Endocrine Abstracts

Introduction: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD), large CyP21A2 deletions can also affect the adjacent tenascin-X (TNXB) gene. In patients with or without 21-OHD, pathogenic variants in the TNXB gene cause Ehlers-Danlos syndrome (EDS), a connective tissue dysplasia associated with cardiovascular complications. CAH in conjunction with TNXB-dependent EDS has been termed CAH-X. This study aims to characterize the genetic, biochemical and clinical characteristics of patients with CAH and monoallelic or biallelic TNXB deletions and compare them to patients with CAH and intact TNXB as well as to individuals without CAH.

Methods: CyP21A2 and TNXB genotypes were determined by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Sequence analysis was performed by Alamut. Serum TNX levels were measured by ELISA.

Results: Our cohort comprises 1315 individuals genetically analyzed due to suspicion of CAH. Of 100 patients with classic CAH, we have identified 12 (12%) with heterozygous deletions and 2 (2%) with duplications of TNXB exon 35. In patients with nonclassic CAH, TNXB exon 35 deletions were identified in 1 patient (1.4%). In individuals without 21-OHD, deletions of TNXB exon 35 were rarely detected (0.4%) whereas duplications were more frequent than in the other groups (4.4%). The clinical significance of TNXB duplications is currently not known. Sanger sequencing of TNXB exons 33-44 was performed in 23 samples. A total of 20 different genetic variants were detected, including 4 missense variants, 3 synonymous and 13 intronic variants; 17 were classified as benign or likely benign and 3 were classified as variants of uncertain significance (VUS). The highest serum TNX levels were detected in controls not affected by CAH, whereas patients with CAH-X (genetically characterized by deletion of TNXB exon 35) demonstrated TNX levels significantly lower than those of patients with CAH and intact copy number of TNXB exon 35 as well as controls.

Conclusion: The spectrum of genetic variation affecting TNXB in individuals with or without CAH includes large deletions, often in conjunction with large CyP21A2 deletions, as well as duplications and single nucleotide variants. Further studies are necessary to characterize the clinical relevance of these genetic variants.