Alternative titles; symbols
ORPHA: 306527;
Cytogenetic location: 3q21-q22 Genomic coordinates (GRCh38): 3:122,200,001-139,000,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q21-q22 | Facial paresis, hereditary congenital, 1 | 601471 | Autosomal dominant | 2 |
Hereditary congenital facial paresis (HCFP) is the isolated dysfunction of the facial nerve (CN VII).
HCFP is considered to be distinct from Moebius syndrome (157900), which shares some of the same clinical features.
Genetic Heterogeneity of Hereditary Congenital Facial Paresis
One locus for HCFP (HCFP1) has been mapped to chromosome 3q. Another locus (HCFP2; 604185) has been mapped to chromosome 10q. HCFP3 (614744) is caused by mutation in the HOXB1 gene (142968) on chromosome 17q21.
Skyberg and Van der Hagen (1965) observed congenital unilateral hereditary facial palsy in 4 generations of a family with 16 probably affected persons. Autosomal dominant inheritance was suggested. The stapedial reflex was absent, suggesting involvement of the motor nucleus of the facial nerve. Carmena and Gomez Marcano (1943) reported 4 affected generations in a Spanish family. Autopsy in 3 cases showed partial agenesis of the facial motor nucleus. Wittig et al. (1967) observed congenital facial diplegia in 3 generations of a family. Masaki (1971) reported father and a son and daughter with bilateral facial paralysis. Ocular movements were normal. Anderson et al. (1979) reported a family with aplasia cutis congenita in 3 and possibly 4 generations, to a total of 7 or 8 affected persons. In 4 of these there was also unilateral facial palsy and in 6 there was ear abnormality, usually lop ear. No male-to-male transmission was noted.
Van der Wiel (1957) reported a large Dutch family in which 46 persons in 6 generations had congenital facial paralysis. Inheritance was clearly autosomal dominant. Kremer et al. (1996) examined 31 family members, including 20 affected, who were part of the family reported by van der Wiel (1957). The proband had asymmetric weakness of the facial muscles and unequal involvement of the muscles of the 3 branches of the facial nerve. He was born with facial weakness similar to his grandmother and many of her sibs. EMG showed enlarged polyphasic action potentials of the right orbicularis oculi and orbicularis oris muscles. The right blink reflex was absent and there was a conduction block of the facial nerve to the right orbicularis muscles and prolonged distal motor latency to the orbicularis oculi muscles. His affected brother showed slight asymmetric weakness of the orbicularis oculi muscles. Notably, his obligate carrier mother had no hint of facial muscle weakness on clinical examination and electromyography of her facial muscles revealed no abnormalities.
Neuropathologic Findings
Verzijl et al. (2005) provided postmortem neuropathologic findings of 3 affected family members of the Dutch family reported by van der Wiel (1957) and Kremer et al. (1996). All 3 cases had a grossly normal brainstem with no hypoplasia or malformation of the rhombencephalon. The corticospinal tracts were fully developed. Microscopic examination of the brainstem revealed significantly decreased numbers of neurons in the vicinity of the facial nerve motor nuclei bilaterally compared to controls. The facial nerve roots and nerves were poorly developed, consisting of a few fine fibers only. The decreased neurons corresponded to the ipsilateral clinical weakness. The findings were distinct from those seen in Moebius syndrome, in which the authors found developmental disruption of the entire brainstem and long tracts. Verzijl et al. (2005) concluded that HCFP is a distinct disorder from Moebius syndrome, and suggested that HCFP may be a primary disorder of the fourth rhombomere, from which facial motoneurons arise.
By linkage analysis of a large Dutch family with congenital facial paresis, Kremer et al. (1996) identified a candidate locus on chromosome 3q21-q22 (maximum lod score of 5.76 at theta = 0.0 with D3S1292).
Michielse et al. (2006) performed linkage analysis in a large Pakistani family with dominant congenital facial palsy and obtained a maximum 2-point lod score of 6.90 (theta = 0.0) on chromosome 3q21 at marker GDB:11524498. Haplotype analysis defined a 3.0-Mb critical linkage interval between D3S3607 and GDB:11524498. Penetrance was 100% in this family, with no obligate carriers or unaffected members carrying the at-risk haplotype. Michielse et al. (2006) refined the critical region in the Dutch family reported by Kremer et al. (1996) to 5.7 cM between markers D3S1589 and D3S3514 and noted that the critical region of the Pakistani family is entirely within the critical region of the Dutch family.
Using RNA in situ hybridization, van der Zwaag et al. (2005) identified 4 genes within the HCFP1 critical region, Klf15 (606465), Ccdc37, Tmcc1 (616242), and Podxl2 (616627), that were expressed at spatial and temporal positions during embryonic mouse development that correlated with HCFP regions in humans. They concluded that these 4 genes are primary candidates for HCFP1.
Exclusion Studies
In a large Pakistani family with dominant congenital facial palsy mapping to chromosome 3q21, Michielse et al. (2006) sequenced 7 candidate genes, KLF15, CCDC37, PODXL2 (616627), TMCC1, PLXNA1 (601055), PLXND1 (604282), and GATA2 (137295), but did not identify any causative mutations; deletions or duplications were excluded by multiplex ligation-dependent probe amplification (MLPA) in all 7 genes.
Anderson, C. E., Hollister, D., Szalay, G. C. Autosomal dominantly inherited cutis aplasia congenita, ear malformations, right-sided facial paresis, and dermal sinuses. Birth Defects Orig. Art. Ser. XV(5B): 265-270, 1979.
Carmena, M., Gomez Marcano, E. Paralysis facial hereditaria. Rev. Clin. Esp. 8: 266-268, 1943.
Kremer, H., Kuyt, L. P., van den Helm, B., van Reen, M., Leunissen, J. A. M., Hamel, B. C. J., Jansen, C., Mariman, E. C. M., Frants, R. R., Padberg, G. W. Localization of a gene for Moebius syndrome to chromosome 3q by linkage analysis in a Dutch family. Hum. Molec. Genet. 5: 1367-1371, 1996. [PubMed: 8872479] [Full Text: https://doi.org/10.1093/hmg/5.9.1367]
Masaki, S. Congenital bilateral facial paralysis. Arch. Otolaryng. 94: 260-263, 1971. [PubMed: 5094540] [Full Text: https://doi.org/10.1001/archotol.1971.00770070254014]
Michielse, C. B., Bhat, M., Brady, A., Jafrid, H., van den Hurk, J. A. J. M., Raashid, Y., Brunner, H. G., van Bokhoven, H., Padberg, G. W. Refinement of the locus for hereditary congenital facial palsy on chromosome 3q21 in two unrelated families and screening of positional candidate genes. Europ. J. Hum. Genet. 14: 1306-1312, 2006. [PubMed: 16912702] [Full Text: https://doi.org/10.1038/sj.ejhg.5201706]
Skyberg, D., Van der Hagen, C. B. Congenital hereditary unilateral facial palsy in four generations. Acta Paediat. Scand. 159 (suppl.): 77-79, 1965.
Van der Wiel, H. J. Hereditary congenital facial paralysis. Acta Genet. Statist. Med. 7: 348 only, 1957.
van der Zwaag, B., Burbach, J. P. H., Scharfe, C., Oefner, P. J., Brunner, H. G., Padberg, G. W., van Bokhoven, H. Identifying new candidate genes for hereditary facial paresis on chromosome 3q21-q22 by RNA in situ hybridization in mouse. Genomics 86: 55-67, 2005. [PubMed: 15953540] [Full Text: https://doi.org/10.1016/j.ygeno.2005.03.007]
Verzijl, H. T. F. M., van der Zwaag, B., Lammens, M., ten Donkelaar, H. J., Padberg, G. W. The neuropathology of hereditary congenital facial palsy vs Moebius syndrome. Neurology 64: 649-653, 2005. [PubMed: 15728286] [Full Text: https://doi.org/10.1212/01.WNL.0000151848.65094.55]
Wittig, E. O., Moreira, C. A., Freire-Maia, N. Familial congenital peripheral facial diplegia. (Letter) Lancet 289: 282 only, 1967. Note: Originally Volume I.