Tuesday, May 06, 2008 Metabolic newborn screening program
(Part IV)
Congenital Adrenal Hyperplasia
THE adrenal gland is a very important paired tissue located above the two kidneys. It produces several hormones necessary for growth and development, for metabolism and for the kidney to function normally. Among the hormones produced, aldosterone and cortisol are key to Congenital Adrenal Hyperplasia.
Aldosterone is a hormone that controls the re-absorption of Na and in effect water in the tubules of kidneys. Cortisol is a corticosteroid hormone that is often referred to as the "stress hormone" as it is involved in the response to stress. It increases blood pressure, blood sugar levels and has an immunosuppressive function.
The term congenital adrenal hyperplasia encompasses several genetic and hereditary (autosomal recessive) disorders, all of which involve a deficiency or relative defect in cortisol (steroid) synthesis, aldosterone synthesis, or both that results in some degree of cortisol deficiency, aldosterone deficiency, or both.
Enzymes necessary in the production of these hormones are either lacking or absent.
Many of the enzymes involved in cortisol and aldosterone syntheses are cytochrome P450 (CYP) proteins. CYP21 refers to 21-hydroxylase, CYP11B1 refers to 11-beta-hydroxylase, and CYP17 refers to 17-alpha-hydroxylase. Congenital adrenal hyperplasia occurs among people of all races. Internationally, the 11-Beta-hydroxylase deficiency is most common. Other forms of congenital adrenal hyperplasia are far less common.
Clinical manifestations of the disease are related to the defects brought about by degree of cortisol deficiency, aldosterone deficiency, or deficiency of both. In some cases, these manifestations reflect the accumulation of precursor adrenocortical hormones.
These precursors, when present in very high concentrations, cause abnormalities such as virilization (maculinization) or hypertension.
The signs and symptoms depend on which protein is affected, the severity of the mutation, or the degree of deletion of the particular gene encoding for the protein involved in production of steroids. Two copies of an abnormal gene are required for disease to occur, and not all mutations and partial deletions result in disease.
The manifestations can vary from clinically unapparent disease (occult or cryptic adrenal hyperplasia) to a mild form of disease that is expressed in adolescence or adulthood (non-classic adrenal hyperplasia) to severe disease that results in adrenal insufficiency in infancy with or without virilization and salt wasting (classic adrenal hyperplasia). The most common form of adrenal hyperplasia, due to a deficiency of 21-hydroxylase activity, is clinically divided into a simple virilizing form and a salt-wasting form.
Let us just simplify the clinical manifestations because there are several types with unique characteristics. Generally, female patients with CAH presents with genital ambiguity. Mild forms in females are identified later in childhood because of precocious pubic hair, big clitoris or both often accompanied by accelerated growth and skeletal development due to excess postnatal exposure to adrenal androgens.
Still others may present in adolescence or adulthood with oligomenorrhea, hirsutism, and/or infertility. Some look like females at birth but do not develop breasts or menstruate in adolescence because of inadequate estradiol production. They may present with hypertension.
The diagnosis of congenital adrenal hyperplasia depends on the demonstration of inadequate production of cortisol, aldosterone, or both in the presence of accumulation of excess concentrations of precursor hormones. Other tests like CT scan, X- ray of bones, Biopsy of adrenal gland and genetic studies may be useful.
Infants with ambiguous genitalia should be closely observed for symptoms and signs of salt wasting while a diagnosis is being established. Clinical clues include abnormal weight loss or lack of expected weight gain. Electrolyte abnormalities generally take from a few days to 3 weeks to appear because the placenta maintains the fetal electrolytes in utero. In mild forms of salt-wasting adrenal hyperplasia, salt wasting may not become apparent until an illness stresses the child.
Specific medical treatment entails long-term glucocorticoid or aldosterone replacement (or both), depending on which enzyme is involved and on whether cortisol and/or aldosterone synthesis is affected. Another approach currently under investigation is the combined use of glucocorticoid (to suppress ACTH and adrenal androgen production), mineralocorticoid (to reduce angiotensin II concentrations), aromatase inhibitor (to slow skeletal maturation), and flutamide (an androgen blocker to reduce virilization).
Some patients develop precocious puberty, which further compromises adult height. Suppression of puberty with long-acting gonadotropin-releasing hormone (GnRH) agonists while simultaneously stimulating growth with growth hormone may partially improve the patient's height.
Surgical care is reserved for infants with ambiguous genitalia. They may require corrective surgery like vaginoplasty after puberty. Bilateral adrenalectomies have been suggested in the management of virilizing forms of adrenal hyperplasia in order to prevent further virilization and advancement of skeletal maturation. This approach is experimental and should be considered only in the context of a controlled study.
Patients with CAH need to be referred to endocrinologist should be consulted when adrenal insufficiency is suspected. An experienced surgeon is required if genitalia are ambiguous or inconsistent with genetic sex and corrective surgery is contemplated. A consultation with a geneticist is useful in establishing the genetic defect causing the disorder. In parents contemplating a subsequent pregnancy, genetic counseling for prenatal diagnosis and treatment of this disorder is important.
Patients with congenital adrenal hyperplasia should be on an unrestricted diet. Patients should have ample access to salt because salt wasting is common in some forms of the disease. Infants who have salt wasting generally benefit from supplementation with NaCl (2-4 g/d) added to their formula. Caloric intake may need to be monitored and restricted if excess weight gain occurs because glucocorticoids stimulate appetite. Activity need not be restricted if appropriate glucocorticoid and mineralocorticoid therapy is given.
With adequate medical and surgical therapy, the prognosis is good. However, problems with psychological adjustment are common and usually stem from the genital abnormality that accompanies some forms of congenital adrenal hyperplasia.Early death may occur if patients are not provided with stress doses of glucocorticoid in times of illness, trauma, or surgery. (To be continued)
