What is the likely diagnosis for a 46XX individual with ambiguous genitalia, uterus, and clitoromegaly?

Diagnosis: Congenital Adrenal Hyperplasia (CAH)

The most likely diagnosis for a 46,XX individual presenting with ambiguous genitalia, uterus, and clitoromegaly is congenital adrenal hyperplasia (CAH), specifically 21-hydroxylase deficiency, which accounts for approximately 72.7% of 46,XX cases with genital ambiguity. 1, 2

Clinical Reasoning

Why CAH is the Correct Answer

• CAH is the most common cause of ambiguous genitalia in 46,XX newborns, representing the overwhelming majority of such presentations 1, 3, 2
• The presence of a uterus confirms Müllerian structures are intact, which is characteristic of 46,XX individuals with CAH who have normal internal female anatomy but virilized external genitalia 3
• Clitoromegaly with preserved uterus is the hallmark presentation of virilization from excess adrenal androgens in utero 3, 4
• In one large series, 77.2% of 46,XX cases presented with enlarged phallus and 63.6% had urogenital sinus, with CAH being the final diagnosis in 72.7% 2

Why 46,XX Testicular DSD is Incorrect

• 46,XX testicular DSD patients do not have a uterus because they possess testicular tissue that produces anti-Müllerian hormone, which causes regression of Müllerian structures 1
• This diagnosis involves presence of testicular tissue in a 46,XX individual, which would preclude uterine development 1
• The presence of a uterus in this case definitively excludes this diagnosis 5

Critical Diagnostic Pitfall

A newborn with bilateral nonpalpable gonads and ambiguous genitalia must be immediately evaluated for CAH, as this is a life-threatening emergency. 1 Failure to diagnose CAH can result in:

• Salt-wasting crisis with shock 1
• Severe hyponatremia and hyperkalemia 1, 6
• Death if untreated 1

The patient should not be circumcised until the workup is complete, even if the phallus appears completely normal 1

Immediate Workup Required

• Serum 17-hydroxyprogesterone (markedly elevated in 21-hydroxylase deficiency) 3, 2
• Electrolytes to assess for salt-wasting (hyponatremia, hyperkalemia) 1
• Plasma renin activity (elevated in salt-wasting CAH) 7
• Serum cortisol (low in CAH) 7
• Pelvic ultrasound to confirm presence of uterus and ovaries 3, 2
• Karyotype confirmation (46,XX) 2

Treatment Implications

• Immediate glucocorticoid replacement is essential if CAH is confirmed, particularly in salt-wasting forms 3, 7
• Mineralocorticoid replacement (fludrocortisone) is required for salt-wasting variants 7
• Feminizing genitoplasty can be performed as early as infancy with satisfactory cosmetic and functional results in 46,XX CAH patients 3
• Gender assignment should be female given 46,XX karyotype, presence of uterus and ovaries, and potential for fertility with appropriate treatment 3, 2