ESPE Abstracts (2014) 82 P-D-2-2-279

Genotype-Phenotype Discordant Patients with Homozygous Intron 2 Mutation (IVS2) of CYP21 Gene

Emine Camtosuna, Zeynep Siklara, Hatice Ilgin Ruhib, Nukhet Yurur Kutlayb, Pinar Kocaaya, Ajlan Tukunb & Merih Berberoglua


aDepartment of Pediatric Endocrinology, University of Ankara School of Medicine, Ankara, Turkey; bDepartment of Medical Genetic, University of Ankara School of Medicine, Ankara, Turkey.


Background: 21-Hydroylase deficiency is the most common cause of congenital adrenal hyperplasia (CAH) and resulted from CYP21 gene mutations. Genotype and phenotype are usually concordant. Homozygous intron 2 splice mutation (IVS2/IVS2) is frequently associated with severe enzyme deficit, and causes classical CAH. Here, we present genotype–phenotype discordant members of two different families with IVS2/IVS2 mutation.

Family 1: First child of family 1 was a girl diagnosed as salt wasting (SW) CAH, died at 6 days old and IVS2/IVS2 mutation of CYP21 gene was detected. Analysis of chorion villus sample showed 46, XX karyotype and IVS2/IVS2 mutation in the second pregnancy and mother received dexamethasone treatment. Postnatally, child was treated with hydrocortisone (HC) up to 21 months old. Due to suppressed hormone profile with low dose HC, treatment was discontinued. After this, she was admitted to our hospital at 25 months. She was followed-up for 3 years without medicine and she is still hormonally and clinically normal. The third child was diagnosed as SWCAH with IVS2/IVS2 mutation.

Family 2: The daughter of family 2 was diagnosed Type 1 DM at 4.7 years old. On her follow-up at 8.17 years old, thelarche and axillary hair was detected. Her basal and stimulated 17-hydroxyprogesterone levels were high (7.5 and 18.4 ng/ml respectively), compatible with nonclassical CAH. Her genetic analysis revealed IVS2/IVS2 mutation. Asymptomatic brother also had the same mutation. Considering pseudogene state, molecular analysis of asymptomatic homozygous cases was reevaluated and the same result was observed. Sequence analysis still is going on.

Conclusion: Although patients who has IVS2/IVS2 mutation can present with nonclassical CAH infrequently, asymptomatic patient as seen in our two cases have not been reported yet. In the CYP21 gene mutations, genotype–phenotype discordance is an issue still open for debate.

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