ESPE Yearbook of Paediatric Endocrinology

Endocrine. 2024 Jul;85(1):363-369. PMID: 38441846 doi: 10.1007/s12020-024-03747-x

Brief Summary: This genetic screening study in South India evaluated the carrier frequency of CYP21A2 mutations in a population with high incidence of CAH and high rate of consanguinity. The authors advocate for genetic screening in those at high risk due to a family history of CAH, history of consanguinity, or history of early infant death.

Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency is more common in India than many other countries. While newborn screening allows for identification of cases, it has limitations. Given the high incidence of CAH in India and a rate of consanguineous marriage as high as 30%, the authors screened 1034 healthy individuals with no known relevant history to identify the carrier frequency of hotspot mutations in CYP21A2in the South Indian population.

Blood samples were obtained from 1034 asymptomatic individuals (432 males and 602 females) collected as control samples for other projects. Genotyping was performed for 9 common mutations in CYP21Q2 (30kb deletion. P30L, I2G, 8 bp del, 1172N, E6CLUS (I235N, V236E, M238K), V281L, Q318X and R356W). Genotypingidentified 101 carriers (39 males and 62 females) giving a carrier frequency of 9.76%. The most common mutation was the 30kb deletion (4.6%) with chimera I(CHI) in 18 cases.

While the carrier frequency in the South India population is similar to that previously reported in Europe, there is a high frequency of classical mutations compared to non-classical mutations (8.64% vs 1.07%). This suggests that some subgroups may be at high risk of developing classical CAH. The authors calculate that the identified heterozygous carrier frequency would result in an estimated prevalence of classical CAH of 1 in 416. This is 5 times higher than the reported incidence based on South Indian newborn screening data reported by the Indian Council of Medical Research (1 in 2036). This disparity may be attributed to a higher neonatal mortality among the unscreened newborns or to other unknown factors.

The authors advocate for CAH carrier screening programs among those with a family history of CAH, a family history of consanguinity, partners of CAH affected individuals, and couples with a history of infant death to allow appropriate decision-making and early intervention if indicated.