Disorders of sexual development (DSDs), formerly known as intersex conditions, are a group of congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. They are classified according to genetic characteristics and gonadal development and may result from virilization of individuals with a 46,XX karyotype, undervirilization of individuals with a 46,XY karyotype, or disorders of gonadal development such as mosaicism, streak ovary, ovotestis, or dysgenetic testes. The most common form of DSD is congenital adrenal hyperplasia (CAH). Early diagnosis is essential to prevent life-threatening complications, particularly salt-wasting crises in CAH, and to facilitate appropriate multidisciplinary management.

Pathophysiology

Normal sexual development depends on coordinated chromosomal, gonadal, hormonal, and anatomical differentiation during fetal life. Disruption at any stage may result in ambiguous genitalia or discordance between chromosomal, gonadal, and phenotypic sex.

DSDs may result from:

• 46,XX DSD (virilization): Excess androgen exposure, most commonly due to congenital adrenal hyperplasia.

• 46,XY DSD (undervirilization): Defects in androgen synthesis, androgen action, or testicular development.

• Sex chromosome DSDs: Disorders involving chromosomal abnormalities or mosaicism leading to abnormal gonadal development, including streak gonads, ovotestis, or dysgenetic testes.

Classification

• 46,XX DSD (virilization)

• 46,XY DSD (undervirilization)

• Sex chromosome DSD (mosaicism, streak ovary, ovotestis, dysgenetic testes)

Risk factors

• Congenital adrenal hyperplasia

• Family history of DSD

• Consanguinity

• Disorders of steroid hormone synthesis

• Disorders of androgen action

• Chromosomal abnormalities

• Gonadal dysgenesis

Signs and symptoms

Clinical presentation varies according to the underlying disorder and severity.

Common features include:

• Ambiguous genitalia at birth

• Undescended testis (unilateral or bilateral)

• Hypospadias

• Discordance between genital appearance and chromosomal sex

• Failure to thrive in infants with salt-wasting congenital adrenal hyperplasia

• Vomiting and dehydration in neonatal salt-wasting crisis

• Delayed or abnormal pubertal development (later presentation)

Diagnostic criteria

A disorder of sexual development should be suspected in:

• An infant born with ambiguous or abnormal genitalia.

• An infant with unilateral or bilateral undescended testes.

• An infant with hypospadias.

Investigations

Initial investigations include:

• Serum electrolytes

• Chromosomal analysis

• Karyotyping in a phenotypic male with undescended testis and/or hypospadias, whether the genitalia appear normal or abnormal

• Endocrine screening

• Anti-Müllerian hormone (AMH)

Additional investigations may be guided by the suspected underlying diagnosis.

Management

Management should be individualized according to the specific type of DSD and should involve a multidisciplinary team including endocrinologists, pediatric surgeons or urologists, geneticists, psychologists, and specialized nursing staff.

Non-pharmacological management

Parents should receive comprehensive counselling regarding:

• The nature of the condition

• Naming of the child

• Gender assignment

Psychological support and long-term follow-up should be provided for both the child and family.

Pharmacological management

Treatment depends on the underlying type of DSD.

Congenital adrenal hyperplasia (CAH)

Salt-wasting crisis

• Bolus 0.9% sodium chloride (normal saline) followed by appropriate maintenance fluids.

• If hypoglycaemia is present, administer 10% dextrose 2–4 mL/kg intravenously.

Long-term treatment

• Fludrocortisone (PO) 0.05–0.3 mg once daily.

Non-CAH disorders of sexual development

Hormonal therapy may be indicated in selected patients.

• Testosterone 50–400 mg monthly for 3 cycles, followed by reassessment.

± Testosterone cream, depending on clinical response and indication.

Prognosis

The prognosis depends on the underlying cause, the presence of associated endocrine abnormalities, and the timing of diagnosis and treatment. Infants with congenital adrenal hyperplasia generally have an excellent prognosis when salt-wasting crises are promptly treated and lifelong hormone replacement is maintained. Long-term outcomes are optimized through early multidisciplinary management, appropriate gender assignment, psychological support, and regular follow-up addressing growth, pubertal development, fertility, and psychosocial well-being.