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

Abstract

Wolf-Hirschhorn syndrome (WHS) is a well known genetic condition caused by a partial deletion of the short arm of chromosome 4. The great variability in the extent of the 4p deletion and the possible contribution of additional genetic rearrangements lead to a wide spectrum of clinical manifestations. The majority of the reports of prenatally diagnosed WHS cases are associated with large 4p deletions identified by conventional chromosome analysis; however, the widespread clinical use of novel molecular techniques such as array comparative genomic hybridization (a-CGH) has increased the detection rate of submicroscopic chromosomal aberrations associated with WHS phenotype. We provide a report of two fetuses with WHS presenting with intrauterine growth restriction as an isolated finding or combined with oligohydramnios and abnormal Doppler waveform in umbilical artery and uterine arteries. Standard karyotyping demonstrated a deletion on chromosome 4 in both cases [del(4)(p15.33) and del(4)(p15.31), respectively] and further application of a-CGH confirmed the diagnosis and offered a precise characterization of the genetic defect. A detailed review of the currently available literature on the prenatal diagnostic approach of WHS in terms of fetal sonographic assessment and molecular cytogenetic investigation is also provided.

Figure 1

Autopsy of a 24 weeks' gestation female fetus after pregnancy termination (Case 2) that showed external features of facial dysmorphism with bilateral cleft lip, hypertelorism, broad and high nasal bridge, small filter and large ears.

Figure 2

a. a-CGH profile of chromosome 4 showing an terminal deletion. To the left, the whole chromosome 4 view. To the right, the enlarged view of the rearrangement as provided by Agilent Technologies, CGH Analytics 3.5.14. The overall size of the deletion was about 14.7 Mb. b. a-CGH profile of chromosome 4 showing a terminal deletion. To the left, the whole chromosome 4 view. To the right, the enlarged view of the rearrangement as provided by Agilent Technologies, CGH Analytics 3.5.14. The overall size of the deletion was about 19.3 Mb.