BASICS
DESCRIPTION
- Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by a defect in one of the five enzymatic steps in the production of cortisol.
- The most common enzyme deficiency is 21-hydroxylase, which accounts for >90% of CAH cases.
- 11-β-hydroxylase deficiency accounts for ~5% of CAH cases.
- Other rare causes include 17-α-hydroxylase deficiency, 3-β-hydroxylase deficiency, and lipoid CAH, which will not be discussed further here.
- CAH is subdivided into classical and nonclassical forms.
- The enzymatic deficiency is defined as "classic"� if the defect is severe enough to cause cortisol insufficiency; or "nonclassical"� if cortisol production is normal but with excessive precursor accumulation to overcome the partial enzymatic block.
- The classic form can be subdivided into salt-wasting (67%) and simple virilizing (33%). The nonclassical form has a milder phenotype.
EPIDEMIOLOGY
- 1/15,000 for the classic form of CAH
- 1/280 among Yupik Eskimo population
- Nonclassical form has a higher estimated incidence of 1/1,000 in Caucasians and up to 2% in inbred populations, such as Eastern European (Ashkenazi) Jews.
ETIOLOGY AND PATHOPHYSIOLOGY
- 21-hydroxylase is one of the five enzymes involved in producing cortisol from cholesterol in the adrenal cortex.
- 21-hydroxylase converts 17-hydroxyprogesterone to 11-deoxycortisol in cortisol synthesis, and progesterone and deoxycorticosterone in aldosterone synthesis.
- Without cortisol for negative feedback, increased ACTH is secreted by the pituitary, leading to hyperplasia of the adrenal cortex.
- This also results in accumulation of cortisol precursors, which are diverted to sex hormone biosynthesis.
- Thus, levels of 17-hydroxyprogesterone are elevated for 21-hydroxylase deficiency.
- In salt-wasting CAH, cortisol and aldosterone production is defective due to total or near-total enzyme deficiency.
- In simple virilizing CAH, there is a partial enzyme deficiency resulting in reduced cortisol and aldosterone production.
- In nonclassical CAH, there is a mild enzyme deficiency with normal cortisol and aldosterone levels, but there is a mild increase in adrenal androgen production.
Genetics
- Autosomal recessive disorder with variable penetrance
- There are two 21-hydroxylase genes located on chromosome 6p21.3.
- One is the active form and the other inactive. CAH is unusual among genetic disorders in that most of the mutant alleles (~90%) are generated by recombinations between the pseudo and active genes.
- When deleterious sequences normally present in the pseudogene are transferred to the active gene, the latter becomes incapable of encoding a normal enzyme; this process is called gene conversion.
- >100 mutations are known.
- Mutations that result in large deletions or splicing that ablate enzyme activity result in salt-wasting CAH.
- Missense mutations with 1-2% enzyme activity correlate with simple virilizing CAH.
- Point mutations with 20-60% enzyme activity correlate with the nonclassical disorder.
- Most affected individuals are compound heterozygotes, and the clinical phenotype correlates with the less severely mutated allele.
RISK FACTORS
- Inbreeding
- Positive family history
COMMONLY ASSOCIATED CONDITIONS
- Upper urinary tract malformations, such as vesicoureteral reflux, hydronephrosis, or duplicated collecting system, are seen in children with CAH.
- Adrenal cortical tumors are thought to be secondary to higher levels of ACTH
- Obesity, insulin resistance, polycystic ovaries
- Testicular adrenal rest tumors
DIAGNOSIS
HISTORY
- CAH has a spectrum of clinical presentations depending on the degree of enzyme deficiency.
- The classic forms present in childhood:
- Female infants present with ambiguous genitalia due to high androgen concentrations in utero.
- Males with classic CAH often have no signs at birth or mild hyperpigmentation and penile enlargement.
- In the salt-wasting form, infants present at 7 to 14 days of life with vomiting, weight loss, lethargy, dehydration, hyponatremia, and hyperkalemia, and possible shock.
- This is seen more commonly in boys, as females are generally recognized at birth due to ambiguous genitalia.
- Boys with simple virilizing CAH not detected during infancy will present at 2 to 4 years of age with signs of accelerated growth and premature adrenarche (pubic hair, axillary odor, axillary hair, and acne).
- In nonclassical CAH, a milder phenotype exists. Children may present with premature adrenarche with accelerated growth and advanced skeletal maturation. Females can present in adolescence or adulthood with hirsutism, acne, oligomenorrhea, polycystic ovaries, and infertility. Adolescent and adult males may be asymptomatic (1)[C].
PHYSICAL EXAM
Newborn female infants with classic CAH have ambiguous genitalia, which can present as clitoromegaly, partially fused labia, common urogenital sinus, or complete masculinization with nonpalpable testes (2)[C]. �
DIFFERENTIAL DIAGNOSIS
Pyloric stenosis, cryptorchidism, Addison disease, adrenal hemorrhage, androgen insensitivity, Denys-Drash (a.k.a. WAGR) syndrome, 5-α-reductase deficiency, adrenal adenoma, polycystic ovary syndrome �
DIAGNOSTIC TESTS & INTERPRETATION
- Newborn screening for 21-hydroxylase deficiency with immunoassay for elevated 17-hydroxyprogesterone:
- As of 2009, all 50 states screen for CAH.
- False-positive findings are common with premature infants. Thus, many programs have established reference ranges based on gestational age and weight.
- Gold standard: cosyntropin stimulation test with baseline and 60-minute 17-hydroxyprogesterone levels to confirm diagnosis of CAH
- Increased corticotropin, androstenedione, and testosterone and decreased cortisol are suggestive of CAH (3)[C].
- Hyponatremia, hyperkalemia, hypoglycemia, metabolic acidosis, and elevated plasma renin activity (PRA), and reduced aldosterone-to-PRA ratio indicate salt wasting (2)[C].
Follow-Up Tests & Special Considerations
- 21-hydroxylase genotyping
- Adrenal androgen profile after cosyntropin stimulation will diagnose enzyme deficiencies other than 21-hydroxylase deficiency (4)[A].
- Karyotyping for ambiguous genitalia
- ECG for hyperkalemia
- CT scan can be helpful in ruling out adrenal hemorrhage.
- Annual bone age, starting at age 2 years
- Testicular ultrasound to look for adrenal rest tumors in adolescent and adult males
Diagnostic Procedures/Other
Amniocentesis or chorionic villus sampling for prenatal diagnosis �
TREATMENT
MEDICATION
First Line
- In classic CAH, glucocorticoids are given to replace cortisol and to partially suppress androgen production. Mineralocorticoids are given to return electrolyte and renin levels to normal.
- Physiologic cortisol secretion rates are 6 mg/m2 daily.
- Glucocorticoid replacement is often with hydrocortisone in children and prednisone or dexamethasone in adults. The dose is higher than physiologic replacement (typical hydrocortisone dose of 10 to 15 mg/m2 daily in a growing child) titrated until 17-hydroxyprogesterone and androgen levels are partially suppressed (4)[A].
- The target 17-hydroxyprogresterone range is generally 12 to 36 nmol/L when measured in early morning prior to medications.
- Mineralocorticoid replacement with fludrocortisone (0.05 to 0.20 mg/day) is recommended in salt-wasting CAH. Plasma renin levels are monitored to determine adequacy of treatment. Fludrocortisone may also be used in simple virilizing CAH because it allows for lower doses of glucocorticoids (4)[A].
- Infants with salt-wasting CAH will initially require 1 to 2 g of NaCl for the first 6 to 12 months of life (4)[A].
Second Line
- Stress-dose glucocorticoids are necessary for classic CAH patients with infection, trauma, or surgery. During stress, oral glucocorticoid dosing is doubled or tripled. If patient is unable to take PO, IV/IM hydrocortisone is given.
- 25 mg for an infant
- 50 mg for a child
- 100 mg for an adolescent or adult
- Dosing may be continued using the same q6-8h frequency or by continuous infusion.
- Patients with nonclassical CAH require no glucocorticoid or mineralocorticoid treatment.
- However, treatment with glucocorticoids may be indicated in children with advanced skeletal maturation to prevent true precocious puberty and normalize adult height, and in females to prevent hirsutism and polycystic ovaries.
- Oral contraceptive pills can be used in adolescent and adult females for menstrual irregularities, acne, and hirsutism (5)[A].
- Ovulation induction may be needed for fertility.
ISSUES FOR REFERRAL
- Those with ambiguous genitalia should consult a pediatric surgeon/urologist with expertise in treating CAH.
- A clinical psychologist experienced in psychosexual counseling may be helpful for women with gender identity issues later in life.
- A genetic counselor may be helpful for patients with CAH who are planning to have children.
ADDITIONAL THERAPIES
- Aromatase inhibitors and androgen receptor blockers are currently being studied to see if they will decrease the dose of steroid replacement and, therefore, side effects of treatment (2)[C].
- Long-term studies of children receiving a four-drug regimen of low-dose hydrocortisone, fludrocortisone, flutamide, and testolactone are currently underway.
- Animal models for gene therapy have also shown promise.
- Single adrenal injection with adenoviral vector encoding 21-hydroxylase restored impaired enzymatic function in 21-hydroxylase knockout mice.
- Currently, consensus guidelines recommend prenatal treatment with dexamethasone remain labeled, as experimental therapy and no specific treatment protocol is recommended at this time (5)[A].
SURGERY/OTHER PROCEDURES
- Female infants with ambiguous genitalia can have it corrected surgically during infancy.
- Intersex patient groups propose waiting until patients are older and can participate in the decision process.
- Bilateral adrenalectomy is recommended rarely in cases of patients who have failed medical therapy.
Admission Criteria/Initial Stabilization
- Hyponatremia, hyperkalemia
- Hypotension, shock
- Illness during which patient is unable to take oral glucocorticoids
IV Fluids
- NS bolus of 20 mL/kg
- Followed by maintenance fluids of D5NS
Nursing
Teach stress-dosing glucocorticoids for illness. �
Discharge Criteria
Resolution of hypotension, shock, and electrolyte abnormalities �
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
A multidisciplinary approach will best serve the patient with CAH, often including a pediatrician or primary care physician, endocrinologist, pediatric urologist or surgeon, clinical psychologist, and Ob/Gyn. �
Patient Monitoring
- Regular assessment of height, weight and physical examination
- Excess androgens can result in premature epiphyseal closure and shortened stature. Achieving adequate height in CAH patients remains a challenge.
- Annual bone ages to assess skeletal maturation
- Regular lab evaluation of adrenal androgens
- 17-Hydroxyprogesterone, androstenedione, and testosterone are considered the best markers when assessing the appropriateness of current therapy.
- Long-term treatment goals in children include normal linear growth, puberty, and bone age maturation.
- Long-term treatment goals in adolescent and adult women include normalization of menses, fertility, and minimizing hirsutism.
- Many females with CAH are infertile, but often conceive after ovulation induction.
DIET
For salt-wasting form, patients may need periods of high-salt diet, particularly in the 1st year of life. �
PATIENT EDUCATION
- www.caresfoundation.org
- www.hormone.org
PROGNOSIS
Good with medication compliance and frequent follow-up visits with a medical and surgical team with expertise in the treatment of CAH �
COMPLICATIONS
Cushing syndrome due to excess exogenous glucocorticoid replacement needs to be monitored carefully. �
REFERENCES
11 Al-Agha �AE, Ocheltree �AH, Al-Tamimi �MD. Association between genotype, clinical presentation, and severity of congenital adrenal hyperplasia: a review. Turkish J Pediatrics. 2012;54(4):323-332.22 Merke �D, Bornstein �S. Congenital adrenal hyperplasia. Lancet. 2005;365(9477):2125-2136.33 Speizer �PW, Azziz �R, Baskin �LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(9):4133-4160.44 Kim �MS, Ryabets-Lienhard �A, Geffner �ME. Management of congenital adrenal hyperplasia in childhood. Curr Opin Endocrinol Diabetes Obes. 2012;19(6):483-488.55 Trapp �CM, Speiser �PW, Oberfield �SE. Congenital adrenal hyperplasia: an update in children. Curr Opin Endocrinol Diabetes Obes. 2011;18(3):166-170.
CODES
ICD10
E25.0 Congenital adrenogenital disorders assoc w enzyme deficiency �
ICD9
255.2 Adrenogenital disorders �
SNOMED
- Congenital adrenal hyperplasia (disorder)
- steroid 21-monooxygenase deficiency, simple virilizing type (disorder)
- salt-losing congenital adrenal hyperplasia (disorder)
CLINICAL PEARLS
- CAH is an autosomal recessive disorder most often caused by deficiency of 21-hydroxylase.
- CAH encompasses a spectrum of disorders, which can be classified as salt wasting, simple virilizing, and nonclassical.
- Treatment involves replacing glucocorticoid and mineralocorticoid with the goal of preventing adrenal crisis and excess androgen secretion for normal growth and development.