The Spectrum of CYP21A2 Gene Mutations from 16 Families of Congenital Adrenal Hyperplasia: Genotype-Phenotype Correlation

Subbiah Sridhar; Ramajayam Govindhan; Balasankar Soundian; Maheshkumar Poomarimuthu; Karuppasamy Nallan; Santhanakrishnan Ramesh Kumar; Subbiah Eagappan; Vasanthiy Natarajan; Sangumani Jayaraman

doi:10.4103/ijem.ijem_442_21

The Spectrum of CYP21A2 Gene Mutations from 16 Families of Congenital Adrenal Hyperplasia: Genotype-Phenotype Correlation

Indian J Endocrinol Metab. 2021 Nov-Dec;25(6):532-537. doi: 10.4103/ijem.ijem_442_21. Epub 2022 Feb 17.

Authors

Subbiah Sridhar¹, Ramajayam Govindhan², Balasankar Soundian³, Maheshkumar Poomarimuthu², Karuppasamy Nallan⁴, Santhanakrishnan Ramesh Kumar⁵, Subbiah Eagappan⁶, Vasanthiy Natarajan¹, Sangumani Jayaraman⁷

Affiliations

¹ Department of Endocrinology, Madurai Medical College and Govt. Rajaji Hospital, Madurai, Tamil Nadu, India.
² Multidisciplinary Research Unit, Madurai Medical College, Madurai, Tamil Nadu, India.
³ Institute of Pediatrics, Madurai Medical College, Madurai, Tamil Nadu, India.
⁴ Department of Pediatric Surgery, Madurai Medical College, Madurai, Tamil Nadu, India.
⁵ ICMR - National Institute for Research in Tuberculosis, Madurai Unit, Govt Rajaji Hospital, Madurai, Tamil Nadu, India.
⁶ Department of Diabetology and Endocrinology, Madurai Medical College, Madurai, Tamil Nadu, India.
⁷ Department of Endocrinology, Madurai Medical College, Madurai, Tamil Nadu, India.

Abstract

Aim: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of the adrenal steroidogenic pathway. The most common form of CAH is due to 21-hydroxylase deficiency resulting from mutations in CYP21A2 gene. The present study aimed to identify CYP21A2 common gene mutations, phenotype correlation, and to analyze the segregation pattern in CAH patients, parents, and siblings.

Materials and methods: Sixteen families having at least one classic CAH child in each family, a total of 58 subjects were recruited. The presence of six most common gene mutations, namely, Intron 2 (c.293-13A/C>G), c.844G>T (p.Val282Leu), c.1019G>A (p.Arg340His), c.92C>T (p.Pro31Leu), c.955C>T (p.Gln319*), and c.518T>A (p.Ile173Asn) in CYP21A2 gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using specific primers.

Results: Out of 16 classic CAH females analyzed, salt-wasting (SW) form was present in 12 (75%) and simple virilizing form in four (25%) children. Isolated clitoromegaly was the most common clinical presentation followed by ambiguous genitalia. The most common mutation observed in CAH patient population was Intron 2 (c.293-13A/C>G) (100%) followed by p.Pro31Leu (98%), p.Gln319* (93%), p.Val282Leu (91.4%), and p.Ile173Asn (19%). Although p.Arg340His mutation was not observed in this study. Interestingly, Intron 2 (c.293-13A/C>G) homozygous was observed in 31.3% of the entire study cohort and p.Ile173Asn mutation was found to be associated with SW form.

Conclusions: Our results suggested a high prevalence of CYP21A2 gene mutations among CAH patients and heterogeneous mutation spectrum in their families of south Indian cohort. The outcomes afford valuable evidence for premarital and prenatal screening as well as planning suitable programs to prevent the development of CAH in Indian population.

Keywords: 21-hydroxylase deficiency; CYP21A2 gene mutations; India; ambiguous genitalia; clitoromegaly; congenital adrenal hyperplasia.