Advanced laboratory services

INTRODUCTION

Defective conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol accounts for more than 95 percent of cases of congenital adrenal hyperplasia (CAH). This conversion is mediated by 21-hydroxylase and the defect is due to mutations in the CYP21A2 gene. 

CLINICAL MANIFESTATIONS

The clinical spectrum of disease ranges from the most severe to mild forms, depending on the degree of 21-hydroxylase deficiency (21OHD). Three main clinical phenotypes have been described: classic salt-losing, classic non-salt-losing (simple virilizing), and nonclassic (late-onset):

Females with the classic form (salt-losing and non-salt-losing) present with genital atypia. 

Males with the salt-losing form who are not identified by neonatal screening present with failure to thrive, dehydration, hyponatremia, and hyperkalemia typically at 7 to 14 days of life.

Males with the classic non-salt-losing form who are not identified by neonatal screening typically present at two to four years of age with early virilization (pubic hair, growth spurt, adult body odor).

Nonclassic or late-onset 21OHD may present as early pubarche or sexual precocity in school-age children, hirsutism and menstrual irregularity in young women, or there may be no symptoms. 

Infants/children

Atypical genitalia

  46,XX infants with classic 21OHD are born with atypical genitalia characterized by clitoral enlargement, labial fusion, and formation of a urogenital sinus caused by the effects of in utero androgen excess on development of the external genitalia. Rarely, virilization may be so profound that genital atypia is unrecognized, and male sex assignment is made at birth in a 46,XX patient. 

Affected 46,XY infants are normal appearing at birth but may have subtle findings such as hyperpigmentation of the scrotum or an enlarged phallus. 

Growth

 Children with congenital adrenal hyperplasia (CAH) are at risk for early puberty and adult short stature. Exposure to high levels of sex hormones can induce early puberty and premature epiphyseal closure. 

DIAGNOSIS

The diagnosis of classic 21-hydroxylase deficiency (21OHD) is based upon a very high serum concentration of 17-hydroxyprogesterone (17OHP), the normal substrate for 21-hydroxylase. Most affected neonates have random concentrations greater than 3500 ng/dL (105 nmol/L). The diagnosis of classic 21OHD is almost always made in neonates (75 percent are salt-losing). 

Classic congenital adrenal hyperplasia (CAH) in girls presents as neonates with atypical genitalia, with clitoral enlargement and a common urethral-vaginal orifice (urogenital sinus). Partial or complete fusion of the labial folds. Internal female reproductive organs (uterus and ovaries) are normal. 

Historically, boys presented as neonates with a salt-losing adrenal crisis (hyponatremia, hyperkalemia, and failure to thrive) or as toddlers with signs of puberty (non-salt-losing form). Newborn males show no overt signs of CAH. With the advent of neonatal screening programs, affected males are typically diagnosed before they develop clinical symptoms.In countries where routine neonatal screening is not available, the diagnosis is sometimes made after infancy. 

Newborn screening

 In many countries, neonatal screening for 21OHD is an approved part of the neonatal screening program. The screening test for 17OHP is measured using a filter paper blood sample obtained by a heel puncture preferably between two and four days after birth.  Newborns with findings suggestive of CAH (eg, atypical genitalia) should undergo further endocrine evaluation even if the neonatal screening test is negative. 

GENETIC TESTING

 Genetic testing detects approximately 90 to 95 percent of mutant alleles and can be used to evaluate borderline cases. Genetic testing should be done if the biochemical testing is equivocal or for purposes of genetic counseling.

PRENATAL DIAGNOSIS

 Prenatal diagnosis can be considered when a fetus is known to be at risk because of an affected sibling or when both partners are known to be heterozygous for one of the severe mutations, thus predicting a one-in-eight chance of female genital atypia. The molecular analysis of CYP21A2 genes is now the method of choice.