Step-by-Step Algorithmic Approach to Disorders of Sexual Development (DSDs)

1) Assess Phenotypic Sex and External Genitalia

a) Female Phenotype (46,XX or 46,XY DSDs)

i) Normal or ambiguous genitalia (clitoromegaly, labial fusion)

b) Male Phenotype (46,XX or 46,XY DSDs)

i) Normal or ambiguous genitalia (hypospadias, micropenis)

2) Initial Evaluation and Basic Laboratory Tests

a) Physical Examination:

i) Note the presence and degree of ambiguity in genitalia.

ii) Check for palpable gonads (testes) or labial/scrotal folds.

b) Laboratory Tests:

i) Serum testosterone

ii) Serum dihydrotestosterone (DHT)

iii) Luteinizing hormone (LH)

iv) Follicle-stimulating hormone (FSH)

v) Anti-Müllerian hormone (AMH)

vi) Electrolytes (check for salt-wasting forms)

3) Analyze Laboratory Results and Clinical Presentation

a) Females with Ambiguous Genitalia

i) High Testosterone and Androstenedione:

(1) Congenital Adrenal Hyperplasia (CAH):

21-hydroxylase deficiency (most common), 11β-hydroxylase deficiency.

(2) Labs: Elevated 17-hydroxyprogesterone (21-hydroxylase deficiency) or elevated 11-deoxycortisol (11β-hydroxylase deficiency).

ii) Normal or Low Testosterone:

(1) Androgen Insensitivity Syndrome (AIS):

Complete or partial; usually 46,XY with normal female external genitalia but absent Müllerian structures.

b) Males with Ambiguous Genitalia or Undervirilization

i) High LH and FSH, Low Testosterone:

(1) Primary Gonadal Failure:

Turner Syndrome (45,X/46,XY)
Klinefelter Syndrome (47,XXY).

ii) Low LH, FSH, Low Testosterone:

(1) Hypogonadotropic Hypogonadism:

Kallmann syndrome, pituitary or hypothalamic disorders.

iii) High Testosterone, Low DHT:

(1) 5α-Reductase Deficiency:

Inability to convert testosterone to DHT.

iv) High Testosterone and LH:

(1) Leydig Cell Dysfunction or Resistance to Androgens:

(a) May suggest partial AIS or other receptor defects.

4) Consider Specific Clinical Clues and Additional Tests

a) Congenital Adrenal Hyperplasia (CAH):

i) Signs of salt-wasting crisis, hyperkalemia, hyponatremia (classic forms).

ii) Early virilization in females.

b) Androgen Insensitivity Syndrome (AIS):

i) Normal female external genitalia, undescended testes, minimal to no pubic/axillary hair.

c) 5α-Reductase Deficiency:

i) Female external genitalia at birth with virilization at puberty.

d) Gonadal Dysgenesis:

i) Turner Syndrome (45,X): Short stature, webbed neck, primary amenorrhea, streak gonads.

ii) Klinefelter Syndrome (47,XXY): Tall stature, gynecomastia, small testes, infertility.

5) Confirm Diagnosis with Specific Tests as Needed

a) Karyotype Analysis: Useful but not always provided in exams.

b) Hormonal Stimulation Tests:

i) ACTH stimulation test for CAH.

c) Imaging Studies:

i) Ultrasound or MRI to evaluate internal genital structures and gonads.