A novel deletion in the C4/CYP21/TNX/CREB-rp locus is associated with EDS. The C4 genes, the CYP21 genes and part of TNX are duplicated on chromosome 6. Dashed lines indicate the limits of the duplication event. The normal locus is shown in the top panel. Arrows indicate direction of transcription. TNX is overlapped at its 3′ end by the CYP21B (21B) gene encoding steroid 21-hydroxylase and, at its 5′ end, by CREB-related protein (CREB-rp). XA is a partial duplicate of TNX that is a pseudogene transcribed but not translated in the human adrenal. XA contains a 121 bp deletion (Δ) that truncates the open reading frame corresponding to TNX. CYP21A (21A) is a pseudogene. One-quarter of CYP21B-deficient alleles carry a 30 kb deletion extending from CYP21A to CYP21B (middle panel). This creates a nonfunctional CYP21AB fusion gene and deletes XA, but does not alter TNX. We described a similar deletion (lower panel) extending from XA to TNX that completely deletes CYP21B and creates a TNX/XA fusion gene. This deletion is associated with a new contiguous gene syndrome consisting of congenital adrenal hyperplasia, due to CYP21B deficiency, and EDS, due to TNX deficiency.