Congenital Adrenal Hyperplasia Due to a Previously Undescribed Homozygous Mutation in 17-Alpha-Hydroylase (CYP17A1) Gene

Presentation Number: SAT-0752
Date of Presentation: June 21st, 2014

Mohammed Almehthel1, Ebtesam Qasem2 and Ali Saeed Alzahrani*2
1King Faisal Specialist Hosp & Research Centre, Riyadh, Saudi Arabia, 2King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia


Background: Congenital adrenal hyperplasia (CAH) due to 17-alpha-hydroylase (CYP17A1) deficiency is a rare autosomal recessive disorder.  Several CYP17A1 gene mutations have been reported (1, 2).  We report here a case of a young “female” who has this condition.

Case: An 19-year-old patient, raised as a female, presented with delayed puberty. She was a product of full term, spontaneous vaginal delivery without any complications; particularly there was no history of neonatal crisis. Her childhood and adolescence were uneventful. She presented with primary amenorrhea and lack of secondary sexual characteristics.  She has never been told to have hypertension of hypokalemia. Parents are first-degree relatives and she has 5 sisters who all achieved puberity by age 13 years. Physical examination was remarkable for BP of 136/99 mmHg and Tanner I breasts. She has scant axillary and pubic hair. Genital exam showed female external genitalia with small blind vaginal pouch. No clitromegaly and no palpable gonads in the pubic or inguinal areas. She has no alopecia or acne.  Laboratory investigations are remarkable for the following(normal values are presented between the brackets): K 2.3 mmol/L (3.5-5.0), CO2 33 mmol/L (22-30), ACTH 124 ng/L (5-60), AM cortisol 154 nmol/L (low normal), peak cortisol after ACTH stimulation was 225 nmol/L (expected >550 nmol/l), renin <0.5 mU/L, Aldosterone 384 pmol/L (normal), deoxycorticosterone 829 ng/dL (3.5-11.5) , 17-hydroxyprogesterone <0.4 nmol/L, DHEAS 0.13 µmol/L (1.8-8.3), testosterone < 0.08 nmol/L, DHT <50 pg/mL, 11-deoxycortisol <5 ng/dL, Estradio 25 pmol/L and progesterone 33 nmol/L. Karyotyping 46XY. MRI of pelvis showed no uterus, cervix or ovaries with distal vagina and bilateral inguinal oval-shaped structure which could represent bilateral undescended testes.

Molecular studies:DNA was extracted from peripheral leucocytes using Puregene DNA extraction kit.  Primers and PCR conditions to amplify the 8 exons and the exon-intron boundaries of the CYP17A1 gene were previously described (3). The PCR products were purified and directly sequenced. 

Results: A biallelic homozygous mutation changing guanine to adenine in exon 8 (c.G1247A) and changing the codon 416 from CGT to CAT resulting in a substitution of arginine with histidine (R416H).  This mutation was previously described in a patient with CYP17A1 deficiency in a heterozygous form as part of a compound heterozygous mutation with another heterozygous mutation in exon 2 (R125Q) but has never been described as an isolated homozygous mutation. It was previously functionally characterized and was shown to abolish the activity of the CYP17A1.    

Conclusion: We present a case of CAH with clinical and laboratory investigations consistent with 17-alpha-hydroxylase deficiency which was confirmed by genetic testing showing a mutation in CYP17A1 gene (R416H) that has never been described in a homozygous form.


Nothing to Disclose: MA, EQ, ASA