Okihiro syndrome refers to the association of forearm malformations with Duane syndrome of eye retraction. Based on the reported literature experience, clinical diagnosis of the syndrome can be elusive, owing to the variable presentation in families reported. Specifically, there is overlap of clinical features with other conditions, most notably Holt-Oram syndrome, a condition resulting from mutation of the TBX5 locus and Townes-Brocks syndrome, known to be caused by mutations in the SALL1 gene. Arising from our observation of several malformations in Okihiro syndrome patients which are also described in Townes-Brocks syndrome, we postulated that Okihiro syndrome might result from mutation of another member of the human SALL gene family. We have characterized the human SALL4 gene on chromosome 20q13.13-q13.2. Moreover, we have identified literature reports of forelimb malformations in patients with cytogenetically identifiable abnormalities of this region. We here present evidence in 5 of 8 affected families that mutation at this locus results in the Okihiro syndrome phenotype.

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SALL4 is one out of four human homologues of the Drosophila region-specific homeotic gene spalt(sal). Heterozygous mutations of SALL4 on chromosome 20q13.13→ q13.2 cause the autosomal dominant Okihiro syndrome which is characterized by radial limb defects, Duane anomaly and hearing loss. We have partially cloned the murine homologue of this gene, named Sall4, and completed the coding sequence by comparison to available EST and genomic sequences in the GenBank database. This comparison also revealed the chromosomal location of Sall4 on mouse chromosome 2H3 and suggested that a predicted testis expressed gene Tex20 at the very same locus is most likely not a gene on its own but part of the Sall4 3′ UTR. We analyzed the expression of Sall4 during early embryogenesis by whole mount in situ hybridization and in the adult mouse by Northern blotting. In adult tissues, Sall4 expression is only found in testis and ovary. During embryonic development, Sall4 expression is widespread in early embryos and becomes gradually confined to the head region and the primitive streak. Prominent expression in the developing midbrain, branchial arches and the limbs suggests an important function of Sall4 during development of these structures as expected from the observation in Okihiro syndrome patients.

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