If your child has congenital adrenal hyperplasia (CAH), should the parents get genetic testing?

Genetic Testing for Parents of Children with Congenital Adrenal Hyperplasia

Parents of a child diagnosed with congenital adrenal hyperplasia (CAH) should undergo genetic testing to determine their carrier status, as this information is crucial for family planning and identifying potential health risks in the parents themselves. 1, 2

Rationale for Parental Testing

• CAH is an autosomal recessive disorder primarily caused by mutations in the CYP21A2 gene (21-hydroxylase deficiency), which accounts for 90-99% of all CAH cases 1
• Parents of affected children are obligate carriers of at least one mutation, and research has shown that approximately 4% of parents may actually have nonclassic CAH (NCCAH) themselves, which was previously undiagnosed (termed "cryptic NCCAH") 2
• Determining parental carrier status helps interpret genetic results and determine recurrence risk in subsequent pregnancies 1
• The carrier frequency for CYP21A2 mutations can be high in certain populations, with studies showing rates as high as 9.76% in some regions 3

Benefits of Parental Genetic Testing

• Provides accurate recurrence risk assessment for future pregnancies (25% risk if both parents are carriers) 1, 2
• Enables prenatal diagnosis options for subsequent pregnancies 4
• Identifies parents who may have undiagnosed nonclassic CAH and might benefit from medical intervention, particularly during stress situations 2
• Allows for extended family screening, especially important for women of reproductive age who may have fertility issues related to undiagnosed NCCAH 2

Clinical Implications for Parents with Cryptic NCCAH

• Among parents identified with cryptic NCCAH through genetic testing, studies have found:
  • Female parents may have experienced infertility (found in 4 out of 7 women in one study) 2
  • Some women report irregular menses and hirsutism 2
  • Approximately 38% of affected parents may have suboptimal cortisol response to stress, which has implications for medical management 2
  • Male carriers are typically asymptomatic 2

Testing Process

• Genetic testing should include analysis of common CYP21A2 mutations 1, 3
• If genetic testing is not available or conclusive, biochemical testing with an ACTH stimulation test can be performed to assess 17-hydroxyprogesterone levels 1
• A 17-OHP level above 1000 ng/dL is diagnostic of 21-hydroxylase deficiency; borderline levels (200-1000 ng/dL) require an ACTH stimulation test 1

Management Considerations

• Parents identified with NCCAH through genetic testing are mostly asymptomatic and typically do not require ongoing glucocorticoid therapy 2
• However, glucocorticoid stress coverage should be considered for those with suboptimal cortisol response during major surgery, trauma, or childbirth 2, 5
• Female carriers with fertility issues may benefit from specific interventions 2

Important Caveats

• Genetic testing for CAH can be complex due to the presence of a pseudogene (CYP21A1P) that shares 98% sequence identity with the functional CYP21A2 gene 3
• Cost-effective screening methods are becoming more available but may not be accessible in all regions 3
• The risk of having NCCAH for parents of a child with CAH is approximately 1:25, which is significantly higher than the general population risk 2
• If the mother of a child with CAH experiences infertility, evaluation for NCCAH is particularly indicated 2

By understanding their genetic status, parents can make informed decisions about future family planning and manage any potential health implications related to their carrier status or undiagnosed NCCAH.