Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder; 21 hydroxylase deficiency is the most common cause accounting for 95% of cases [1]. The extent of the enzyme impairment and the clinical phenotype of the disease are determined by the severity of the genetic defect in the CYP 21 gene [2]. We present here the gene mutations seen in patients with CAH from Chennai, India, presenting to the department of Pediatric endocrinology at Kanchi Kamakoti CHILDS Trust Hospital, Chennai, India from August 2013 to July 2014. Children diagnosed with classical congenital adrenal hyperplasia (salt-wasting phenotype) based on the clinical features, serum electrolytes, 17 hydroxy progesterone levels and molecular genetic analysis, and followed during the study period were included. Informed consent was obtained and the study was approved by the Institutional ethics committee. Molecular genetic testing of CYP21A2 gene was performed at All India Institute of Medical Sciences, New Delhi.

Abnormal genotype in CYP21A2 gene was detected in 6 (4 boys) out of 10 children with CAH screened. Their clinico-laboratory characteristics are shown in Table I. 8 base pair deletion in exon 3 of CYP21A2 gene was the commonest mutation seen in 4 children, followed by 12 g deletion mutation in Intron 2 in the remaining two. Mutation was not detected in four children. All children were treated with hydrocortisone and fludrocortisone, and are doing well at follow-up. Boys with CAH were diagnosed later than girls in our study which is similar to an earlier study by Bajpai, et al. [3], thus stressing the need to rigorously implement neonatal screening of all children which will enhance the earlier diagnosis of less severe forms of CAH, reduce the virilization in classical forms and promote normal growth. Vomiting and failure to thrive were the most common clinical presentation seen in both genders in our series, similar to an earlier observation by Begum, et al. [4].

TABLE I Clinico – Laboratory Profile of Children with CAH

To date there are approximately 100 different mutations reported in CYP 21 gene including deletions, point mutations and insertions. Severe mutations are associated with classical CAH whereas milder mutations are associated with non-classical CAH [5,6]. Marumudi, et al. from New Delhi reported Intron 2 mutation as the most common mutation in patients with CAH [7]. Mathur, et al. [6] from New Delhi reported Ile173Asn followed by intron 2 splice and Gln 319 stop mutations in children with classical CAH. In our series, 8 bp deletion in exon 3 of the CYP21A2 gene was the most common (66.7%) followed by 12 g mutation in Intron 2 of the CYP21A2 gene [IVS2-13A/C>G]. As complete sequencing of CYP21A2 gene is expensive and is available only in select laboratories, knowledge of common mutations prevalent in our population helps us to make a reliable pre-, peri- and post-natal diagnosis, and also to offer genetic counseling to the affected families.

1. Huynh T, McGown I, Cowley D, Nyunt O, Leong GM, Harris M, et al. The clinical and biochemical spectrum of congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. Clin Biochem Rev. 2009;30:75-86.

2. Dolzan V, Stopar-Obreza M, Zerjav-Tansek M, Breskvar K, Krzisnik C, Battelino T. Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: A novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease. Eur J Endocrinol. 2003;149:137-44.

3. Bajpai A, Kabra M, Menon PS. 21-Hydroxylase deficiency: Clinical features, laboratory profile and pointers to diagnosis in Indian children. Indian Pediatr. 2004;41:1226-32.

4. Begum JA, Sarker AK, Hoque M, Mamum MAA, Mobarak MR, Biswas R, et al. Clinical profile of congenital adrenal hyperplasia(CAH): A treatable disease. Dhaka Shishu (Children) Hospital Journal. 2010;26:108-12.

5. Forest MG. Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod Update. 2004; 10:469-85.

6. Marumudi E, Sharma A, Kulshreshtha B, Khadgawat R, Khurana ML, Ammini AC. Molecular genetic analysis of CYP21A2 gene in patients with congenital adrenal hyperplasia. Indian J Endocrinol Metab. 2012;16:384-8.