgenesis/malfunction, a biosynthetic defect, and end-organ unresponsiveness (table 2). If the gonads are palpable, they are likely to be testes (or rarely ovotestes). Investigations are directed at determining the anatomy of the internal genitalia, and establishing whether the testicular tissue is capable of producing androgens. Investigations that may help with the former include pelvic ultrasound, examination under anaesthetic with cystoscopy and laparoscopy. Genital skin biopsy specimens can be taken at the time of endoscopies. Occasionally urogenital sinogram or MRI can be helpful. Laparoscopy/laparotomy and gonadal biopsy may be required.
Testicular dysgenesis/malfunction A 46 XY karyotype, with low basal and hCG stimulated testosterone and low testosterone precursors suggests either gonadal dysgenesis (which may require laparoscopy and testicular biopsy) or lipoid CAH (caused by an abnormality in the steroidogenic acute regulatory (StAR) protein)

In the latter condition total adrenal failure is confirmed on Synacthen test, electrolytes, and urinary steroids. Because of the other associated gene defects (table 1), there may be other anomalies such as bony dysplasias or renal anomalies, which should be looked for. The poorly functioning testicular tissue is likely to give a subnormal testosterone response to hCG and basal gonadotrophins will usually be increased, consistent with primary gonadal failure. In addition, the dysgenetic testes may secrete inadequate amounts of anti-Mllerian

hormone, and Mllerian structures may be present (although often hypoplastic) in children with gonadal dysgenesis and a 46XY karyotype. A mosaic karyotype, for example 45X/46XY suggests gonadal dysgenesis. There is a very variable phenotype both in terms of internal and external genitalia, which is not dependent on the percentage of each karyotype as determined by lymphocyte analysis. Over 90% of individuals with prenatally diagnosed 45X/46XY karyotype have a normal male phenotype, suggesting most individuals with this karyotype escape detection and that an ascertainment bias exists towards those with clinically evident abnormalities.13,14
Biosynthetic defect A 46XY karyotype, low basal and peak testosterone level on hCG testing, often with increased gonadotrophins suggests a diagnosis of an inactivating mutation of the LH receptor (Leydig cell hypoplasia)

This condition is associated with a variable phenotype from a completely phenotypic female to undervirilisation of varying degrees.15
A 46XY karyotype with normal or increased basal and peak testosterone on hCG test, and an increased T:DHT ratio is seen in 5-reductase deficiency

DHT dependent virilisation of external genitalia is deficient, resulting in a small phallus and perineal hypospadias. Wolffian structures are normal but spermatogenesis is usually impaired.16 This condition is rare in the UK, but recognised in the Dominican Republic, where individuals are often raised as female and convert to male in puberty, when body habitus and psychosexual orientation becomes male. Virilisation improves but is incomplete. A biochemical diagnosis is made by showing a ratio of T:DHT >30 after puberty or following hCG stimulation before puberty, and the ratio of 5:5 metabolites in a urine steroid profile will be increased after 6 months of age. The urinary 5:5 metabolites can also be used if the gonads have been removed. The diagnosis is confirmed by screening for mutations in the 5reductase type II gene (5RD5A2).
A 46XY karyotype, low basal and hCG stimulated testosterone levels with increased testosterone precursors indicates a testosterone biosynthetic defect

Those forms of CAH that cause undervirilisation of male genitalia include 17hydroxylase/17,20-lyase deficiency and 3-hydroxysteroid dehydrogenase deficiency (table 3). The conversion of androstenedione to testosterone occurs predominantly in the gonad and a post-hCG stimulated ratio of androstenedione to testosterone of >20:1 suggests 17hydroxysteroid dehydrogenase deficiency. A urine steroid profile is generally not helpful in this diagnosis before puberty. Molecular analysis of the HSD III gene (HSD17B3) is sought as confirmation of the diagnosis.

End-organ unresponsiveness A 46XY karyotype with genital ambiguity, normal or increased basal and peak testosterone on hCG test, and a normal T:DHT ratio points to partial androgen insensitivity

There is a variable phenotype, and sex of rearing depends on the degree of phallic development, and sometimes cultural considerations. The child may benefit from a trial of topical DHT cream or intramuscular testosterone (for example using 12.525 mg, monthly for three months) on penile growth to help anticipate response in puberty. The diagnosis is suggested by showing an abnormality in androgen binding in genital skin fibroblasts, or a mutation in the androgen receptor gene. This requires DNA and a genital skin biopsy, taken at the time of EUA or genital surgery. Despite clear evidence of a phenotype consistent with partial androgen PAIS and normal production and metabolism of androgens, only a minority of patients are found to have an androgen receptor gene mutation. The likelihood of finding a mutation is increased if there is a family history consistent with X linkage. The majority of XY infants with undervirilisation remain unexplained.
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DNA ANALYSIS
Many of the causes of genital ambiguity have a genetic basis, and in these cases genetic counselling will be required. For example, androgen insensitivity syndrome is X-linked recessive, and CAH is autosomal recessive. In addition, identification and characterisation of a number of mutations of the genes involved in sexual differentiation has resulted in DNA tests which can be used in prenatal diagnosis. Identification of carriers will facilitate genetic counselling.
Congenital adrenal hyperplasia

Several laboratories within the UK will undertake DNA analysis for this condition. Once the diagnosis has been made, a DNA sample from the proband should be taken. If a gene mutation is identified, the carrier status of the parents may be determined and the family should be counselled about the possibility of antenatal screening of subsequent pregnancies, and of steroid treatment of the mother in an attempt to reduce virilisation of a subsequent affected female fetus. In the UK, antenatal diagnosis and treatment is offered as part of a national British Society for Paediatric Endocrinology and Diabetes supported study monitoring efficacy, short and long term side effects, and outcome measures.
Androgen insensitivity

DNA analysis is now being undertaken in Cambridge as part of a molecular genetics service in collaboration with Professor Ieuan Hughes. Samples are only analysed following collection of clinical, biochemical, and histological data that are consistent with an androgen insensitive pathophysiology.

Suspected 5-reductase deficiency and 17-hydroxysteroid dehydrogenase deficiency

DNA samples in patients with suspected 5-reductase deficiency and 17-hydroxysteroid dehydrogenase deficiency can also be processed through the Cambridge laboratory.
Unusual cases of sexual ambiguity

Mutations of developmental genes such as DAX1, SOX9, and WT1 may account for rarer cases of sexual ambiguity. Samples should be taken and DNA extracted and either stored or forwarded to the relevant laboratories, depending on clinical suspicion.
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ASSIGNMENT OF SEX OF REARING

A decision about the sex of rearing should be made as soon as is practicable, usually based on the internal and external genital phenotype and the results of the various investigations. Cultural aspects may also be important in cases of severe ambiguity. Assignment of sex of rearing can be extremely difficult, particularly as there is a paucity of data on long term outcome in this area. In the case of a virilised female (usually CAH), there is usually the potential for fertility and these babies are usually raised as girls. This is much easier if the diagnosis of CAH is made early. Decisions about nature and timing of any surgery are made with the family acknowledging the considerable psychological impact of having a child with genital ambiguity. There is considerable debate as to the optimal timing of any genital surgery.17 In the presence of marked clitoromegaly, clitoral reduction is usually undertaken in infancy. Lesser degrees of clitoral enlargement may be left until puberty when the child can be involved with the decision making. The timing of any vaginoplasty is dependent on the anatomy of the internal and external genitalia and influenced by local practice. However, there has been a move away from early vaginoplasty in all infants. It may be appropriate to delay surgery until puberty when a single stage reconstruction can be undertaken. Recent outcome data on clitoral sensation18 and success of early vaginoplasty19,20 in adult women who underwent genital surgery in infancy and childhood has induced a more cautious surgical approach.21,22 The appropriate sex of rearing of a very undervirilised male requires as much information as possible, from the investigations discussed, as well as thorough, multidisciplinary discussions involving the parents, urologist, endocrinologist, geneticist, and a clinical psychologist. It may be appropriate to defer gender assignment until the results of relevant investigations are reviewed and the effects of exogenous androgens have been assessed. The birth registration should be delayed for as long as it takes for the final decision to be made.
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CONCLUSIONS
Genital ambiguity resulting in uncertainty of sex at birth is uncommon. The most frequent cause in a genetic female is CAH, which may be life threatening if there is a risk of a salt

losing crisis. Reaching a diagnosis, particularly in undervirilised males, is currently not always possible, but many may have a partial androgen insensitivity syndrome yet to be defined in molecular terms or milder variants of testicular dysgenesis. Prompt counselling and investigations (with the backup of recognised biochemical and genetic laboratories) is essential. The decision of sex of rearing and the timing of surgery need careful consideration within a multidisciplinary environment with full informed consent of the family.

Sumber: http://www.medhelp.org/medical-information/show/2686/Ambiguous-genitalia

Considerations The genetic sex of a child is determined at conception. The mother's egg cell (ovum) contains an X chromosome, while the father's sperm cell contains either an X or a Y chromosome. These X and Y chromosomes determine the child's genetic sex. Normally, an infant inherits one pair of sex chromosomes -- one X from the mother and one X or one Y from the father. Thus, it is the father who "determines" the genetic sex of the child. A baby who inherits the X chromosome from the father is a genetic female (two X chromosomes). A baby who inherits the Y chromosome from the father is a genetic male (one X and one Y chromosome). The male and female reproductive organs and genitals both arise from the same tissue in the fetus. If the process that causes this fetal tissue to become "male" or "female" is disrupted, ambiguous genitalia can develop. This genitalia makes it difficult to classify the infant as male or female. The extent of the ambiguity varies. In very rare instances, the physical appearance may be fully developed as the opposite of the genetic sex. For example, a genetic male may have developed the appearance of a normal female. Typically, ambiguous genitalia in genetic females (babies with two X chromosomes) has the following features:

An enlarged clitoris that has the appearance of a small penis. The urethral opening (where urine comes out) can be anywhere along, above, or below the surface of the clitoris. The labia may be fused, resembling a scrotum. The infant may be thought to be a male with undescended testicles. Sometimes a lump of tissue is felt within the fused labia, further making it look like a scrotum with testicles.

In a genetic male (one X and one Y chromosome), ambiguous genitalia typically include the following features:

A small penis (less than 2-3 centimeters or 0.8-1.2 inches) that resemble an enlarged clitoris (the clitoris of a newborn female is normally somewhat enlarged at birth). The urethral opening may be anywhere along, above, or below the penis; it can be placed as low as on the peritoneum, further making the infant appear to be female.

There may be a small scrotum with any degree of separation, resembling labia. Undescended testicles commonly accompany ambiguous genitalia.

Ambiguous genitalia is usually not life threatening (see Causes section for exceptions ), but can create social problems for the child and the family. For this reason, a team of experienced specialists, including neonatologists, geneticists, endocrinologists, and psychiatrists or social workers will be involved. Common Causes

Pseudohermaphroditism. The genitalia are of one sex, but some physical characteristics of the other sex are present. True hermaphrodism. A very rare condition in which both ovarian and testicular tissue is present. The child may have parts of both male and female genitalia. Mixed gonadal dysgenesis (MGD). An intersex condition in which there appears some male structures (gonad, testis), as well as a uterus, vagina, and fallopian tubes. Congenital adrenal hyperplasia. This condition has several forms, but the most common form causes the genetic female to appear male. Many states test for this potentially life-threatening condition during newborn screening exams. Chromosomal abnormalities, includingKlinefelter's syndrome (XXY) andTurner's syndrome (XO). Maternal ingestion of certain medications (particularly androgenic steroids) may make a genetic female look more male Lack of production of specific hormones can cause the embryo to develop with a female body type regardless of genetic sex Lack of testosterone cellular receptors. So even if the body makes the hormones needed to develop into a physical male, the body is unable to respond to those hormones, and therefore, a female body-type is the result even if the genetic sex is male.

Home Care Because of the potential social and psychological effects of this condition, the decision to raise the child as male or female should be made early after diagnosis, preferably within the first few days of the infant's life. Call your health care provider if

You are concerned about the appearance of your child's external genitalia. Your baby takes more than 2 weeks to regain his/her birthweight, is vomiting, looks dehydrated (dry inside of mouth, no tears when crying, less than 4 wet diapers per 24 hours, eyes look sunken in), has decreased appetite, has blue spells, or has trouble breathing (these can all be signs of congenital adrenal hyperplasia).

Ambiguous genitalia may be discovered during the first well-baby examination. What to expect at your health care provider's office The doctor will perform a physical examination, which may reveal a genital structure that is not "typical male" or "typical female," but somewhere in between.

The doctor will ask medical history questions to help identify any chromosomal disorders. Questions may include:

Is there any family history of miscarriage? Is there any family history of stillbirth? Is there any family history of early death? Have any family members had infants who died in the first few weeks of life or who had ambiguous genitalia? Is there any family history of any of the disorders that cause ambiguous genitalia? What medications did the mother take before or during pregnancy (especially steroids)? What other symptoms are present?

Genetic testing can determine if the child is a genetic male or female. Often a small sample of cells can be scraped from inside the cheeks (this is called a buccal smear); examination of these cells is often sufficient to determine the genetic sex of the infant. Chromosomal analysis is a more extensive cell study that may be needed in more questionable cases. Endoscopy, abdominal x-ray, abdominal or pelvic ultrasound, and similar tests may be needed to determine the presence or absence of internal genital structures (such as undescended testes). Laboratory tests may help determine the functioning of reproductive structures, including tests for 17-ketosteroids. In some cases, laparoscopy, exploratory laparotomy, or biopsy of the gonads may be necessary to confirm disorders associated with ambiguous genitalia. Depending on the cause, surgery, hormone replacement, or other treatments are used to treat conditions associated with ambiguous genitalia. Sometimes, the ambiguity is such that a choice must be made whether to raise the child as male or female (regardless of the child's chromosomes). This choice can have tremendous social and psychological impact on the child, so counseling is usually recommended. Note: It is often technically easier to treat (and therefore raise) the child as female (it is easier for a surgeon to make female genitalia than it is to make male genitalia), so in some cases this is recommended even if the child is genetically male. However, this is a difficult decision and should be discussed with your family, your doctor, and the surgeon involved.