Acute lymphoblastic leukemia in a patient with Greig cephalopolysyndactyly and interstitial deletion of chromosome 7 del(7)(p11.2 p14) involving the GLI3 and ZNFN1A1 genes.

Greig cephalopolysyndactyly (GCPS; OMIM 175700) is an autosomal dominant condition caused by mutations of the gene GLI3, located on 7p13. To date, several cases of deletions and/or translocations involving this locus have been reported in patients with GCPS. GLI3 is a transcription factor from the GLI-Kruppel gene family that has been implicated in three distinct entities: GCPS, Pallister-Hall syndrome, and postaxial polydactyly type A. The zinc finger protein, subfamily 1, member 1 gene (ZNFN1A1; OMIM 603023), on 7p12, codes for a lymphoid-restricted zinc finger transcription factor, ZNFN1A1, also called IKAROS, that regulates lymphocyte differentiation and has been associated with the development of childhood leukemia. We present the case of a 9-year-old Latin-American boy who was referred for stem cell transplantation because of recurrent acute lymphoblastic leukemia (ALL). On evaluation, he was found to have dysmorphic features consistent with GCPS, including a prominent forehead, down-slanting palpebral fissures, 1-2-3 toe syndactyly, broad thumbs and first toes, and mild developmental delay. He had developed ALL at 5 years of age. Chromosome analysis of bone marrow and fibroblastic cells showed an interstitial deletion of chromosome arm 7p, del(7)(p11.2p14), in 74% and 44% of the cells, respectively. We performed FISH analysis with a BAC clone containing the ZNFN1A1 gene and demonstrated that it is contained in the deleted segment. To our knowledge, this is the first report of a patient with GCPS and leukemia. We hypothesize that constitutional deletion of the ZNFN1A1 gene in this patient may have resulted in an increased risk of lymphoid malignancy.