ClinVar

Description

This terminal deletion of 4p16.3 is associated with Wolf-Hirschhorn syndrome (WHS), a contiguous gene deletion syndrome associated with a hemizygous deletion of chromosome 4p16.3 (OMIM #194190). It is characterized by typical craniofacial features in infancy consisting of "Greek warrior helmet" appearance of the nose, microcephaly, high anterior hairline with prominent glabella, widely spaced eyes, epicanthus, highly arched eyebrows, short philtrum, downturned corners of the mouth, micrognathia, and poorly formed ears with pits/tags. All affected individuals have prenatal-onset growth deficiency followed by postnatal growth retardation and hypotonia with muscle underdevelopment. Developmental delay/intellectual disability of variable degree is present in all. Seizures occur in 90% to 100% of children with WHS. Other findings include skeletal anomalies (60%-70%), congenital heart defects (~50%), hearing loss (mostly conductive) (>40%), urinary tract malformations (25%), and structural brain abnormalities (33%). Although WHSC1/NSD2 and LETM1 are typically deleted in WHS, deletion of additional genes is likely required for the full expression of the phenotype. About 40%-45% have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. These unbalanced translocations may be de novo or inherited from a parent with a balanced rearrangement. (Battaglia et al., GeneReviews. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1183/; Paradowska-Stolarz Adv Clin Exp Med. 2014 May-Jun;23(3):485-9. PMID: 24979523).