Webb et al. (2012) studied 2 brothers, born of consanguineous parents of conservative German American background, who had previously been diagnosed with Moebius syndrome (157900). The sibs were noted to have bilateral facial weakness, sensorineural hearing loss, and ... Webb et al. (2012) studied 2 brothers, born of consanguineous parents of conservative German American background, who had previously been diagnosed with Moebius syndrome (157900). The sibs were noted to have bilateral facial weakness, sensorineural hearing loss, and esotropia in the first months of life, and developed feeding difficulties and speech delays requiring oromotor and speech therapies. Both underwent surgery to correct esotropia, and both wore glasses for high hyperopia. MRI in the older brother at 8 months of age revealed bilateral absence of the facial nerve and bilateral abnormal tapering of the basal turn of the cochlea. Auditory brainstem response testing in both boys revealed bilateral mild to moderate high frequency hearing loss with normal absolute latencies of waveforms, and distortion product otoacoustic emissions were absent in both children, supporting abnormal cochlear function. Stapedius reflexes were intact bilaterally. Examination at 7.25 years and 2.9 years of age, respectively, revealed midface retrusion, low-set and posteriorly rotated ears, upturned nasal tip, and smooth philtrum in both boys. Neither child showed any facial movement. Taste discrimination, salivation, and lacrimation were intact, as was general sensation over the concha of the ear and skin behind the auricle. Webb et al. (2012) noted that because both boys had partially accommodative esotropia with high hyperopia and full eye movements, they did not meet the criteria for Moebius syndrome. Their parents and a brother were unaffected, and there was no family history of strabismus or facial weakness.
Using DNA from 1 of 2 brothers with congenital facial paresis from a consanguineous conservative German American family, Webb et al. (2012) performed whole-exome sequencing and filtering, which yielded 5 missense variants that were homozygous in the affected ... Using DNA from 1 of 2 brothers with congenital facial paresis from a consanguineous conservative German American family, Webb et al. (2012) performed whole-exome sequencing and filtering, which yielded 5 missense variants that were homozygous in the affected boys and heterozygous in their unaffected brother and parents, and segregated appropriately in the extended family. A missense mutation in the HOXB1 gene (R207C; 142968.0001) was the most plausible of the candidates, since Hoxb1-deficient mice have hypoplasia of the facial nucleus and congenital facial paralysis. Webb et al. (2012) sequenced HOXB1 in 175 additional probands, some with a diagnosis of Moebius syndrome (157900) and others with variable combinations of facial weakness, hearing loss, and complex or common strabismus, and identified homozygosity for the same R207C mutation in an adult brother and sister with congenital bilateral facial weakness, who had previously been diagnosed with Moebius syndrome and were also of conservative German American ('Pennsylvania Dutch') background. In addition to facial weakness, the sister had esophoria at both near and far distances, and mild hearing loss of unknown origin. Her younger brother also had sensorineural hearing loss, wore glasses, and had undergone strabismus surgery in childhood for 'lazy eye,' most consistent with a diagnosis of esotropia. Both sibs had micrognathia, normal intelligence, and no other known anomalies. Webb et al. (2012) stated that although all 4 affected individuals had congenital facial paresis, none had limited abduction of either eye, and thus did not meet the diagnostic criteria for Moebius syndrome. The R207C mutation was found to occur on a haplotype shared by the 2 German American families that was infrequent in the European population (0.787%), supporting a founder mutation.