Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency

Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency

References Pediatric Practice ENDOCRINOLOGY (Michael S. Kappy,MD,PhD) An Endocrine Society Clinical Practice Guideline WILLIAMS Textbook of Endocrinology The new england journal of medicine

Salt-Wasting form of CYP21 deficiency

Clinicalmanifestations Increased androgen production starts early in fetal life, between 6 and 10 weeks of gestation. In the female fetus, this results in variable degrees of posterior fusion of the labia, and hypertrophy of the clitoris. The degree of masculinization of the external genitalia of the female fetuses is usually classified as described by Prader. Despite the virilized appearance of the external genitalia, the uterus and fallopian tubes are normal.

Later in life, hypersecretion of androgens in either sex causes early appearance of pubic hair, usually between 6 months and 2 years of age. This is followed by early appearance of axillary hair between 2 and 4 years of age, and facial hair between 8 and 14 years of age. Acne and deepening of the voice will also occur. The anabolic effect of elevated adrenal androgens in infancy and early childhood causes rapid skeletal maturation.

Simple virilizing form of CYP21 deficiency

CYP21 deficiency is not complete. Decreased in cortisol secretion A decrease in cortisol secretion reduces negative feedback at the hypothalamic-pituitary level, which leads to increased secretion of CRH and ACTH. The increased ACTH activity is capable of restoring cortisol secretion to an approximately normal rate. Increased secretion of cortisol precursors The increased ACTH concentration required to normalize cortisol secretion markedly elevates production of cortisol precursors. The immediate precursor, which reaches the highest plasma concentration, is 17- hydroxyprogesterone. There is also increased secretion of progesterone and 17-hydroxypregnenolone. High concentrations of plasma ACTH cause the adrenocortical hyperplasia characteristic of the syndrome.

Nonclassical form of CYP21 deficiency (late-onset)

This form of CAH has the mildest degree of CYP21 deficiency. Patients with nonclassic 21-hydroxylase deficiency produce normal amounts of cortisol and aldosterone at the expense of mild-to- moderate overproduction of sex hormone precursors.

In females there is no abnormality of the external genitalia at birth. There are little or no signs of androgen effects during childhood. Hirsutism is the single most common symptom at presentation in approximately 60 percent of symptomatic women, followed by oligomenorrhea (54 percent) and acne (33percent). Infertility appears to be a presenting symptom in only 13 percent of women.

Heterozygote 21-Hydroxylase Deficiency

Salt-wasting, simple virilizing, and late-onset 21- hydroxylase deficiency are all caused by homozygous or compound heterozygote mutations in the human 21-hydroxylase gene (CYP21A2). In the carrier or heterozygote state, only one allele is mutated. The clinical significance of the heterozygote state is uncertain; it does not appear to disadvantage reproductive capability but may cause signs of hyperandrogenism in adult women.

Diagnosis

Approximately 10 percent of severely affected term newborns have low initial base-line 17- hydroxyprogesterone levels. False negative results occur when infants are discharged early from the hospital and thus have been screened before they are two to three days old, a time for which there are no established normative data. Conversely, most sick or premature infants have elevated 17- hydroxyprogesterone levels without having inborn errors in steroid biosynthesis, especially those with gestational ages of less than 31 weeks.

The gold standard for differentiating 21-hydroxylase deficiency from other steroidogenic enzyme defects is the corticotropin (cosyntropin) stimulation test, performed by injecting a 0.125-mg or 0.25-mg bolus of cosyntropin and measuring base-line and stimulated levels of 17-hydroxyprogesterone.

Medical treatment of CAH in growing patients

Patients with classic 21-hydroxylase deficiency require long-term glucocorticoid treatment. The goal of therapy is to reduce excessive androgen secretion by replacing the deficient hormones. Treatment with GCs prevents adrenal crisis and virilization, allowing normal growth and development. Overtreatment may suppress growth, increase blood pressure, and cause iatrogenic Cushing s syndrome. Attempts to completely normalize 17-OHP levels typically result in overtreatment.

During childhood, the preferred GC is HC. In one trial, the estimated growth-suppressive effect of prednisolone was about 15-fold more potent than HC , dexamethasone is 70- to 80-fold more potent. When HC doses exceed 20 mg/m2 . d in infants and 15 17 mg/m2 . d in adolescents, there is loss of height SD score (SDS) and shorter adult height SDS. Therefore, as with younger patients, it is important during puberty to treat with the lowest possible dose.

At or near completion of linear growth, long-acting GCs may be used although HC remains a treatment option. Infants with salt-wasting 21-hydroxylase deficiency require MCs in addition to GC treatment as well as supplemental sodium chloride. Although the aldosterone biosynthetic defect is clinically apparent only in the salt-wasting form, subclinical aldosterone deficiency is present in all forms of 21-hydroxylase deficiency and can be best evaluated by the aldosterone to PRA ratio. Consequently, all patients with elevated PRA or aldosterone to PRA ratio benefit from fludrocortisone therapy and adequate dietary sodium.

Sensitivity to MCs may vary over time, and recovery from salt wasting has been described in some patients, most probably secondary to extraadrenal 21-hydroxylation. Therefore, the need for continuing MCs should be reassessed periodically based on blood pressure, PRA, and the aldosterone to PRA ratio. It is particularly important to monitor blood pressure in infants who are often initially treated with high doses of MC due to immature renal tubular capacity to reabsorb sodium.

Feminizing surgery Recommendation: We suggest that for severely virilized (Prader stage3) females, clitoral and perineal reconstruction be considered in infancy and performed by an experienced surgeon in a center with similarly experienced pediatric endocrinologists, mental health professionals, and social work services.

The adult short stature of many CAH patients may be caused by hypercortisolism, hyperandrogenism, or both. In a study of 341 treated patients with classic CAH, 124 were examined at adult height. Males and females were 10 and 8 cm shorter than expected, respectively. A metaanalysis of data from 18 centers worldwide showed that the mean adult height of patients with classic CAH was 1.37 SD (10 cm) below the mean, and patients diagnosed before 1 yr of age had increased adult height outcomes (0.54 SD) . Patients who were diagnosed late or were exposed to GC doses higher than 15 mg/m2 d had diminished height . Overtreatment during infancy or treatment with long-acting, high- potency GCs may also reduce height.

Monitoring therapy in growing children

Normal growth and growth velocity are important variables in children. The therapeutic goal is to use the lowest dose of glucocorticoid that adequately suppresses adrenal androgens and maintains normal growth and weight gain. 17-OHP, androstenedione, and testosterone are the best indicators of the adequacy of GC treatment. Normal levels of 17-OHP and the other steroids are not a treatment goal but instead indicate overtreatment. ACTH measurements are not useful for a diagnostic or therapeutic profile in CAH patients. Acceptably treated CAH patients have mildly elevated steroid levels and dose adjustments should be made in the overall clinical picture and not solely based on a single 17-OHP measurement.

GC treatment of adults with CAH or NCCAH

Recommendation: We suggest that adult patients with classic CAH be treated with HC or long-acting GCs. The need for MCs decreases with age.

Monitoring treatment of adults with CAH

Optimal levels for 17-OHPand androstenedione have not been defined. Testosterone levels in men normally reflect gonadal rather than adrenal function and therefore are not useful for monitoring therapy. Men with large testicular adrenal rests may have low morning testosterone indicating poor Leydig cell function.