Jackson-Weiss Syndrome

A number sign (#) is used with this entry because Jackson-Weiss syndrome is caused by heterozygous mutations in the gene encoding fibroblast growth factor receptor-2 (FGFR2; 176943).

One patient with a disorder considered to be Jackson-Weiss syndrome was found to have a mutation in the FGFR1 gene (see 136350.0001).

Clinical Features

Jackson et al. (1976) reported a syndrome of craniosynostosis, midfacial hypoplasia, and foot anomalies in an Amish kindred. Enlarged great toes and craniofacial abnormalities suggested Pfeiffer syndrome (101600); however, thumb abnormalities were not present. In all, 88 affected persons were observed and another 50 were reliably reported to be affected. An autosomal dominant pedigree pattern with variable severity was observed. Indeed, phenotypic expression was so variable that the entire spectrum of the dominantly inherited craniofacial dysostoses and acrocephalosyndactylies (except classic Apert syndrome, 101200) was seen in the kindred. Jackson et al. (1976) noted that one branch of the same family with webbing of the second and third toes had been reported by Cross and Opitz (1969) as having nonspecific craniostenosis with recessive inheritance. Jackson et al. (1976) identified other family members with webbing of the second and third toes. They concluded that all affected members of the family had the same dominant disorder. Although Jackson et al. (1976) concluded that mental retardation was not a feature, it was present in some of the patients reported by Cross and Opitz (1969).

Heike et al. (2001) studied a previously unrecognized branch of the original family reported by Jackson et al. (1976) and emphasized the importance of including foot radiographs as part of the clinical evaluation of Jackson-Weiss syndrome patients. See MOLECULAR GENETICS section.

Apparent validation of the Jackson-Weiss syndrome was provided by the report of Escobar and Bixler (1977).

Winter and Reardon (1996) proposed that the designation Jackson-Weiss syndrome should for the time being 'be reserved for large pedigrees showing extreme intrafamilial variability of craniosynostosis phenotypes encompassing features of Crouzon, Pfeiffer, and Apert syndromes.' The confused state of the nosology of the FGFR-related craniosynostosis syndromes is indicated by the disputes raised by Cohen (1996) on the Winter and Reardon (1996) letter.

Mapping

By 2-point linkage and haplotype analyses using 13 dinucleotide repeat markers on chromosome 10, Li et al. (1994) showed that the Jackson-Weiss syndrome maps to the same region, 10q23-q26, as the Crouzon syndrome (123500).

Exclusion Studies

Lewanda et al. (1994) used markers spanning the entirety of the short arm of chromosome 7 to exclude the Jackson-Weiss locus from that region, thus proving that it is not allelic to the Saethre-Chotzen syndrome (101400) or to Greig cephalopolysyndactyly (175700).

Molecular Genetics

In a study of the family in which the Jackson-Weiss syndrome was originally described, Jabs et al. (1994) discovered an ala344-to-gly (A344G; 176943.0007) mutation in the conserved region of the immunoglobulin IIIc domain of the gene for fibroblast growth factor receptor-2. Mutations in the FGFR2 gene have also been found in patients with Crouzon syndrome.

Heike et al. (2001) studied a previously unrecognized branch of the original family reported by Jackson et al. (1976) and found the A344G mutation in FGFR2 in all affected members. The proband in this family had a leg-length discrepancy and unilateral absence of the fifth digital ray in her right foot. The family demonstrated the wide variability in expression of this mutation. Only one of the affected patients in this branch of the family demonstrated the classic clinical features of craniosynostosis, and all patients exhibited radiographic changes in the feet.

In a patient with Jackson-Weiss syndrome, Meyers et al. (1996) identified heterozygosity for a 1045A-C transversion in exon IIIa of the FGFR2 gene, resulting in a gln289-to-pro (Q289P; 176943.0014) substitution.

Roscioli et al. (2000) reported a patient with what they considered to be the Jackson-Weiss syndrome, who had the FGFR1 pro252-to-arg (P252R) mutation (see 136350.0001).