Facial Paresis, Hereditary Congenital, 3

A number sign (#) is used with this entry because of evidence that hereditary congenital facial paresis-3 (HCFP3) is caused by homozygous mutation in the HOXB1 gene (142968) on chromosome 17q21.

Description

HCFP3 is an autosomal recessive congenital cranial dysinnervation disorder characterized by isolated dysfunction of the seventh cranial nerve resulting in facial palsy. Additional features may include orofacial anomalies, such as smooth philtrum, lagophthalmos, swallowing difficulties, and dysarthria, as well as hearing loss. There is some phenotypic overlap with Moebius syndrome (see, e.g., 157900), but patients with HCFP usually retain full eye motility or have esotropia without paralysis of the sixth cranial nerve (summary by Vogel et al., 2016).

For a phenotypic description and a discussion of genetic heterogeneity of hereditary congenital facial paresis, see 601471.

Clinical Features

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 (ABR) 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.

Uyguner et al. (2015) reported an 7-year-old girl, born of consanguineous Turkish parents, with HCFP3. She had facial paresis, midface retrusion, left-sided ptosis with bilateral lagophthalmos, depressed nasal bridge, short nose with anteverted nares, tented vermilion of the upper lip, downturned corners of the mouth, high palate, and low-set ears. She was unable to smile or frown, and nasolabial folds were flattened. She had left esotropia with mild inferior oblique muscle hyperfunction; there was no paralytic component of the sixth cranial nerve, and ABR showed normal results. She had normal neurologic development.

Vogel et al. (2016) reported a consanguineous Moroccan family in which 4 individuals had HCFP3. Two brothers presented in childhood with facial paresis, a history of feeding difficulties, and speech delay. A similarly affected paternal uncle and aunt were subsequently identified. All had full eye motility, excluding a clinical diagnosis of Moebius syndrome. The patients had dysmorphic facial features, including masked facies, midface retrusion, upturned nose, smooth philtrum, lagophthalmos, epicanthal folds, flat nasal bridge, and variable cone-shaped incisors. They had mild oral dysfunction due to facial paresis, including feeding and swallowing difficulties, palatal weakness, dysarthria, and speech delay. Brain imaging in the 2 younger patients showed facial nerve hypoplasia with no cochlear abnormalities. However, ABR showed moderate high frequency hearing loss indicating cochlear dysfunction. In addition, all patients had external auricular malformations apparent at birth.

Inheritance

The transmission pattern of HCFP3 in the family reported by Vogel et al. (2016) was consistent with autosomal recessive inheritance.

Mapping

In 2 brothers with congenital facial paresis and their unaffected consanguineous conservative German American parents, Webb et al. (2012) performed linkage and homozygosity mapping and identified a single approximately 30-Mb region of shared homozygosity on chromosome 17q21.31-q25.1, flanked by SNPs rs9900383 and rs4969059. Linkage and haplotype analyses using DNA from 11 additional family members refined the interval to 27 Mb, with a maximum 2-point lod score of 2.3 for all fully informative markers across the critical interval.

Molecular Genetics

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.

In a 7-year-old girl, born of consanguineous Turkish parents, with HCFP3, Uyguner et al. (2015) identified a homozygous missense mutation in the HOXB1 gene (R207H; 142968.0002). The mutation, which was found by direct sequencing of the HOXB1 gene in 95 patients with similar features, segregated with the disorder in the family. Molecular modeling suggested that the mutation would alter DNA-binding capacity, with an increase in binding. In vitro functional studies of the variant and studies of patient cells were not performed, but the same residue was affected in 2 other patients with the disorder (R207C; 142968.0001).

In 4 members of a consanguineous Moroccan kindred with HCFP3, Vogel et al. (2016) identified a homozygous nonsense mutation in the HOXB1 gene (Y22X; 142968.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted either to encode a truncated protein without the DNA-binding homeodomain or to result in nonsense-mediated mRNA decay, both of which would result in a complete loss of function. Vogel et al. (2016) commented that their findings suggested that loss of HOXB1 function is the underlying pathogenetic mechanism.

Animal Model

Expression of Hoxb1 is prominent in rhombomere 4 during mouse embryonic development. Studer et al. (1996) found that Hoxb1 -/- mice were indistinguishable from wildtype at birth; however, about 98% died within 24 hours. Early patterning of rhombomere 4 initiated properly, but was not maintained, and facial branchiomotor, vestibuloacoustic efferent, and visceromotor neurons were missing from their normal locations and showed abnormal axonal trajectories. Studer et al. (1996) concluded that Hoxb1 is involved in regulating neuronal migration in the hindbrain.

Goddard et al. (1996) generated mice homozygous for 2 different mutations in the Hoxb1 gene: a deletion of exon 2, which encodes the homeodomain, or deletion of both exons 1 and 2. They found that mice homozygous for either mutation failed to form the somatic motor component of the seventh (facial) nerve and showed facial paralysis. Mice homozygous for deletion of both exons 1 and 2, but not those lacking only exon 2, exhibited a high degree of lethality, which was likely due to impaired feeding behavior. The structure of rhombomere 4, neural crest cell production, and neural crest cell migration appeared to be normal in all mutant mice.