Okihiro/
Duane-radial ray syndrome (DRRS) is an autosomal dominant condition characterized by radial ray defects and
Duane anomaly (a form of
strabismus). Other abnormalities reported in this condition are anal, renal, cardiac, ear, and foot malformations, and
hearing loss. The disease is the result of a mutation in the SALL4 gene, a human gene related to the developmental regulator spalt (sal) of Drosophila melanogaster. SALL4 mutations may also cause acro-renal-ocular syndrome (AROS), which differs from DRRS by the presence of structural eye anomalies, and phenotypes similar to
thalidomide embryopathy and
Holt-Oram syndrome (HOS). The SALL4 gene product is a zinc finger
protein that is thought to act as a
transcription factor. It contains three highly conserved C2H2 double zinc finger domains, which are evenly distributed. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL4 contains a C2HC motif. Seventeen of the 22 SALL4 mutations known to date (five of which are presented here for the first time) are located in exon 2, and five are located in exon 3. These are
nonsense mutations, short duplications, and short deletions. All of the mutations lead to preterminal
stop codons and are thought to cause the phenotype via haploinsufficiency. This assumption is supported by the detection of six larger deletions involving the whole gene or single exons. This article summarizes the current knowledge about SALL4 defects and associated syndromes, and describes the clinical distinctions with similar phenotypes caused by other gene defects.