ESPE Abstracts (2018) 89 P-P3-015

A Homozygous Mutation c.518T>A (p.lle173Asn) of the CYP21A2 Gene Presenting as Non-Classical Congenital Adrenal Hyperplasia (NCAH)

Teodora Karamfilovaa, Iva Stoevab, Kalina Mihovac, Rada Kanevac, Kaloyan Tsocheva & Violeta Iotovaa,d


aUniversity Hospital St. Marina – Varna, Varna, Bulgaria; bUniversity Pediatric Hospital ‘Prof. Ivan Mitev’, Screening and Functional Endocrine Diagnostics, Medical University of Sofia, Sofia, Bulgaria; cMolecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University of Sofia, Sofia, Bulgaria; dDepartment of Pediatrics, Medical University of Varna, Varna, Bulgaria


Congenital adrenal hyperplasia due to P450c21 (21-hydroxylase) deficiency is an autosomal recessive disorder presenting as three phenotypes dependent on the residual enzyme activity: two classical ones (salt wasting and simple virilizing, SV) and the milder NCAH. All forms have increased adrenal androgens. Around 0.1% of Caucasians and up to several percent of certain ethnic groups are affected by NCAH. Most NCAH patients remain undiagnosed. Symptoms of NCAH may develop at any age, but are more typical during late childhood/adolescence. We present a 20-year-old patient followed since she was 14 due to hirsutism and overweight. Menarche started at 12 years, initially with regular periods. After 15 years of age periods started to occur 6-8 times a year with increase in body hairs. Metabolic syndrome was also diagnosed and Metformin therapy was administered at 850 mg/day. Weight was reduced with 10%, but hirsutism and irregular menstruation persisted. Baseline 17-OH-Progesterone (17OHPG) was 8 nmol/l and Dehydrocortisone was added to therapy. Over the years, the level of 17OHPG has decreased without full normalization (Table 1). In the last year the patient had regular periods and no further progression of hirsutism. Family history was non-contributory. The patient was selected as a candidate for CYP21A2 genotyping because of the elevated basal 17OHPG, hirsutism and metabolic syndrome, as well as menstrual irregularities. By Sanger sequencing a homozygous missense mutation c.518T>A (p.Ile173Asn) was found, also known as p.I172N. The mutation leads to markedly reduced enzyme activity and has been associated with SV.

Table 1 Clinical and hormonal studies.
Age14.5 years15.0 years15.5 years19 years
We (kg)/He (cm)/BMI(kg/m2)65/158/26.160.5/159/24.058/159/23.058/159/23.0
17OHPG ng/ml (r.r. 0.2–1.3)8.02.51.8
LH mIU/ml (r.r. 1.1–11.6)5.56.88.5
FSH mIU/ml (r.r.2.8–11.3)5.54.95.5
Testosterone nmol/l (r.r. 0–1.38)1.91.80.9
TreatmentMetformin 850 mg/dMetformin 850 g/d Dehydrocortisone 2.5 mg/dMetformin 850 g/d Dehydrocortisone 2.5 mg/dDehydrocortisone 5 mg/d

Conclusion: The precise etiological diagnosis was established at 20 yrs of age with subsequent changes of the therapeutic strategy. Sequencing of the CYP21A2 gene was established after the introduction of the 17OHPG screening and is of great importance not only for the classical forms of CAH. This patient contributes to the variability in the genotype-phenotype relations in CAH due to CYP21A2 mutations.

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