History

A 6-year-old boy presents with 6 month history of pubic hair growth. For the past 4 years, he has had a history of rapid somatic growth.

The obstetric history was unremarkable. He was a full-term infant born to a 34-year-old healthy mom by normal vaginal delivery after an uncomplicated gestation. His birth weight was normal and there were no neonatal problems. At 9 - 18 months, his growth was at the 95th percentile for his age; his height at age 2 1/2 was average for 4 1/2 years (his parents were tall). His penis appeared larger than those of his peers at 3 years, he developed some facial acne at 4 years, and pubic hair was seen at 5 1/2 years.

Physical Exam

His height was average for 10 years and 3 months and his weight was average for 9 years and 10 months. The blood pressure was normal. He was tall, well-proportioned, and muscular with mild facial acne. The penis was large for his age and there was fine pubic hair (Tanner stage II of puberty). The testes were estimated to be 3 ml volume each (small for puberty stage). The neurological exam normal.

Questions

1. What do you think the primary problem might be? 2. What laboratory tests would you ask for?

Excess androgen production

The increased growth rate seen in this child could also raise the possibility of growth hormone excess (i.e., a pituitary lesion). However, the appearance of secondary sexual features and a well-proportioned muscular build suggests an androgen effect. These androgens could be derived either from the testes or adrenal glands. The testes are small for the level of physical development of the child, suggesting an adrenal source of steroids.

Laboratory Studies

Laboratory studies should be directed toward confirming the impression of androgen (testosterone) excess and localizing the source.

Patient ReferenceTestosterone (S) 172 ng/dl 2 - 12

Lutenizing Hormone (LH), basal (S) 1.7 mU/ml <2 (pre-puberty)FSH, basal (S) <1 mU/ml <117-OH-progesterone basal (S) 11,690 ng/dl <100 60 min after ACTH stim (S) 22,000 ng/dl <250Cortisol basal (S) 7 ug/dl 5 - 20 (morning) after ACTH stimulation (S) 10 ug/dl 2 - 3 x basal

Questions

How would you interpret these test results?

Congenital Adrenal Hyperplasia

These results (repeated below) indicate partial 21-hyroxylase deficiency with simple virilization. Testosterone is markedly elevated, confirming the impression of androgen excess. LH and FSH are not elevated, indicating that a pituitary lesion is not driving the testes to produce androgens. The physical features of the testes (small, without masses) do not suggest a primary testicular lesion.

On the other hand, 17-OH-progesterone, the substrate for the 21-hydroxylase reaction in the adrenal, is dramatically elevated and responds appropriately (a two-fold elevation) to ACTH stimulation. Cortisol (the final product of the 21-hydroxylase pathway) is normal and responds only slightly to ACTH stimulation (less than 50% increase).

Patient ReferenceTestosterone (S) 172 ng/dl 2 - 12Lutenizing Hormone (LH), basal (S) 1.7 mU/ml <2 (pre-puberty)FSH, basal (S) <1 mU/ml <117-OH-progesterone basal (S) 11,690 ng/dl <100 60 min after ACTH stim (S) 22,000 ng/dl <250Cortisol basal (S) 7 ug/dl 5 - 20 (morning) after ACTH stimulation (S) 10 ug/dl 2 - 3 x basalIn partial 21-hydroxylase deficiency, 21-hydroxylase activity is reduced, but some cortisol can be made. However, the pituitary has to drive the adrenal hard (by ACTH stimulation) keep cortisol near the normal level. Precursors to the 21-hyroxylase reaction are markedly increased, while the output of the pathway (cortisol) is normal or mildly decreased. In the process, the amount of material coming out of the side reactions in the adrenal (e.g., androgens) is markedly increased and can cause physiological effects.

The adrenal glands respond to the high levels of ACTH with hyperplasia, and a CT or MRI scan of the abdomen will reveal bilaterally and symmetrically enlarged adrenals.

Treatment

Hydrocortisone replacement therapy suppresses the pituitary output of ACTH, allowing the adrenal gland to decrease its metabolic output and normalizing the androgen synthesis rate.

Additional notes

More severe 21-hydroxylase deficiencies may present with electrolyte and volume disturbances resulting from mineralocorticoid deficiency. These patients may require replacement with both glucocorticoids and mineralocorticoids. Treatment requires care because rapid changes in the testosterone level may initiate central (pituitary) puberty. In any case, the patients require pituitary suppression until puberty.

Congenital Adrenal Hyperplasia

These results (repeated below) indicate partial 21-hyroxylase deficiency with simple virilization. Testosterone is markedly elevated, confirming the impression of androgen excess. LH and FSH are not elevated, indicating that a pituitary lesion is not driving the testes to produce androgens. The physical features of the testes (small, without masses) do not suggest a primary testicular lesion.

On the other hand, 17-OH-progesterone, the substrate for the 21-hydroxylase reaction in the adrenal, is dramatically elevated and responds appropriately (a two-fold elevation) to ACTH stimulation. Cortisol (the final product of the 21-hydroxylase pathway) is normal and responds only slightly to ACTH stimulation (less than 50% increase).

Patient ReferenceTestosterone (S) 172 ng/dl 2 - 12Lutenizing Hormone (LH), basal (S) 1.7 mU/ml <2 (pre-puberty)FSH, basal (S) <1 mU/ml <117-OH-progesterone basal (S) 11,690 ng/dl <100 60 min after ACTH stim (S) 22,000 ng/dl <250Cortisol basal (S) 7 ug/dl 5 - 20 (morning) after ACTH stimulation (S) 10 ug/dl 2 - 3 x basalIn partial 21-hydroxylase deficiency, 21-hydroxylase activity is reduced, but some cortisol can be made. However, the pituitary has to drive the adrenal hard (by ACTH stimulation) keep cortisol near the normal level. Precursors to the 21-hyroxylase reaction are markedly increased, while the output of the pathway (cortisol) is normal or mildly decreased. In the process, the amount of material coming out of the side reactions in the adrenal (e.g., androgens) is markedly increased and can cause physiological effects.

The adrenal glands respond to the high levels of ACTH with hyperplasia, and a CT or MRI scan of the abdomen will reveal bilaterally and symmetrically enlarged adrenals.

Treatment

Hydrocortisone replacement therapy suppresses the pituitary output of ACTH, allowing the adrenal gland to decrease its metabolic output and normalizing the androgen synthesis rate.

Additional notes

More severe 21-hydroxylase deficiencies may present with electrolyte and volume disturbances resulting from mineralocorticoid deficiency. These patients may require replacement with both glucocorticoids and mineralocorticoids. Treatment requires care because rapid changes in the testosterone level may initiate central (pituitary) puberty. In any case, the patients require pituitary suppression until puberty.