Background Limb development is a complex process requiring proper spatio-temporal expression of a network of limb specific morphogens. Grem1 and Fmn1 play an important role in mouse and chick limb development. The mouse limb deformity (ld) phenotype with digit reduction, syndactyly, radio-ulnar synostosis, variable renal defects and absent fibulae is caused by loss of Grem1 function. This could be due to either coding Grem1 homozygous mutations or homozygous deletions of the neighbouring Fmn1 gene, which also removes limb specific regulatory sequences of Grem1. Recent studies reinforce the hypothesis that a loss of Fmn1 protein could also contribute to the observed ld anomalies. In addition, an over-expression of Grem1 in developing chick limbs represses the programmed cell death in the interdigital mesenchyme, resulting in interdigital webbing and truncation of distal cartilage elements.

Aims/Results For the first time, chromosomal imbalances in the GREM1 FMN1 region in individuals with limb defects are reported here. A 263 Kb homozygous deletion of FMN1 was associated with oligosyndactyly, radioulnar synostosis, hearing loss and renal defects, features identical to ld mice. A 1.7 Mb duplication encompassing both the GREM1 and FMN1 genes was detected in a patient with isolated Cenani–Lenz-like oligosyndactyly of the hands, resembling the transgenic chick wings in which Grem1 was over-expressed.

Conclusions The phenotypes of these two patients represent new entities/syndromes within the Cenani–Lenz clinical spectrum: (1) an autosomal recessive oligosyndactyly, radio-ulnar synostosis, hearing loss and renal defect syndrome; and (2) an autosomal dominant Cenani–Lenz-like non-syndromic oligosyndactyly.