Differences in Sex Development

Terminology in this area of medicine is controversial and is evolving rapidly. Disorders of sex development or differences in sex development (DSD) are currently accepted diagnostic terms for a discordance between appearance of the external genitalia, gonadal sex (presence of ovaries, testes, or ovotestis), and chromosomal sex.

• DSDs occur in about 1:1000 to 1:4500 infants and range from severe hypospadias in males to complete virilization of female genitalia.

• The term DSD does not include conditions such as isolated undescended testes, isolated hypospadias (unless severe [perineal]), Turner syndrome, or Klinefelter syndrome.

• In the past, infants with DSD were considered an emergency. Increasingly, the trend is for a slower approach to evaluation and management, often with delay of genital surgery until individuals with DSD have a chance to declare preferences regarding gender identity and genitalia.

• Infants with DSD should be cared for by a multidisciplinary team including endocrinology, urology, social work, psychology or psychiatry, and other relevant specialties.

Evaluation of Genital Abnormalities in Infants

Physical Exam

• It is important to be sensitive to the family’s anxiety when performing genital exams in infants with DSD. Use gender-neutral terms (e.g., “your baby” rather than “he” or “she” if there is not a clear gender assignment).

• Look for possible syndromic features, as genital anomalies are a feature of many syndromes (e.g., CHARGE, Prader-Willi, Noonan, trisomy 13, trisomy 18).

• Look for other signs of hypopituitarism or midline defects (e.g., high-arched palate, cleft lip or palate, umbilical hernia).

• Normal penile length in newborn term males is ≥2.5 cm. A smaller penile length is known as micropenis or microphallus.

• The range of virilization from unvirilized to completely virilized is often described by using Prader stages, a scale developed to characterize virilization in 46,XX infants.

From left to right: normal female; Stage I: clitoromegaly without labial fusion; Stage II: clitoromegaly and posterior labial fusion; Stage III: greater degree of clitoromegaly, single perineal urogenital orifice, and almost complete labial fusion; Stage IV: increasingly phallic clitoris, urethra-like urogenital sinus at base of clitoris, and complete labial fusion; Stage V: penile clitoris, urethral meatus at tip of phallus, and scrotum-like labia (appear like males without palpable gonads); normal male. (Source: Genital Findings in the Female Pseudo-hermaphroditism of the Congenital Adrenogenital Syndrome; Morphology, Frequency, Development and Heredity of the Different Genital Forms. Helv Paediatr Acta 1954.)

Panel B shows severe clitoral hypertrophy caused by masculinization of the external genitalia of a 46,XX patient with female pseudohermaphroditism caused by congenital adrenal hyperplasia. (Source: Sex Determination and Differentiation. N Engl J Med 2004.)

Panel C shows incomplete masculinization of the external genitalia of a 46,XY patient with male pseudohermaphroditism. There is a microphallus with perineoscrotal hypospadias and bifid and prepenile scrota. (Source: Sex Determination and Differentiation. N Engl J Med 2004.)

Laboratory and Ultrasound Evaluation in Infants with DSD

• The most urgent possibility in children with DSD is often CAH. When this is a possibility, electrolytes, 17-hydroxyprogesterone, and cortisol should be ordered as soon as possible. (Unstimulated cortisol may not be helpful, but a robust value may alleviate concern for cortisol deficiency; ACTH stimulation testing may be necessary.)

• Karyotype with fluorescence in situ hybridization (FISH) for detecting the SRY gene is often performed as a first step to assess chromosomal sex.

• If testes are not palpable in the scrotum, an ultrasound can often be helpful to determine the presence of ovaries or undescended testes in the inguinal canal.

• Measurement of testosterone is not useful in the first week of life but is useful from 1 to 2 weeks and at about 6 months, when infants are undergoing minipuberty of infancy, and male infants should have robust levels. Similarly, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) rise at about 1 week and can be ordered thereafter.

• If gonads are not palpable, antimüllerian hormone (AMH, also known as müllerian inhibiting substance) can be measured to assess for the presence of testicular tissue, as AMH is secreted by Sertoli cells.

Differential Diagnosis of DSD in Infancy

The differential diagnosis of DSD is broad, and a review of the differential facilitates an understanding of the process of sexual differentiation in utero and the genes involved therein.

An infant with virilized genitalia but no palpable testes may be a female with 21-hydroxylase deficiency CAH; considering that possibility right away is crucial in order to achieve timely diagnosis and prevent a potential salt-wasting crisis. If 21-hydroxylase deficiency is ruled out, a methodical stepwise approach integrating physical exam findings with laboratory results is appropriate to diagnose other conditions. In many cases of DSD, an etiology is not identified and likely represents an unknown genetic condition.

Information from initial physical exam and evaluation can be used to differentiate between one of the following three scenarios:

• 46,XX karyotype with virilization, suggesting possibility of CAH, exposure to androgens during gestation, or presence of testicular tissue due potentially to SOX9 duplication or translocation of the SRY gene. Important history for androgen exposure includes perinatal maternal exposure to androgens or synthetic progesterone or signs of maternal virilization that may suggest a luteoma or aromatase deficiency. For infants with 46,XX karyotype in whom testicular tissue is suspected, AMH and/or inhibin B levels can be helpful. Some infants with 46,XX karyotype will have both ovarian and testicular tissue. The origins of this condition are not completely understood, and genetic etiologies will likely be elucidated in the future.

• 46,XY karyotype with undervirilization, suggesting possibilities of the following:

  • one of the rarer types of CAH (3-beta-hydroxysteroid dehydrogenase type 2 deficiency, 17-alpha-hydroxylase deficiency, steroidogenic acute regulatory protein deficiency, or P-450 side-chain cleavage enzyme deficiency)

  • testicular dysfunction, with causes such as gonadal dysgenesis, testicular regression (or vanishing testes)

  • abnormal androgen synthesis or response, such as LH receptor defects or partial androgen insufficiency syndrome

  • complete androgen insensitivity syndrome, which presents with female-appearing genitalia, often with testes present in the labia and/or inguinal canal

• Mixed-sex chromosome pattern (often 46,XX/46,XY or 45,X/46,XY)