The HoxD cluster is critical for vertebrate limb development. Enhancers located in both the telomeric and centromeric gene deserts flanking the cluster regulate the transcription of HoxD genes. In rare patients, duplications, balanced translocations or inversions misregulating HOXD genes are responsible for mesomelic dysplasia of the upper and lower limbs. By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber fluorescent in situ hybridization, we studied patients from two families displaying mesomelic dysplasia limited to the upper limbs. We identified microduplications including the HOXD cluster and showed that microduplications were in an inverted orientation and inserted between the HOXD cluster and the telomeric enhancers. Our results highlight the existence of an autosomal dominant condition consisting of isolated ulnar dysplasia caused by microduplications inserted between the HOXD cluster and the telomeric enhancers. The duplications likely disconnect the HOXD9 to HOXD11 genes from their regulatory sequences. This presumptive loss-of-function may have contributed to the phenotype. In both cases, however, these rearrangements brought HOXD13 closer to telomeric enhancers, suggesting that the alterations derive from the dominant-negative effect of this digit-specific protein when ectopically expressed during the early development of forearms, through the disruption of topologically associating domain structure at the HOXD locus.

Two adolescent patients with therapy-refractory ulnocarpal wrist pain because of mild ulnar longitudinal deficiency (ULD; ulna hypoplasia type I according to Bayne) underwent surgical treatment with a Z-shaped ulna lengthening osteotomy and interposition of the iliac crest bone graft. Long-term ULD correction and pain-free motion were maintained in both patients. Pediatric patients with symptomatic mild ULD are often mistaken for ulnar negative variance with radioulnar impingement and may be successfully treated using this newly described technique. The ulnar malangulation is corrected at the apex of the deformity, and the clinical and radiographic outcomes have been successful.