BACKGROUND AND PURPOSE:

• Epidemiology of congenital adrenal hyperplasia (CAH) is well established, due to newborn screening (NBS) programs, now available in over 40 countries
  • 95% of cases related to deficiency in 21-hydroxylase (CYP21A2 gene)
    • While 100s of mutations described, only 12 mutations account for 95% of pathogenic variants
  • Prevalence estimated between 1:10,000 – 1:20,000
  • May be life-threatening with glucocorticoid insufficiency and salt wasting
• NBS programs do not screen for more mild forms of nonclassic or mild forms of CAH, and rates are based on a paper dating from 1985
  • Ashkenazi Jews; 3.7% affected; 30.9% carrier rate)
  • Caucasians: 0.1% affected
• Only 3 mutations make up the majority of nonclassic CAH
• Nonclassic CAH may be asymptomatic or present with signs and symptoms of androgen excess
  • In adults: Hirsutism, menstrual disorders and/or infertility
• Hannah-Shmouni et al. (Genetics in Medicine, 2017) sought to reassess prevalence of nonclassic CAH in the Ashkenazi Jewish and Caucasian populations using the latest technologies

METHODS:

• CYP21A2 genotyping was performed on Ashkenazi Jewish subjects and US Caucasians
• 200 Ashkenazi Jewish individuals: Classification based on having 4 Ashkenazi Jewish grandparents
• 200 Caucasians who did not self-identify with any ethnicity

RESULTS:

• Ashkenazi Jews
  • 15% (1/7) were nonclassic carriers (not statistically different than Caucasians)
  • 2.5% (1/40) were classic carriers
  • 0.5% (1/200) affected
• Caucasians
  • 9.5% (1/11) were nonclassic carriers
  • 1.5% (1/67) were classic CAH carriers
  • 0.5% (1/200) affected

CONCLUSION:

• Carrier rates for nonclassic CAH is higher in Caucasians and lower in Ashkenazi Jews than previously reported
• Carrier rates for nonclassic CAH related mutations seen across all ethnicities suggesting there may be some evolutionary advantage to being a carrier
• Important implications
  • Consider nonclassic CAH in the setting of female hyperandrogenism as treatment different than for that of PCOS
  • Infertility and miscarriage associated with nonclassic CAH can be treated with glucocorticoid therapy
  • 1/200 disease risk of nonclassic CAH suggests benefit of screening regardless of ethnicity in the setting of infertility
• Nonclassic CAH is a common condition, regardless of ethnicity, and should be considered with preconception and infertility counseling

Learn More – Primary Sources:

Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians

Related ObG Topics:

Polycystic Ovary Syndrome: Making the Diagnosis

Secondary Amenorrhea: Workup and Diagnosis  

Infertility Evaluation: Who, When and How