Initial evaluation of an infant with atypical genitalia for disorders of sex development: Overview

Clinical features
Newborn infant with:
Largely male appearance of the external genitalia and any of the following: Bilaterally nonpalpable gonads Severe hypospadias Any degree of hypospadias accompanied by unilateral or bilateral cryptorchidism and/or micropenis
Largely female appearance of the external genitalia and any of the following: Clitoromegaly Posterior labial fusion Gonads palpable in the labioscrotal folds or inguinal region Genital appearance discordant with sex chromosomes
Family communication
Congratulate family on the new addition.
If the baby is healthy, reassure the family.
Avoid premature designation of gender, naming of the baby, and completion of the birth certificate; counsel that it will take days or weeks to conduct the initial evaluation.
Initial laboratory testing
Expedited determination of sex chromosomes (karyotype or other method).
Adrenal steroids – 17-OHP (essential; this test is part of newborn screening in the United States). Tests for uncommon causes of CAH (17-hydroxypregnenolone, cortisol, 11-deoxycortisol) are sometimes done at this point but may be deferred to minimize blood loss.
Gonadal function – FSH, LH, testosterone^*, dihydrotestosterone, AMH.
Electrolytes (baseline; follow every 24 to 48 hours until CAH is confirmed or excluded).
Abdominal and pelvic ultrasound to assess for gonads, uterus, and vagina.
Interpretation and next steps
XX karyotype
17-OHP	AMH	Likely diagnosis	Comments
Very elevated	Within female range	CAH due to 21-hydroxylase deficiency	Risk for adrenal crisis; treat immediately Gonads are not palpable
Elevated	Within female range	CAH due to 21-hydroxylase deficiency Other form of XX CAH^¶ Stress	Risk for adrenal crisis Follow electrolytes Repeat 17-OHP if stress is present Interpret other adrenal steroids and/or ACTH stimulation test for definitive diagnosis
Normal	Within female range	Gestational hyperandrogenism	Maternal virilization during pregnancy
Normal	Elevated above female range	Testicular or ovotesticular DSD	Elevated testosterone and AMH (above female range) suggests that testicular tissue is present To determine cause, test for presence of SRY, sequence NR5A1, and consider next-generation sequencing May have palpable gonads
XY karyotype
Ultrasound	AMH	Likely diagnosis or category	Comments
No uterus	Within male range	Defect in androgen synthesis or action	Testosterone:dihydrotestosterone (when expressed in same units) <10:1 (normal) Elevated testosterone – Probable AIS Normal testosterone – Likely AIS, possible 17-beta-HSD or partial gonadal dysgenesis Low testosterone – 3-beta-HSD2 or other forms of XY CAH^Δ Testosterone:dihydrotestosterone >10:1 (elevated) 5-alpha-reductase deficiency If LH is low, repeat after 2 weeks of age or consider hCG stimulation testing
Uterus present or absent	Below male range	Gonadal dysgenesis (global impairment of testicular function)	Genetic testing to determine cause: NR5A1 sequencing Other mutations^◊
Y chromosome mosaicism/chimerism (eg, 45,X/46,XY)
Gonads		Likely diagnosis or category	Comments
Many possibilities: Normal or dysgenetic testes Normal or dysgenetic ovaries Streak gonads Ovotestes Mixed gonadal dysgenesis^§		Sex chromosome DSD	Increased risk for gonadoblastoma if dysgenetic gonad is present If 45,X karyotype in some cells, evaluate with echocardiography and kidney ultrasound

17-beta-HSD: 17-beta-hydroxysteroid dehydrogenase deficiency; 17-OHP: 17-hydroxyprogesterone; 3-beta-HSD2: 3-beta-hydroxysteroid dehydrogenase type 2 deficiency; ACTH: adrenocorticotropic hormone; AIS: androgen insensitivity syndrome; AMH: anti-müllerian hormone; CAH: congenital adrenal hyperplasia; DSD: disorder of sex development; FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; LH: luteinizing hormone.

* Testosterone tests should be performed no sooner than 48 hours of life. Samples taken during the first few days of life may not be a valid reflection of testicular function, because of transient suppression of gonadotropins after birth. LH should be measured concurrently to determine whether there is sufficient stimulus to Leydig cells to produce testosterone. The assay should be performed using gas or liquid chromatography/mass spectroscopy because interfering substances in neonates may give falsely elevated results on immunoassay.

¶ Forms of CAH that present with atypical genitalia in an XX infant include 21-hydroxylase deficiency (by far the most common), 11-beta-hydroxylase deficiency, 3-beta-HSD2, and P450 oxidoreductase deficiency.

Δ 3-beta-HSD2 is characterized by high 17-hydroxypregnenolone and high 17-hydroxypregnenolone:cortisol ratio.

◊ In addition to NR5A1, gene mutations that have been associated with gonadal dysgenesis include SRY, WT1, NROB1 (gain-of-function); MAP3K1, CBX2, DHH, DMRT1, FGF9, FOG, GATA4, SOX9, and ZFPM2; and Y chromosome mosaicism.

§ Mixed gonadal dysgenesis refers to asymmetric gonadal development with Y chromosome mosaicism. In most cases, the right gonad has testicular tissue and the left gonad is a streak gonad or an ovary.

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Initial evaluation of an infant with atypical genitalia for disorders of sex development: Overview