Prenatal diagnosis of Wolf-Hirschhorn syndrome confirmed by comparative genomic hybridization array: report of two cases and review of the literature

Wolf-Hirschhorn syndrome (WHS; OMIM 194190) [1], also known as deletion 4p and 4p-syndrome, is a well known clinical condition caused by a partial deletion of the short arm of chromosome 4. WHS was first (and independently) described by Wolf et al. (1965) and Hirschhorn et al. (1965) [2,3]; thereafter, more than 180 documented cases have been published in the literature, most of them diagnosed postnatally. The prevalence of WHS is reported to be around 1/50.000 live births with a 2:1 female/male ratio; however, this is likely underestimated because of under-recognition or misdiagnosis of affected individuals [4,5].In the majority of cases, WHS is caused by a "pure" deletion of 4p16 with no other cytogenetic abnormality while in the remaining cases, there could be a more complicated cytogenetic finding such as chromosome 4 ring, 4p- mosaicism, or a derivative chromosome 4 resulting from either a de novo or inherited unbalanced translocation [5,6]. The complexity of the WHS-associated basic genomic changes is an important factor explaining phenotypic variability; though the typical clinical features include growth restriction of prenatal onset, profound psychomotor retardation, seizures, skeletal abnormalities, and a distinctive facial appearance [7]. Associated major malformations with variable incidence (30-70%) are mainly related to midline fusion defects such as midline scalp defects, agenesis of corpus callosum, cleft lip/palate, heart defects, and urinary tract malformations [7,8].Most prenatally diagnosed cases of WHS are associated with large 4p deletions identified by conventional chromosome analysis while the widespread clinical use of novel high-resolution molecular techniques such as array comparative genomic hybridization (a-CGH) increased the detection rate of submicroscopic chromosomal aberrations that could also lead to a WHS phenotype. Herein, we present two WHS cases suspected upon abnormal signs in prenatal ultrasonography, diagnosed with convention