CATSHL Syndrome-:Tall Stature, Hearing Loss, and Mutant FGFR3

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This story begins with the delineation of a large multigenerational family with dominant inheritance of tall stature, hearing loss, camptodactyly, and in some cases, developmental delay, microcephaly, and scoliosis. The clinical phenotype was designated CATSHL for camptodactyly, tall stature, and hearing loss. Radiographs showed tall vertebral bodies, long tubular bones, osteochondroma in the femurs, tibiae, and phalanx. In addition, bilateral sensorineural hearing loss was detected on audiologic testing. Since affected members did not match a recognized syndrome and the family was large and potentially genetically informative, genome-wide linkage studies were performed, revealing linkage to a ~7-Mb interval on chromosome 4p that contained ~30 genes.

One of the candidate genes on chromosome 4p was FGFR3, which is mutated in the achondroplasia group of dwarfing conditions. Although the patients in this family clearly did not have achondroplasia, the investigators headed by Mike Bamshad were struck that their clinical phenotype was almost the antithesis of the achondroplasia phenotype, as well as the features similar to those observed in the Fgfr3 knockout mouse. Sequencing of FGFR3 identified a missense mutation in the kinase domain of the receptor that segregated with the CATSHL phenotype in the family.

The authors speculated that the clinical features resulted from the loss of FGFR3 function. They did not document this, but pointed out that the mutation substitutes an arginine for a histidine residue that is invariant in the tyrosine kinase superfamily. They noted that this histidine residue is predicted to be critical to the kinase function of the very similar FGFR1 receptor, and that mutation of the homologous amino acid residue in the kinase domain of the insulin receptor lead to loss of function. Thus, although circumstantial, the authors built a strong case that the mutation inactivated FGFR3 as a receptor tyrosine kinase.

An important question raised by the authors is why loss of receptor function would be inherited as a dominant trait. They argued that the mechanism was not haploinsufficiency, since patients with Wolf-Hirschhorn syndrome in which one copy of FGFR3 was deleted did not exhibit features of CATSHL, nor to mice heterozygous for knockout of Fgfr3 .They proposed alternatively a dominant negative mechanism in which the protein product of the mutant FGFR3 gene somehow interfered with the function of the product of the normal FGFR3 allele, but offered no experimental evidence to support this contention.

Toydemir RM, Brassington AE, Bayrak-Toydemir P, et al: A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am J Hum Genet. 2006;79:935-41.

Editor’s Comment

This paper is interesting, not only because a mechanism was identified to explain the CATSHL phenotype, but also because of how the mutation was found. In retrospect, the phenotype fits well with loss of FGFR3 function, but it is unlikely that anyone would have suspected this a priori. Consequently, the classic genetic approach led to a surprising result.

Genetically engineered mice with loss of Fgfr3 function develop precocious osteoarthritis, probably because of the receptor’s inhibitory effect on chondrocyte differentiation, which is needed for endochondral ossification but also adversely affects articular cartilage integrity. It would be interesting to know if adult members of this family are predisposed to joint disease.

William A. Horton, MD

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Last Updated: 04/30/2008