An additional family with association of hereditary thrombocytosis and transverse limb deficiency: confirmation of a rare clinical spectrum.

Hereditary thrombocytosis, usually inherited as a dominant trait, can be caused either by heterozygous mutations in the thrombopoietin gene (THPO) that increase gene translation, or by heterozygous mutations in the THPO receptor (called myeloproliferative leukemia virus oncogene, MPL). Limb deficiencies are a relatively common birth defect, with a reported prevalence of 0.79/1,000 in a recent survey. In most cases, the etiology is not clear, and less than 2% of affected infants have a positive family history; vascular disruption is thought to be the most common cause, but solid data are lacking. Recently, we described a family where thrombocytosis caused by a dominant THPO mutation was associated with unilateral transverse limb defects in three out of four affected family members and this condition found its place in the last nosology of the genetic disorders of skeletal development. Here, we present another family in which thrombocytosis and unilateral limb defects were found to cosegregate. THPO screening revealed heterozygosity for a single base-pair deletion in the 5'-UTR of the gene in two patients.This new observation of unilateral limb defects in individuals with thrombocytosis provides further evidence that the association is non-random and apparently linked to THPO mutations.