Camptodactyly, Tall Stature, And Hearing Loss Syndrome

A number sign (#) is used with this entry because of evidence that the camptodactyly, tall stature, and hearing loss syndrome (CATSHLS) is caused by mutation in the FGFR3 gene (134934) on chromosome 4p16. Two such families have been reported, one with a heterozygous mutation and the other with a homozygous mutation.

Clinical Features

Toydemir et al. (2006) evaluated a large Utah pedigree in which 27 living affected family members spanning 4 generations (from a total of 35 affected individuals in 7 generations) had an autosomal dominant syndrome of camptodactyly, tall stature, and hearing loss, otherwise known as the CATSHL (pronounced 'cat-shul') syndrome. Phenotypic information and DNA were available for 20 of the 27 affected members. Adult height in 5 of 5 men was more than the 97th percentile, with a mean height of 77 inches, and adult height in females was more than the 75th percentile in 9 of 9 and more than the 97th percentile in 8 of 9 women, with a mean height of 70 inches. Camptodactyly of the hands and/or feet was present in 18 (90%) of 20 individuals and 17 (85%) of 20 had hearing loss. Of 20 individuals, 12 had developmental delay and/or mental retardation, and several of these had microcephaly. Several had scoliosis and/or pectus excavatum. No individual had characteristics of LADD syndrome (149730) or craniosynostosis syndromes caused by mutations in FGFR3. The diagnosis of Marfan syndrome was excluded by the fact that no affected individuals had severe myopia, lens dislocation, or aortic root abnormalities. Radiographic findings included tall vertebral bodies with irregular borders and broad femoral metaphyses with long tubular shafts. In otologic examination, each tested individual had bilateral sensorineural hearing loss and absent otoacoustic emissions. By report, the hearing loss was congenital or developed in early infancy, progressing variably in early childhood and ranging from mild to severe.

Makrythanasis et al. (2014) reported 2 brothers, born of consanguineous Egyptian parents, with tall stature, severe lateral tibial deviation, scoliosis, hearing impairment, camptodactyly, and arachnodactyly. The older brother was more severely affected and was unable to walk due to the severity of the skeletal deformity of the lower legs. He also had mildly delayed development and intellectual disability (IQ of 70). The younger brother was less severely affected and had a normal IQ. Other features included high-arched palate and increased length of the upper limbs without elbow swelling or other abnormalities. Neither patient had cataracts or cardiac abnormalities.

Mapping

By linkage analysis in the large Utah family with CATSHL syndrome, Toydemir et al. (2006) mapped the disorder to the tip of chromosome 4p (lod score of 3.76 with maker D4S412). Haplotype analysis delimited a 7-Mb critical interval in a region including the FGFR3 gene.

Molecular Genetics

Because the features of CATSHL syndrome overlap with those of mice homozygous for an Fgfr3-null allele (Deng et al., 1996; Colvin et al., 1996), Toydemir et al. (2006) screened affected individuals for FGFR3 mutations by direct DNA sequencing and identified a missense mutation (R621H; 134934.0029) in the tyrosine kinase domain. These findings indicated that abnormal FGFR3 signaling can cause human anomalies by promoting as well as inhibiting endochondral bone growth.

In 2 brothers, born of consanguineous Egyptian parents, with autosomal recessive inheritance of camptodactyly, tall stature, and hearing loss, Makrythanasis et al. (2014) identified a homozygous missense mutation in the FGFR3 gene (T546K; 134934.0037). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but Makrythanasis et al. (2014) postulated a loss-of-function effect. The unaffected parents and an unaffected sister were heterozygous for the mutation, suggesting a differential functional effect of the mutation compared to that of the heterozygous mutation reported by Toydemir et al. (2006).