'Crommelin-type' symmetrical tetramelic reduction deformity: a new case and breakpoint mapping of a reported case with de-novo t(2;12)(p25.1;q23.3)

We report a male fetus with symmetrical peromelic reduction of the upper limbs (missing distal, mesial and proximal elements) and symmetrical phocomelic reduction of the lower limbs (missing proximal and mesial elements) without other major malformations. We identified 11 previously reported cases with very similar features and have named this entity 'Crommelin-type' symmetrical tetramelic reduction deformity. Interphase fluorescence in-situ hybridization on isolated nuclei from paraffin-embedded tissue was used to map the breakpoints in a previously reported case with a de-novo t(2;12)(p25.1;q23.3). The 2p25.1 breakpoint disrupted ROCK2, encoding Rho-associated, coiled-coil-containing protein kinase. The 12q23.3 breakpoint maps 0-25 kb 5 of CMKLR1, encoding chemokine-like receptor 1. Homozygous loss-of-function of either gene causes no major limb effect in mouse embryos. However, Cmklr1 shows both site-specific and stage-specific expression in mouse limb buds, but no mutations were identified in CMKLR1 or a nearby putative cis-regulatory region in the new case. We cannot assign a specific genetic mechanism in the translocation case but developmental disregulation of gene expression at one, or both, breakpoints may provide an explanation for the phenotype.