Congenital Adrenal Hyperplasia: Clinical Manifestation

The clinical picture of 21-hydroxylase deficiency combines the effects of androgen excess with, in the classical forms, the loss of aldosterone.

Clinical picture

Virilization and the internal genitalia

In female patients with 21OHD CAH there is accumulation of androgen that interferes with the sexual differentiation that happens during the 9th to 12th week after gestation, which causes different degrees of virilization, especially of the external genitalia. The degree of virilization in females with 21OHD CAH can range from clitoral enlargement to a penile urethra.

The internal genitalia — the uterus, fallopian tubes, and ovaries — of a female with CAH develop and function completely normally, and therefore these patients are fertile despite the developmental changes that happen due to the high level of androgen.

Puberty and behavior

Excessive androgen production in both male and female patients with 21OHD CAH results in puberty abnormalities:

• progressive penile and clitoral enlargement, with masculinization of the external genitalia in females
• development of premature pubic hair and axillary hair
• acne
• male-pattern alopecia
• delayed menarche with irregular menstrual cycle
• altered gender role behavior (gender dysphoria): masculinized behavior in females with CAH and less attraction to heterosexual relations; unlike females, males with CAH do not show any behavioral changes or lack of heterosexual desire

Fertility

Fertility is also affected, for different reasons in each sex. In females with CAH it can be limited by amenorrhea, secondary polycystic ovary syndrome (PCOS), a serum progesterone level that cannot be suppressed, and irregular menses. In males with CAH it can be limited by a reduced sperm count, which happens because the suppressed gonadotropin release leaves the testes small.

Stature

A high level of androgen in these patients also has an effect on stature: because of it, the somatic and epiphyseal (growth plate) growth happens very early, and subsequently the closure of the epiphyseal growth plate happens very early, which causes under-development of stature in these cases.

Salt wasting

A low level of aldosterone, which happens especially in the classical forms of 21OHD CAH, leads to salt wasting in these patients, which is characterized by:

• dehydration
• hyponatremia
• hypotension
• hyperkalemia
• metabolic acidosis
• vomiting

Adrenal crisis can happen in patients with a severe lack of 21-hydroxylase, which is more common in the classical forms of the disease.

Phenotypes of 21-hydroxylase deficiency

The clinical picture falls into groups that follow the severity of the enzyme defect.

In simple-virilizing 21OHD CAH the activity of 21-hydroxylase is reduced but still detectable, enough to drive androgen excess without salt wasting. These patients have virilization and early rapid growth that leads to short stature. In females it is more obvious, because of ambiguous external genitalia; in males other signs have to be looked for, such as hyperpigmentation and an enlarged phallus.

Salt-wasting 21OHD CAH is the more severe form, with almost no activity of 21-hydroxylase.

Signs and symptoms related to hyperandrogenism are common in both the classes of CAH manifestations; the difference between salt-wasting and simple-virilizing is due to the difference in production of aldosterone.

In patients with non-classical CAH (NC-CAH), which is also known as late-onset CAH, there is mild-to-moderate enzyme activity in early life, but over time there is gradual loss of activity and accumulation of clinical manifestations; therefore, in NC-CAH there is no virilization at birth in females, and hyperandrogenism appears during adolescence.