Case Files Pediatrics, (LANGE Case Files) 4th Ed.

CASE 31

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.

Image What is the most likely diagnosis?

Image What is the next step in evaluation?

ANSWERS TO CASE 31: Ambiguous Genitalia

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 17αhydroxyprogesterone level.

ANALYSIS

Objectives

1. Understand the underlying causes of ambiguous genitalia.

2. Describe factors that influence gender assignment in infants with ambiguous genitalia.

3. Describe the treatment and follow-up of infants after gender assignment.

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 assignmentin 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.

APPROACH TO:

Child with Ambiguous Genitalia

DEFINITIONS

CONGENITAL ADRENAL HYPERPLASIA (CAH): Autosomal recessive disorder of adrenal steroid production with an enzymatic deficiency (usually 21-hydroxylase) causing inadequate production of cortisol, excessive production of androgenic intermediary metabolites, and virilization.

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/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; etiologies include testosterone dyssynthesis, 5α-reductase/dihydrotestosterone deficiency, and decreased androgen binding to target tissues (androgen insensitivity syndrome most common form of male pseudohermaphroditism); phenotypically normal females with functioning testicular tissue, variable incomplete virilization of genitalia, and short, pouchlike 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 (approximately 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 testes 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 hyperpigmentation of the labioscrotal folds (common in infants with CAH); phallic size and location of urethral opening; palpation of a uterus on bimanual examination; evidence of failure to thrive (failure to regain birth weight, progressive weight loss, vomiting); and dehydration. Phallic size is the most important factor in determining an infant’s sex assignment.

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 can be available in less than 72 hours. To determine mosaicism, repeat studies on multiple tissues may be necessary. If CAH is suspected, biochemical studies might include a serum 17α-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 cosmetically and functionally normal external genitalia by surgical and hormonal means. 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.

COMPREHENSION QUESTIONS

31.1 A 3650-g term infant has ambiguous genitalia, including an enlarged clitoris or microphallus and one palpable testis in the labioscrotal folds. Sonogram reveals a uterus and ovaries. Which of the following is the most likely explanation for the child’s ambiguous genitalia?

A. Aromatase deficiency

B. Congenital adrenal hyperplasia

C. Female pseudohermaphroditism

D. Male pseudohermaphroditism

E. True hermaphroditism

31.2 A mother brings in her 1-week-old son who has vomited four times over the last 24 hours. He has no fever or diarrhea. The infant is breast-feeding poorly and is “floppy” per the mother. He has had only one wet diaper in the last 12 hours. Physical examination reveals a lethargic infant who has lost 250 g since birth, with pulse of 110 bpm, dry oral mucosa, and no skin turgor. Which of the following levels should be checked after stabilization and electrolyte measurement?

A. Serum cortisol

B. Urine cortisol

C. Serum 21-hydroxylase

D. Serum 17α-hydroxyprogesterone

E. Serum testosterone

31.3 A mother brings in her 15-year-old daughter because she has never started her periods. She otherwise is healthy and takes no medications. Her past medical history is unremarkable except for inguinal hernia repair as an infant. Family history is unremarkable. She is at the 75th percentile for height and weight, has Tanner stage IV breast development, and no pubic or axillary hair development. Her anogenital examination reveals a short, pocketlike vaginal opening. Which of the following is the most likely explanation for her amenorrhea?

A. Adrenal tumor

B. Congenital adrenal hyperplasia

C. Pituitary tumor

D. Testicular feminization

E. Turner syndrome

31.4 You examine a full-term 3780-g newborn in the nursery and notice that he has marked hypotonia, a very small penis, and unilateral cryptorchidism. Which of the following is the most likely explanation for these findings?

A. Congenital adrenal hyperplasia

B. Male pseudohermaphroditism

C. Maternal treatment with steroids

D. Mixed gonadal dysgenesis

E. Prader-Willi syndrome

ANSWERS

31.1 E. The gonad in the labioscrotal fold suggests a testis, but a uterus and an ovary on sonography are highly suggestive of a true hermaphrodite. Gender assignment in this case should be based on the possibility of surgical correction of the external genitalia. Assignment of female sex and an attempt to preserve ovarian tissue is appropriate.

31.2 D. Male infants with salt-losing CAH develop clinical symptoms similar to pyloric stenosis, intestinal obstruction, heart disease, cow’s milk intolerance, and other causes of failure to thrive. Their genitalia appear normal. A serum 17α-hydroxyprogesterone level typically is elevated. Without appropriate treatment (hydrocortisone, mineralocorticoid, and sodium supplementation), cardiovascular collapse and death may occur within a few weeks. Many states have neonatal screening programs for CAH, yet infants with salt-losing CAH (21-hydroxylase deficiency) can become very ill and die before the screening results are known.

31.3 D. Testicular feminization results from decreased androgen binding to target tissues or androgen insensitivity. Patients have 46,XY karyotypes, yet appear as phenotypically normal females with a short or atretic vagina. Androgen insensitivity is the most common form of male pseudohermaphroditism. Maintaining female gender assignment is appropriate, and vaginoplasty is frequently needed after puberty.

31.4 E. Although severe hypotonia, failure to thrive, and hypogonadism characterize Prader-Willi syndrome in early life, hyperphagia, obesity, mental retardation, and the appearance of bizarre behavior manifest by the age of 6 years. Morbid obesity, limited sexual function, and severe behavioral abnormalities may occur. Mixed gonadal dysgenesis is a reasonable choice given the unilateral cryptorchidism and hypogonadism, but severe hypotonia usually is not a finding in that disorder.


CLINICAL PEARLS

Image The goal of evaluating a neonate with sexual ambiguity is to determine the etiology of the intersex problem, assign gender, and intervene with surgical or other treatment as soon as possible.

Image Treatment of sexual ambiguity is directed toward achieving cosmetically and functionally normal external genitalia by surgical and hormonal means.

Image Reconstructive surgery for a patient with ambiguous genitalia is performed as early as medically and surgically feasible, usually before the age of 6 months.


REFERENCES

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Diamond DA. Pediatric Urology. In: Wein AJ, Kavassi LR, Novick AC, et al. Campbell’s Urology. 9th ed. Philadelphia, PA: WB Saunders; 2007:3799-3829.

Donohoue PA. Disorders of sex development. In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: WB Saunders; 2011: 1959-1968.

Grumbach MM. Disorders of sexual development (DSD). In: Rudolph CD, Rudolph AM, Lister GE, First R, Gershon AA, eds. Rudolph’s Pediatrics. 22nd ed. New York, NY: McGraw-Hill; 2011:2063-2074.

Laufer MR, Goldstein DP. Pediatric and adolescent gynecology—Part I. In: Ryan KJ, Berkowitz RS, Barbieri RL, Dunaif A, eds. Kistner’s Gynecology and Women’s Health. 7th ed. St. Louis: Mosby; 1999: 233-259.

White PC. Disorders of the adrenal glands. In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: WB Saunders; 2011: 1923-1930.