Deletion of a 760 kb region at 4p16 determines the prenatal and postnatal growth retardation characteristic of Wolf-Hirschhorn syndrome

Background

Recently the genotype/phenotype map of Wolf‐Hirschhorn syndrome (WHS) has been refined, using small 4p deletions covering or flanking the critical region in patients showing only some of the WHS malformations. Accordingly, prenatal‐onset growth retardation and failure to thrive have been found to result from haploinsufficiency for a 4p gene located between 0.4 and 1.3?Mb, whereas microcephaly results from haploinsufficiency of at least two different 4p regions, one of 2.2–2.38?Mb and a second one of 1.9–1.28?Mb.

Methods and Results

We defined the deletion size of a ring chromosome (r(4)) in a girl with prenatal onset growth retardation, severe failure to thrive and true microcephaly but without the WHS facial gestalt and mental retardation. A high‐resolution comparative genome hybridisation array revealed a 760?kb 4p terminal deletion.

Conclusions

This case, together with a familial 4p deletion involving the distal 400?kb reported in normal women, may narrow the critical region for short stature on 4p to 360–760?kb. This region is also likely to contain a gene for microcephaly. “In silico” analysis of all genes within the critical region failed to reveal any strikingly suggestive expression pattern; all genes remain candidates for short stature and microcephaly.Attempts are ongoing to better correlate specific symptoms or malformations in patients with 4p deletions to specific genes or, at least, molecularly defined regions. The most recent genotype–phenotype map¹ confirmed that WHSC1 hemizygosity is essential to the development of the Wolf‐Hirschhorn syndrome (WHS) facial gestalt with the typical “Greek helmet” profile whereas the other key features (growth retardation, microcephaly, cleft palate, mental retardation and epilepsy) result from haploinsufficiency of more than one gene in that region. Particularly, the presence of a dose‐sensitive gene at 4p15–p16, involved in linear growth, was suggested several years ago because of the finding of prenatal and postnatal harmonic short stature in most patients with WHS.² Patients with the typical WHS facial gestalt but normal stature and interstitial rather than terminal 4p deletions confirmed the presence on 4p of at least two genes with complete penetrance, one for linear growth and the other, more proximal, for distinctive facial features.We have detected a 760?Kb terminal deletion of the short arm of chromosome 4 due to a ring chromosome in a 34‐month‐old girl examined for growth retardation with microcephaly and normal psychomotor development. Comparison of this case to other critical 4p cases seems to define a 360?kb region containing a gene(s) for which haploinsufficiency correlates with short stature and microcephaly.