ESPE Abstracts

Introduction: With an overall prevalence of 1:200 to 1:1,000, NCCAH due to 21-hydroxylase deficiency is an important cause of premature pubarche in 5 to 20% of cases. Clitoromegaly is present in up to 11% of adolescents with NCCAH but is not regularly reported in infancy and childhood. Affected children may exhibit advanced bone age, rapid linear growth, and tall stature. Genetically, several compound heterozygous mutations of the CYP21A2 gene are known, as well as mutations in non-coding regulatory regions, leading to NCCAH.

Case Report: We report on triplets (P1,P2,P3) born SGA and preterm (GA 35+0) who presented at the age of 4 years and 8 months with premature pubarche (PH2, B1, C1) in P1 and P2, and a clinically milder presentation in P3 (PH1-2, B1-2 right, B1 left, C1). All of them presented with clitoromegaly (P1: 2.66cm, P2: 2.68cm, and P3: 2.24cm measured by ultrasound imaging). P1 and P2 showed advanced bone age (P1: delta BA +1.47yrs, height -0.45SDS, BMI -0.36SDS; P2: delta BA +1.49yrs, height -0.44SDS, BMI -0.38SDS), whereas P3 showed delayed bone age (P3: delta BA -1.07years, height -1.45SDS, BMI -0.61SDS). Target height is -1.11SDS. Urine multisteroid analysis showed slightly altered metabolites in P1 (24h: pregnanetriol 126µg, 5-pregnenetriol 81µg, pregnanetriolone 2µg, androsterone 163µg, etiocholanolone 111µg) and P2 (spontaneous urine: pregnanetriol 104µg, 5-pregnenetriol 77µg, pregnanetriolone 2µg, androsterone 48µg, etiocholanolone 90µg). No significant alterations were found in P3 (24h: pregnanetriol 53µg, 5-pregnenetriol 40µg, pregnanetriolone 1µg, androsterone 85µg, etiocholanolone 55µg). Serum values of T and 17OHP were normal in all patients; DHEAS levels were 1.64µg/L in P1, 1.14µg/L in P2, and 0.33µg/L in P3. Androstenedione levels were 0.58µg/L in P1, 0.53µg/L in P2, and 0.32µg/L in P3. Genetic testing identified a complete paternal CYP21A2 gene duplication without a mutation (NGS of CYP21A2 exons 1-10, including the promoter region up to -400 bp), and a paternal heterozygous deletion of the CYP21A1P pseudogene in P1 and P2. The CYP21A2:CYP21A1P ratio was 3:1. No genetic abnormality was found in P3. The mother showed a heterozygous deletion of CYP21A1P as well. This indicates that P1 and P2 clinically have NCCAH without a typical mutation in the coding CYP21A2 gene. The milder presentation in P3, with mild premature pubarche and slightly enlarged clitoris, remains idiopathic.

Conclusion: Our family case shows that clinical evidence of NCCAH can arise from a non-mutated CYP21A2 gene duplication. This may result in disrupted gene regulation and reduced enzyme activity of 21-hydroxylase.