Vertebrates have four clusters of Hox genes (HoxA, HoxB, HoxC, and HoxD). A 
variety of expression and mutation studies indicate that posterior members of 
the HoxA and HoxD clusters play an important role in vertebrate limb 
development. In humans, mutations in HOXD13 have been associated with type II 
syndactyly or synpolydactyly, and, in HOXA13, with hand-foot-genital syndrome. 
We have investigated two unrelated children with a previously unreported pattern 
of severe developmental defects on the anterior-posterior (a-p) limb axis and in 
the genitalia, consisting of a single bone in the zeugopod, either monodactyly 
or oligodactyly in the autopod of all four limbs, and penoscrotal hypoplasia. 
Both children are heterozygous for a deletion that eliminates at least eight 
(HOXD3-HOXD13) of the nine genes in the HOXD cluster. We propose that the 
patients' phenotypes are due in part to haploinsufficiency for HOXD-cluster 
genes. This hypothesis is supported by the expression patterns of these genes in 
early vertebrate embryos. However, the involvement of additional genes in the 
region could explain the discordance, in severity, between these human 
phenotypes and the milder, non-polarized phenotypes present in mice hemizygous 
for HoxD cluster genes. These cases represent the first reported examples of 
deficiencies for an entire Hox cluster in vertebrates and suggest that the 
diploid dose of human HOXD genes is crucial for normal growth and patterning of 
the limbs along the anterior-posterior axis.