Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease emerging from mutations of genes for enzymes that lead to the biochemical steps of production of glucocorticoids, mineralocorticoids, or sex steroids from cholesterol by the adrenal glands. Most of these diseases involve the excessive or deficient production of sex steroids that can alter the development of primary or secondary sex characteristics in some affected infants, children, or adults. Sometimes, deficient production of mineralocorticoids can lead to severe salt wasting increasing neonatal morbidity and mortality. Universal newborn screening for CAH done in the US and many developed countries is recommended for early diagnosis and institution of therapy.
CAH most commonly results from mutations or deletions of CYP21A. This mutation produces a 21-hydroxylase deficiency in 90-95% of adrenal hyperplasia cases. Mutations or partial deletions that alter CYP21A also are common. The estimated prevalence is one case per 60 individuals in the general population but increases to one in three in select genetically isolated communities with a smaller gene pool. CAH which is caused by 21-hydroxylase deficiency is found in all populations whereas 11-beta-hydroxylase deficiency is more common in individuals of Iranian, Jewish, or Moroccan descent. Disease severity and phenotypic presentation vary depending on the location and extent of gene mutations or deletions which lead to complex allelic variations. For example, almost 300 CYP21A2 mutations have been identified, making genotyping these individuals a cumbersome undertaking. Patients with classic CAH may present as simple virilizing CAH or salt wasting CAH and are usually diagnosed in infancy while patients with nonclassic CAH may be asymptomatic or present with a milder form of virilization postnatally.
In the United States, CAH is more common in Native Americans and Yupik Eskimos. Among Caucasians, the incidence is approximately 1 in 15,000.
Since all forms of CAH have an autosomal recessive pattern of inheritance, both sexes are equally affected. However, because of the accumulated testosterone or precursor hormones, the phenotypic expression may be different in both genders. CAH is usually obvious at birth or soon after because of the ambiguous genitals, early virilization, or salt wasting. Atypical cases may be recognized around puberty with the presence of virilizing signs or oligomenorrhea in females.
The adrenal cortex is the site for steroidogenesis and produces three significant steroids–glucocorticoids in the form of cortisol - which regulates the body’s metabolism and immune response; the mineralocorticoid, aldosterone - which modulates electrolytes, blood pressure and vascular volume and adrenal androgens, the sex hormones - which regulates secondary sex characteristics in females. Cholesterol got from endogenous synthesis, or dietary sources are the precursor for steroid synthesis. The pathway for steroid synthesis is mediated by various enzymes including 21-hydroxylase, 11-beta-hydroxylase and 17-alpha-hydroxylase. 21-hydroxylase is crucial in the path leading to production of all steroids because it is required for the conversion of 17 hydroxyprogesterone (17OHP) to 11-deoxycortisol (the precursor for cortisol) and also the conversion of progesterone to 11 Deoxycorticosterone (the precursor of aldosterone) while 11-beta-hydroxylase is essential for the production of cortisol and the androgen, dehydroxyandrostendione (DHEA) . Deficiency of either of these enzymes impairs production of the major steroids stimulating corticotropin mediated accumulation of cortisol precursors causing a shift in steroid pathogenesis towards androgen production. Fetal androgen excess leads to various degrees of virilization at birth.
CAH is associated with a defective gene. The most common gene defect in 95% of cases is on CYP21A2 which is the gene coding for 21-hydroxylase which is found on 6p21.3 as part of the human leukocyte antigen (HLA) complex. Inefficiency produced by the specific alleles found in each patient introduces variability. Milder degrees of inefficiency leads to excessive sex hormone effects in childhood or adolescence. The mildest form interferes with ovulation and fertility in adults.
The histological features of CAH include:
The symptoms of Congenital Adrenal Hyperplasia include:
Under-virilization may occur in XY males, which may cause female external genitalia. In females, hypogonadism may cause sexual infantilism or abnormal pubertal development and infertility.
Female infants will have ambiguous genitalia because of exposure to high concentrations of androgens in-utero. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a common cause of ambiguous genitalia in genotypically normal female infants (46XX). Females less severely affected may present with early pubarche. Young women may present with oligomenorrhea polycystic ovaries and hirsutism (polycystic ovarian syndrome).
Most males have no signs of CAH at birth. However, some may present with hyperpigmentation and penile enlargement while those with salt-wasting disease present early with hyponatremia and hypovolemia. Males with non-salt-wasting disease present later with signs of virilization. In rare forms, males are under-masculinized.
A two-tier approach to the diagnosis of CAH is recommended. The initial screening test is done by measuring serum 17OHP to screen for 21-hydroxylase deficiency. If positive, then repeat 17OHP test should be obtained along with measurement of the serum electrolyte panel. Classic 21-hydroxylase deficiency causes 17 alpha-hydroxyprogesterone blood levels greater than 242 nmol/L.
Neonatal screening programs typically have specific reference ranges by weight and gestational age because high levels may be seen in sick, stressed or premature infants without congenital adrenal hyperplasia. Salt-wasting patients may have higher 17 alpha-hydroxyprogesterone levels than non-salt-wasting patients. In mild cases, 17 alpha-hydroxyprogesterone may not be elevated initially, but it will rise during a corticotropin stimulation test. In many countries, children are screened for 21-hydroxylase at birth. This test will detect elevated levels of 17-hydroxyprogesterone. Identifying patients with high levels can result in early treatment and a relatively normal life.
A second tier test using liquid chromatography-tandem mass spectrometry allows diagnosis of CAH due to other enzyme defects such as 11-beta-hydroxylase. Patients with inconclusive results may need further evaluation using a cosyntropin stimulation test followed by complete adrenocortical profile. When indicated, the cosyntropin stimulation test should be done 24 to 48 hours after birth to reduce the incidence of false-positive and negative results .
Genetic analysis may be helpful, but it is unnecessary if classic clinical, and laboratory findings are present.
In classic 21-hydroxylase deficiency, laboratory tests will show:
Unless hemorrhage is suspected in the adrenal glands, imaging studies are not required in evaluating patients with CAH. However, in patients with ambiguous genitalia, pelvic ultrasound may be done to assess for other anomalies and define the anatomy of the urogenital tract.
Children with precocious puberty may benefit from a bone scan.
The goal of medical treatment of CAH defers by the age of the patient. CAH is a recessive gene, so both the mother and father must be recessive carriers. Couples with the recessive CAH genes may prevent CAH through preimplantation genetic diagnosis . Prenatal treatment is not recommended and currently considered experimental.
During infancy and childhood treatment aims to prevent adrenal crises, early virilization, promote normal growth, avoid electrolyte abnormalities and dehydration. In adolescents and adults, the goal of treatment shifts to achieving normal reproductive function and fertility while avoiding chronic complications of medication insufficiency or excess including Cushing syndrome. To achieve this balance requires close monitoring. Educating parents, caregivers and older patients with CAH about the signs, symptoms, prevention and emergency treatment of adrenal crises is an integral part of the management of CAH. All patients with CAH are advised to wear medical identification and have a glucocorticoid emergency injection kit for use in adrenal crises.
General principles in the treatment of CAH include:
Supplying enough glucocorticoid to reduce hyperplasia and reduce overproduction of androgens and mineralocorticoids.Providing replacement of mineralocorticoids and extra salt if deficient.Providing testosterone or estrogen replacement at puberty if deficient.Additional therapy, as needed, to optimize growth by delaying puberty or delaying bone maturation.
Spironolactone should be avoided in salt wasting CAH due to increased risk for dehydration.
Patent’s with CAH require stress dose steroids in cases of significant trauma, surgery requiring general anesthesia, febrile illnesses and gastroenteritis leading to dehydration however not for minor ailments, everyday stress or exercise.
Surgery is not required for the majority of infants with mild forms of virilization.
Infants with ambiguous genitalia need a surgical consult for corrective surgery. The risks and benefits of early versus delayed operation should be carefully discussed with the child's parents by a multidisciplinary team of specialists involving the pediatric endocrinologist, urologist, surgeon, and anesthesiologist. Surgery should only be done in centers that specialize in genitoplasty. Surgery is only undertaken in a few selected infants and must be done by experienced surgeons.
In the past, some infants required bilateral adrenalectomies to manage severe virilization and prevent premature skeletal maturation- however, today this procedure is rarely done.
Patients with CAH need lifelong follow up to monitor the doses of glucocorticoids and mineralocorticoids and monitor the side effects of these hormones. Patients with CAH should have routine screening for cardiovascular and metabolic diseases as the general population.
If the disorder is promptly diagnosed and treated, the prognosis for most patients is good. However, even though the physical deficits can be overcome, most patients have lifelong emotional issues that stem from the ambiguous genitalia. Other problems that can occur in these patients include:
Cortisol is an adrenal steroid hormone required for endocrine function that is produced in the second month of fetal life. Poor cortisol production is a hallmark of CAH. Inefficient cortisol production results in elevated adrenocorticotropic hormone (ACTH). Increased ACTH stimulation induces hyperplasia of the steroid-producing cells of the adrenal cortex. The defect results in adrenal hyperplasia.
Cortisol deficiency in CAH is usually partial. The synthesis of cortisol shares steps with the creation of aldosterone, testosterone, and estradiol. The resulting excess or decreased production of these hormones produces multiple problems.
Prenatal chorionic villus sampling or amniocentesis can detect CAH during pregnancy.
CAH is a relatively common disorder, but the clinical presentation does vary with the severity of enzyme deficiency. Besides disordered genital development, many of these infants present with other systemic features like electrolyte abnormalities and hypoglycemia. Thus, CAH is best managed by a multidisciplinary team that includes a geneticist, endocrinologist, a pediatric surgeon, a fertility expert, and a nurse educator. Also, referral to a mental health counselor is highly recommended because many patients develop emotional distress over the ambiguous genitals. These infants need lifelong monitoring because too little or too much glucocorticoids can have detrimental effects. Even as adults many of these patients need assessment of their genitals because problems like vaginal stenosis and dyspareunia are not uncommon. (Level V)
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