A 3740-g infant is delivered vaginally after an uncomplicated 38-week gestation.
Health care providers have immediate difficulty in determining whether the
infant is a boy or girl. There appear to be small scrotal sacs that resemble enlarged
labia and no palpable testes, with either a microphallus and hypospadias or an
enlarged clitoris. No vaginal opening is apparent. The remainder of the examination
is normal.
» What is the most likely diagnosis?
» What is the next step in evaluation?
Summary: A full-term newborn has ambiguous genitalia.
Most likely diagnosis: Congenital adrenal hyperplasia (CAH).
Next step in evaluation: Karyotype, serum electrolyte levels, and serum
17-hydroxyprogesterone level.
ANALYSIS
Objectives
- Understand the underlying causes of ambiguous genitalia.
- Describe factors that influence gender assignment in infants with ambiguous
genitalia. - Describe the treatment and follow-up of infants after gender assignment.
- Understand the importance of timely diagnosis and treatment of CAH.
Considerations
This neonate with sexual ambiguity represents a psychosocial emergency. Upon
proper gender assignment for rearing and appropriate medical management, individuals born with ambiguous genitalia should be able to lead well-adjusted lives and
satisfactory sex lives. Making a correct diagnosis as early as possible is critical. Gender assignment in the neonate born with sexual ambiguity should be influenced by
the possibility of achieving unambiguous and sexually useful genital structures. Clear
and comprehensive discussions with the parents, focusing on their understanding,
anxieties, and religious, social, and cultural beliefs, are critical for an appropriate
gender assignment. Once gender is assigned, it should be reinforced by appropriate
surgical, hormonal, and psychological measures.
HERMAPHRODITISM: Discrepancy between gonad morphology and external
genitalia.
INTERSEX STATE: Infant with ambiguous genitalia.
MICROPHALLUS: Penis size below the fifth percentile for age; neonate with a
stretched penile length of less than 2 cm.
VIRILIZATION: Masculinization where infant girls exhibit clitoromegaly, labial
fusion, and labial pigmentation; infant boys usually appear normal.
CLINICAL APPROACH
Evaluation of the infant with ambiguous genitalia must occur rapidly to alleviate
family anxiety. An endocrinologist, clinical geneticist, urologist, and psychiatrist
are essential members of the intersex evaluation team. The goals of the evaluation
are to determine the etiology of the intersex problem, assign gender, and intervene
with surgical or other treatment as soon as possible. Intersex abnormalities include
the following:
Female pseudohermaphroditism: 46,XX karyotype; largest neonatal group
with ambiguous genitalia; predominant etiology is CAH; rarer etiologies include
exposure to maternal androgens or progestins and congenital vaginal absence
with uterine absence or abnormality; degree of masculinization depends on stage
of development at time of androgenic stimulation and potency and duration of
exposure.
Male pseudohermaphroditism: 46,XY karyotype; primary etiology is decreased
androgen binding to target tissues (androgen insensitivity syndrome); other etiologies include testosterone dyssynthesis and 5α-reductase or dihydrotestosterone
deficiency; phenotypically normal females with functioning testicular tissue, variable incomplete virilization of genitalia, and short, pouch-like vaginas; typically
diagnosed at puberty when primary amenorrhea noted; maintain as females and
offer vaginoplasty.
True hermaphroditism: About 70% 46,XX and remainder 46,XY or mosaic;
comprises less than 10% of all intersex cases; bilateral ovotestes or ovary and testis
on opposite sides; testicular tissue determines virilization degree; gender assignment based on genitalia appearance (~75% assigned male gender); contradictory
reproductive structures removed in older patients with assigned gender.
Mixed gonadal dysgenesis: Most 46,XY/45,XO karyotype; testis with Sertoli and
Leydig cells, but no germinal elements, on one side and streak gonad on other;
hypospadias, partial labioscrotal fusion, and undescended testes most common
(incompletely virilized male appearance); usually assigned female gender and
undergo gonadectomy (25% of streak gonads develop malignancy); assign as male
if testis descended.
Assessment
After obtaining a careful history, a family pedigree should be constructed to identify
consanguinity and to document cases of genital ambiguity, infertility, unexpected
pubertal changes, or inguinal hernias. Physical findings could support a genetically
transmitted intersex condition. The history of an unexplained neonatal death may
suggest a family history of CAH. Maternal exposure to endogenous or exogenous
androgens should be investigated.
A thorough physical examination is crucial in determining the diagnosis and
making the most reasonable gender assignment. A critical physical finding is the
presence or absence of a testis in a labioscrotal compartment. Other physical findings include appearance of the labioscrotal folds (hyperpigmentation common in
infants with CAH), phallic size and location of urethral opening, and palpation of
a uterus on bimanual examination. Evidence of failure to thrive (failure to regain
birth weight, progressive weight loss), vomiting, and dehydration in the infant with
ambiguous genitalia may signify CAH. Early consideration of CAH in the infant
with ambiguous genitalia is important, given the disease can be life threatening; timely
diagnosis and intervention (fluid resuscitation, electrolyte repletion, adrenocorticoid
replacement) are paramount to survival.
Karyotype analysis using activated lymphocytes is an important first step in the
laboratory evaluation of infants with ambiguous genitalia. Results with a high degree
of accuracy typically can be available in less than 48 hours. To determine mosaicism, repeat studies on multiple tissues may be necessary. If CAH is suspected,
biochemical markers might include an elevated serum 17-hydroxyprogesterone
level. Plasma testosterone levels alone usually are not helpful. Urinary steroids and
plasma androgens, measured before and after administration of corticotropin (adrenocorticotropic hormone [ACTH]) and human chorionic gonadotropin (hCG),
help to determine whether a block in testosterone synthesis or 5α-reductase deficiency exists.
An ultrasonogram or pelvic magnetic resonance imaging (MRI), urogenital
sinus x-ray after contrast injection, and fiberoptic endoscopy may also aid in the
evaluation. Laparoscopy usually is not necessary in the newborn because primary
emphasis is placed on the external genitalia and the possibilities for adequate sexual
function in assigning gender.
Treatment
The major treatment consideration for infants with ambiguous genitalia is the
possibility of achieving functionally normal external genitalia by surgical and hormonal means, with judicious emphasis on cosmetic appearance. Because the presence of ambiguous external genitalia may reinforce doubt about the sexual identity
of the infant, reconstructive surgery is performed as early as medically and surgically feasible, usually before 6 months of age. Feminizing genitoplasty is the most
common surgical procedure performed in female pseudohermaphrodites, in true
hermaphrodites, and in male pseudohermaphrodites reared as females. The goal
of this surgery is to reduce the size of the clitoris while maintaining vascularity
and innervation, feminizing the labioscrotal folds, and ultimately creating a vagina.
Because of the high incidence of gonadal tumors in individuals with certain forms
of gonadal dysgenesis, gonadectomy performed concurrently with the initial repair
of the external genitalia is mandatory. A male with hypospadias often requires multiple procedures to create a phallic urethra. Circumcision is avoided in these individuals because the foreskin tissue is commonly used for reconstruction.
If steroid production is the underlying etiology of the intersex problem, treatment is provided to prevent further virilization. Administration of hydrocortisone to
individuals with CAH helps to inhibit excessive production of androgens and further
virilization. Hormone substitution therapy in hypogonadal patients is prescribed
so that secondary sexual characteristics develop at the expected time of puberty.
Oral estrogenic hormone substitution is initiated in females, and repository injections of testosterone are given to males. With the exception of some female pseudohermaphrodites and true hermaphrodites reared as females, disorders that cause
ambiguous genitalia usually lead to infertility