Basics
Description
Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders that have in common the deficiency of an enzyme needed for cortisol biosynthesis. The disease exists along a spectrum of severity and is typically subdivided into "classic" (severe) and "nonclassic" (milder) forms.
- There are 5 specific causes of CAH:
- 21-hydroxylase deficiency
- 11-hydroxylase deficiency
- 3β-hydroxysteroid dehydrogenase deficiency
- 17α-hydroxylase deficiency
- Congenital lipoid hyperplasia (stAR mutation)
- The vast majority of cases of CAH (~95%) are due to 21-hydroxylase (21OHase) deficiency, which will therefore be the focus of this chapter. The 21OHase enzyme is in the glucocorticoid and mineralocorticoid biosynthetic pathways.
Epidemiology
- The incidence of classic CAH is 1:10,000-1:20,000 live births.
- More common in certain ethnic groups and in remote areas.
- ~75% of cases are characterized by overt salt wasting due to mineralocorticoid deficiency, whereas the remaining cases are described as simply virilizing.
- The prevalence of non-classic CAH (also called late-onset) is approximately 1:1,000.
- More common in some ethnicities such as Ashkenazi, Italian, and Yugoslavian and may be as common as 1:50 individuals in these groups.
Risk Factors
Genetics
- CAH is caused by mutations in the CYP21A2 gene, which is located on chromosome 6p21.3 and encodes for the 21OHase enzyme. This locus is characterized by many overlapping transcripts and a high rate of recombination.
- Most mutations involve large deletions or arise from the transfer of small sequences of the nearby pseudogene CYP21A1P during meiosis. More than 100 different CYP21A2 mutations are known. Most patients are compound heterozygotes, with the phenotype reflecting the milder mutation. Approximately 1% of mutations are estimated to arise de novo and uniparental disomy has been reported in one case.
- Although genotype-phenotype correlations are generally high, the genetic complexity of CAH renders them sometimes problematic.
Pathophysiology
- The enzymatic block in cortisol biosynthesis results in diminished negative feedback at the level of the hypothalamus and pituitary gland with a subsequent increase in CRH and ACTH. The buildup of precursors proximal to the block results in increased adrenal androgen production. Variable degrees of mineralocorticoid deficiency cause salt wasting and contribute to the risk of adrenal crisis. The clinical consequences of this process vary according to gender and to the severity of the CAH (Appendix, Table 13).
- Classic CAH; genetic females
- Androgen excess during early prenatal life (1st trimester) results in ambiguous genitalia. Typical features include elongation of the urethra, development of a urogenital sinus, and enlargement of the clitoris.
- Development of the internal reproductive structures is unaffected.
- If not diagnosed and treated early, progressive virilization occurs postnatally. Girls with salt-wasting CAH are also at risk for an adrenal crisis.
- Classis CAH; genetic males
- Prenatal androgen exposure has no clinical consequence in infant boys with CAH. However, infant boys with salt-wasting CAH are at risk for an adrenal crisis.
- As with girls, if not diagnosed and treated early, progressive virilization occurs postnatally.
- Non-classic CAH; females
- The far milder degree of androgen excess in non-classic CAH has no effect during embryologic development but can result in symptoms of hyperandrogenism during childhood, adolescence, or adulthood.
- Non-classic CAH; males
- Symptoms of androgen excess can occur during childhood, adolescence, or adulthood.
Diagnosis
History
- Any family history of CAH should be sought as well as any history of exposures and/or maternal virilization during pregnancy. In infants, poor feeding, lethargy, and vomiting are important potential clues to an impending adrenal crisis.
- Children with previously undiagnosed CAH typically present with precocious puberty due to androgen excess. Typical symptoms in classic CAH include adult body odor, acne, pubic and axillary hair, penile enlargement in boys, clitoromegaly in girls, and linear growth acceleration. Symptoms of nonclassic CAH during childhood are usually limited to adult body odor and early pubic/axillary hair.
- Symptoms of CAH in adolescent girls include irregular periods, hirsutism, and acne.
Physical Exam
- Classic CAH; genetic females
- Ambiguous genitalia in infant girls with classic CAH exists along a continuum known as the Prader scale. Prader 1 is a typical female, whereas Prader 5 denotes the most extreme degree of masculinization in which the urethral opening is at the tip of the clitoris and complete labial fusion has occurred. Thus, a male sex assignment is sometimes mistakenly made. This scenario is the rationale for the admonition "Never circumcise a male infant with bilaterally nonpalpable testes!"
- Most girls with classic CAH are Prader 3 or 4. Significant clitoromegaly will be present along with increased rugation and pigmentation of the labioscrotal structures but no palpable gonads. Posterior labial fusion and a single perineal opening is usually found.
- Physical findings in the setting of salt wasting are nonspecific but would include low weight percentile, poor skin turgor, dry mucous membranes, and vital signs suggesting dehydration.
- Although the vast majority of infant girls with classic CAH are diagnosed in the newborn period, occasional cases are missed. If this occurs, the external genitalia will exhibit the same features as in infancy. Other signs of hyperandrogenism will be present such as pubic hair and extreme tall stature from linear growth acceleration. The presence of a urogenital sinus and posterior labial fusion indicate 1st-trimester androgen excess, whereas androgen exposure after this critical period results in clitoromegaly only.
- Classic CAH; genetic males
- Although average penile size in newborn boys with classic CAH is increased, the external genitalia appear normal and thus there is nothing on physical exam to alert providers to the presence of CAH. As is the case in girls, physical exam findings associated with salt wasting include low weight percentile, poor skin turgor, dry mucous membranes, and vital signs indicating dehydration.
- Boys with classic CAH who are missed in infancy come to medical attention due to early secondary sexual development. On physical exam, tall stature, adult body odor, acne, pubic and axillary hair, and penile enlargement are seen. A hallmark of CAH and other forms of peripheral precocious puberty in boys is a prepubertal testicular volume, indicating a source of sex steroids other than the HPG axis.
- Nonclassic CAH; females
- Girls with nonclassic CAH have pubic and/or axillary hair, adult body odor, and ± acne. Adolescent girls typically have hirsutism. Mild clitoromegaly may also be seen.
- Nonclassic CAH; males
- Boys with nonclassic CAH will also have signs of mild androgen excess on physical exam including pubic and axillary hair, adult body odor, and acne.
Diagnostic Tests & Interpretation
Lab
- CAH is included on the newborn screen in all 50 states. The biochemical hallmark is an elevated 17-hydroxyprogesterone (17OHP). Depending on the 17OHP concentration, a repeat newborn screen or a serum concentration is obtained. In any presumptive positive case, serum electrolytes need to be monitored closely for early detection of an adrenal crisis. False positives are extremely common in preterm and sick neonates. An elevated plasma renin will confirm overt salt wasting.
- Any report of an abnormal newborn screen for CAH, particularly in a term infant male, should be considered an emergency.
- Serum 17OHP is also the diagnostic test for classic CAH that was missed in the newborn period and for nonclassic CAH. Testosterone, dehydroepiandrosterone-sulfate (DHEAS), and androstenedione should also be measured.
Imaging
- In infants with ambiguous genitalia, a pelvic ultrasound and genitogram are often performed. In girls with CAH, a normal uterus is seen on ultrasound, whereas a urogenital sinus, "male-type" urethra, and cervical impression are typical findings on genitogram. No routine imaging is performed in infant boys with CAH. However, periodic testicular ultrasound to detect adrenal rest tumors is recommended starting in adolescence, particularly in boys whose CAH is poorly controlled as evidenced by chronic elevations in 17OHP concentrations.
- A bone age x-ray is an important part of the evaluation in children with precocious puberty. In the setting of undiagnosed classic CAH, skeletal maturation will be markedly advanced.
Diagnostic Procedures/Other
- In equivocal cases, a full ACTH stimulation test can distinguish between classic and nonclassic CAH, affected individuals and heterozygous carriers, and between 21OHase deficiency and other forms of CAH.
- Genotyping can also confirm the diagnosis and is helpful for genetic counseling. However, complete sequencing (rather than targeted mutation analysis) of the CYP21A2 gene may be necessary to accurately determine genotype because complex genetic variations are often present.
Differential Diagnosis
- CAH is the most common 46,XX disorder of sex development. Other causes for ambiguous genitalia are outlined in other chapters.
- The differential diagnosis of classic CAH presenting during childhood includes etiologies of androgen excess such as an androgen-secreting tumor or exogenous exposures. In boys, a β-hCG-producing tumor, McCune-Albright syndrome, and familial male precocious puberty should be considered.
- Nonclassic CAH presenting during childhood is often indistinguishable from premature adrenarche. In adolescent girls, the differential diagnosis includes PCOS, which also shares many clinical features with nonclassic CAH.
Treatment
Medication
- Medical treatment of CAH consists of glucocorticoid therapy in doses sufficient to suppress adrenal androgen overproduction, which are generally considered to be 10-15 mg/m2/24 h hydrocortisone equivalent.
- Regardless of salt-wasting status, current recommendations also endorse mineralocorticoid therapy in all patients with classic CAH in the form of Florinef 0.05-0.2 mg/24 h.
- Salt supplementation (NaCl 3-5 mEq/kg/24 h) is also needed during infancy.
Additional Treatment
Girls with CAH usually undergo genital surgery in the form of a feminizing genitoplasty. However, whether and when such surgery should be performed is controversial.
General Measures
Alert
Stress-dose glucocorticoid coverage during illness or injury is essential in patients with CAH.
Ongoing Care
Ongoing clinic visits and monitoring of growth, puberty, and hormonal studies (including serial measurements of 17OHP) are standard of care. Psychological support and educational materials should be provided on a regular basis.
Prognosis
- Adult height is normal when CAH is well controlled but is compromised in poorly controlled or late-diagnosed cases.
- Girls with classic CAH may exhibit boy-typical behaviors but have normal female gender identity.
- Fertility is decreased in women with classic CAH compared to the general population.
- Fertility may be impaired in men with CAH if testicular adrenal rest tumors are present.
- Transition to adulthood ideally takes place in the context of a multidisciplinary team.
Additional Reading
- Auchus RJ, Witchel SF, Leight KR, et al. Guidelines for the development of comprehensive care centers for congenital adrenal hyperplasia: guidance from the CARES Foundation initiative. Int J Pediatr Endocrinol. 2010;2010:275213. [View Abstract]
- Finkielstain GP, Chen W, Mehta SP, et al. Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21- hydroxylase deficiency. J Clin Endocrinol Metab. 2011;96(1):E161-E172. [View Abstract]
- Nebesio TD, Eugster EA. Growth and reproductive outcomes in congenital adrenal hyperplasia. Int J Pediatr Endocrinol. 2010;2010:298937. [View Abstract]
- Speiser 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. [View Abstract]
- Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003;349(8):776-788. [View Abstract]
Codes
ICD09
- 255.2 Adrenogenital disorders
ICD10
- E25.0 Congenital adrenogenital disorders assoc w enzyme deficiency
SNOMED
- 237751000 Congenital adrenal hyperplasia (disorder)
- 698855007 21-hydroxylase deficiency (disorder)
- 237753002 salt-losing congenital adrenal hyperplasia (disorder)
- 237754008 Late onset congenital adrenal hyperplasia (disorder)
FAQ
- Q: When does a salt-wasting crisis usually occur in newborns with CAH?
- A: The most common time is between days 5 and 10 of life. However, it may occur as early as on day 1 of life or not until many weeks or months later.
- Q: When should children with CAH be given a "stress dose" and what does this consist of?
- A: Double or triple the usual glucocorticoid dose is considered a stress dose. This should be given at times of illness or psychological stress. However, if a child is vomiting, an emergency Solu-Cortef injection should be given. Hydrocortisone 100 mg/m2 IV is given prior to any surgery.
- Q: What is the best form of glucocorticoid treatment in children with CAH?
- A: Hydrocortisone has long been considered the optimal glucocorticoid in CAH. However, this is controversial, and some patients do well on prednisone or dexamethasone.
- Q: Should extremely virilized girls with CAH be sex-assigned male?
- A: Because fertility and gender identity are normal in girls with CAH, the current consensus is to raise these girls female regardless of the extent of virilization.