Clinical, Cytogenetic and Molecular Investigation in a Fetus with Wolf-Hirschhorn Syndrome with Paternally Derived 4p Deletion

Abstract

Wolf-Hirschhorn (4p-) syndrome (WHS), caused by partial deletion of the short arm of chromosome 4, has been extensively described in children and young adults. Knowledge on fetuses with WHS is still limited due to the small number of published cases. We report on a fetus with prenatally diagnosed severe intrauterine growth retardation, reduced thoracal diameter, clubfeet deformity and midface hypoplasia including slight microretrognathia indicative for fetal karyotyping. Chromosome analysis after amniocentesis revealed a de novo terminal deletion of chromosome 4p [karyotype: 46,XX,del(4) (p16)] which was confirmed by FISH. Analyses of a set of polymorphic markers mapping in 4pter->4p15.3 showed absence of paternal haplotypes. These observations corroborate the preferential paternal origin of the de novo 4p deletion in WHS patients. Furthermore, the distal breakpoint could be narrowed to band 4p16.1. At autopsy, the fetus showed typical craniofacial dysmorphic signs of WHS, severe IUGR and delayed bone age. This report suggests the possibility of recognising the particular phenotype of WHS in utero by prenatal ultrasound and emphasises the importance of karyotyping fetuses with severe IUGR, especially when the amount of amniotic fluid is normal.

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

“…A wide range of other anatomical abnormalitites as renal hypoplasia, skeletal dysplasias, hypospadias, diaphragmatic hernia, single umbilical artery also complicates these cases with variable incidence [7,25-31]. In addition, craniofacial dysmorphic features such as microcephaly, "Greek warrior helmet" profile (the broad high nasal bridge continuing to the forehead), prominent glabella, high arched eyebrows and hypertelorism are strongly evocative of WHS [7,26,32,33]. …”

Distal 4p microdeletion in a case of Wolf‐Hirschhorn syndrome with congenital diaphragmatic hernia

“…Genetic syndromes occur in 40% of CDH cases (Enns et al,1998) (the most frequent types are listed in Table 1). WHS is rarely associated with CDH, and the majority of reported cases are anecdotal ones within larger series of autopsy reports (Table 2) (Laziuk et al,1980; Lurie et al,1980; Tachdjian et al,1992; Howe et al,1996; Sergi et al,1998; Tapper et al,2002; Dietze et al,2004; van Dooren et al,2004). Recently, a 4p16.3 microdeletion, detectable only by molecular probes, was reported in WHS (Wieczorek et al,2000; Zollino et al,2000).…”

“…Patients with a microdeletion on distal 4p usually present with a milder phenotype that lacks congenital malformations (Wieczorek et al,2000; Zollino et al,2000, 2003). WHS is rarely associated with congenital diaphragmatic hernia (CDH)–only 8 cases are reported in the literature, and only 1 of these patients is still alive (Laziuk et al,1980; Lurie et al,1980; Tachdjian et al,1992; Howe et al,1996; Sergi et al,1998; Tapper et al,2002; Dietze et al,2004; van Dooren et al,2004). In almost all reported cases of CDH and WHS, a large deletion of the short arm of chromosome 4 was present.…”

Prenatal ultrasound findings observed in the Wolf‐hirschhorn syndrome: Data from the registry of congenital malformations in auvergne

“…Postnatal examination revealed a typical facial dysmorphism consisting of a high forehead associated to microcephaly. Microcephaly was detected by prenatal screening in 8 patients (patient 1, 2, 4–8, and patient 10) from our series and in all the cases reported in the literature (Verloes et al, ; Tachdjian et al, ; De Keersmaecker et al, ; Aslan et al, ; Dietze et al, ; Boog et al, ; Sase et al, ; Levaillant et al, ; Basgul et al, ; Casaccia et al, ; Chao et al, ; Sifakis et al, ). In the literature, a high forehead was noticed on prenatal examination in one case (Sase et al, ).…”

“…In the literature, IUGR was the main prenatal finding observed in WHS. It was reported in 22 fetuses (Verloes et al, ; Tachdjian et al, ; De Keersmaecker et al, ; Aslan et al, ; Dietze et al, ; Boog et al, ; Sase et al, ; Basgul et al, ; Casaccia et al, ; Chao et al, ; Levaillant et al, ; Sifakis et al, ). IUGR was isolated in most of the cases (Verloes et al, ; Tachdjian et al, ; De Keersmaecker et al, ; Aslan et al, ; Dietze et al, ; Sase et al, ; Levaillant et al, ).…”