# 602078

FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, 2; CFEOM2


Alternative titles; symbols

FEOM2 LOCUS
FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, AUTOSOMAL RECESSIVE


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
11q13.4 Fibrosis of extraocular muscles, congenital, 2 602078 AR 3 PHOX2A 602753
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
HEAD & NECK
Eyes
- Congenital fibrosis of extraocular muscles (CFEOM)
- Bilateral ptosis
- Eyes fixed in extreme abduction (exotropia strabismus fixus)
- Restrictive ophthalmoplegia
- Unilateral hypotropia
- Unilateral hypertropia
- Severe limitations of eye movements
- Poor visual acuity
- Amblyopia
MOLECULAR BASIS
- Caused by mutation in the paired-like homeobox 2a gene (PHOX2A, 602753.0001)

TEXT

A number sign (#) is used with this entry because of evidence that congenital fibrosis of extraocular muscles type 2 (CFEOM2) is caused by homozygous mutation in the ARIX gene (PHOX2A; 602753) on chromosome 11q13.


Description

Congenital fibrosis of extraocular muscles-2 (CFEOM2) is an autosomal recessive disorder in which affected individuals are born with bilateral ptosis and restrictive ophthalmoplegia with the globes fixed in extreme abduction (exotropia) (Wang et al., 1998, Nakano et al., 2001).

For a general phenotypic description and a discussion of genetic heterogeneity of various forms of CFEOM, see CFEOM1 (135700).


Clinical Features

Engle et al. (1997) observed CFEOM in members of 3 consanguineous Saudi Arabian families and demonstrated an autosomal recessive pattern of inheritance. This form of CFEOM differed by showing features suggesting a defect in the superior and inferior divisions of the oculomotor nerve rather than in the superior division, as in CFEOM1.


Mapping

The locus on chromosome 11q13 is referred to as FEOM2.

By genetic linkage analysis of the 3 Saudi Arabian families containing 18 affected individuals, Engle et al. (1997) demonstrated that the recessive form of the disease was not linked to the 'classic' CFEOM (135700) chromosome 12 locus. A genomewide screen using both individual and pooled DNA revealed linkage to markers near the centromere of 11q. Lod score analysis revealed a maximum combined lod score of 12.2 at D11S4136, with a critical region of 15 cM flanked by D11S1765 and D11S4207. Assuming allelic association secondary to founder effect, the critical region could be reduced to a 0.3-cM region within 11q13.1. Wang et al. (1998) found the same disease-associated haplotype in 2 of the 3 families, suggesting founder effect.

Engle et al. (1997) referred to the classic form as CFEOM1 and this variant form as CFEOM2. They hypothesized that CFEOM2 results from a related developmental defect affecting both the superior and inferior divisions of the oculomotor nerve and their corresponding alpha motor neurons and extraocular muscles. There is a considerable degree of homology (or paralogy) between chromosome 11 and chromosome 12: e.g., HRAS (190020) and KRAS2 (190070); IGF1 (147440) and IGF2 (147470); PTH (168450) and PTHLH (168470); etc. It may be that the existence of these clinically similar disorders, mapping to chromosome 12 and chromosome 11, respectively, have their basis in mutation in paralogous genes originating through an ancient tetraploidization of the genome.


Inheritance

The transmission pattern of CFEOM2 in the families reported by Nakano et al. (2001) was consistent with autosomal recessive inheritance.


Molecular Genetics

Nakano et al. (2001) identified homozygous splice site and point mutations in the ARIX gene (602753.0001-602753.0003) in 4 pedigrees with CFEOM2.


REFERENCES

  1. Engle, E. C., Wang, S. M., Zwaan, J. T., Mullaney, P. B., Jabak, M. H., Beggs, A. H. Linkage and homozygosity mapping of a variant of congenital fibrosis of the extraocular muscles to chromosome 11q13.1. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A30 only, 1997.

  2. Nakano, M., Yamada, K., Fain, J., Sener, E. C., Selleck, C. J., Awad, A. H., Zwaan, J., Mullaney, P. B., Bosley, T. M., Engle, E. C. Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nature Genet. 29: 315-320, 2001. [PubMed: 11600883, related citations] [Full Text]

  3. Wang, S. M., Zwaan, J., Mullaney, P. B., Jabak, M. H., Al-Awad, A., Beggs, A. H., Engle, E. C. Congenital fibrosis of the extraocular muscles type 2, an inherited exotropic strabismus fixus, maps to distal 11q13. Am. J. Hum. Genet. 63: 517-525, 1998. [PubMed: 9683611, related citations] [Full Text]


Ada Hamosh - updated : 10/12/2001
Victor A. McKusick - updated : 9/11/1998
Creation Date:
Victor A. McKusick : 10/24/1997
alopez : 07/13/2021
carol : 10/10/2019
ckniffin : 03/01/2010
carol : 2/3/2010
ckniffin : 2/1/2010
carol : 6/10/2005
wwang : 5/24/2005
alopez : 6/13/2002
alopez : 11/21/2001
alopez : 10/15/2001
terry : 10/12/2001
carol : 11/17/1999
carol : 11/17/1998
carol : 9/16/1998
terry : 9/11/1998
terry : 10/28/1997
jenny : 10/24/1997

# 602078

FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, 2; CFEOM2


Alternative titles; symbols

FEOM2 LOCUS
FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, AUTOSOMAL RECESSIVE


ORPHA: 45358;   DO: 0081016;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
11q13.4 Fibrosis of extraocular muscles, congenital, 2 602078 Autosomal recessive 3 PHOX2A 602753

TEXT

A number sign (#) is used with this entry because of evidence that congenital fibrosis of extraocular muscles type 2 (CFEOM2) is caused by homozygous mutation in the ARIX gene (PHOX2A; 602753) on chromosome 11q13.


Description

Congenital fibrosis of extraocular muscles-2 (CFEOM2) is an autosomal recessive disorder in which affected individuals are born with bilateral ptosis and restrictive ophthalmoplegia with the globes fixed in extreme abduction (exotropia) (Wang et al., 1998, Nakano et al., 2001).

For a general phenotypic description and a discussion of genetic heterogeneity of various forms of CFEOM, see CFEOM1 (135700).


Clinical Features

Engle et al. (1997) observed CFEOM in members of 3 consanguineous Saudi Arabian families and demonstrated an autosomal recessive pattern of inheritance. This form of CFEOM differed by showing features suggesting a defect in the superior and inferior divisions of the oculomotor nerve rather than in the superior division, as in CFEOM1.


Mapping

The locus on chromosome 11q13 is referred to as FEOM2.

By genetic linkage analysis of the 3 Saudi Arabian families containing 18 affected individuals, Engle et al. (1997) demonstrated that the recessive form of the disease was not linked to the 'classic' CFEOM (135700) chromosome 12 locus. A genomewide screen using both individual and pooled DNA revealed linkage to markers near the centromere of 11q. Lod score analysis revealed a maximum combined lod score of 12.2 at D11S4136, with a critical region of 15 cM flanked by D11S1765 and D11S4207. Assuming allelic association secondary to founder effect, the critical region could be reduced to a 0.3-cM region within 11q13.1. Wang et al. (1998) found the same disease-associated haplotype in 2 of the 3 families, suggesting founder effect.

Engle et al. (1997) referred to the classic form as CFEOM1 and this variant form as CFEOM2. They hypothesized that CFEOM2 results from a related developmental defect affecting both the superior and inferior divisions of the oculomotor nerve and their corresponding alpha motor neurons and extraocular muscles. There is a considerable degree of homology (or paralogy) between chromosome 11 and chromosome 12: e.g., HRAS (190020) and KRAS2 (190070); IGF1 (147440) and IGF2 (147470); PTH (168450) and PTHLH (168470); etc. It may be that the existence of these clinically similar disorders, mapping to chromosome 12 and chromosome 11, respectively, have their basis in mutation in paralogous genes originating through an ancient tetraploidization of the genome.


Inheritance

The transmission pattern of CFEOM2 in the families reported by Nakano et al. (2001) was consistent with autosomal recessive inheritance.


Molecular Genetics

Nakano et al. (2001) identified homozygous splice site and point mutations in the ARIX gene (602753.0001-602753.0003) in 4 pedigrees with CFEOM2.


REFERENCES

  1. Engle, E. C., Wang, S. M., Zwaan, J. T., Mullaney, P. B., Jabak, M. H., Beggs, A. H. Linkage and homozygosity mapping of a variant of congenital fibrosis of the extraocular muscles to chromosome 11q13.1. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A30 only, 1997.

  2. Nakano, M., Yamada, K., Fain, J., Sener, E. C., Selleck, C. J., Awad, A. H., Zwaan, J., Mullaney, P. B., Bosley, T. M., Engle, E. C. Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nature Genet. 29: 315-320, 2001. [PubMed: 11600883] [Full Text: https://doi.org/10.1038/ng744]

  3. Wang, S. M., Zwaan, J., Mullaney, P. B., Jabak, M. H., Al-Awad, A., Beggs, A. H., Engle, E. C. Congenital fibrosis of the extraocular muscles type 2, an inherited exotropic strabismus fixus, maps to distal 11q13. Am. J. Hum. Genet. 63: 517-525, 1998. [PubMed: 9683611] [Full Text: https://doi.org/10.1086/301980]


Contributors:
Ada Hamosh - updated : 10/12/2001
Victor A. McKusick - updated : 9/11/1998

Creation Date:
Victor A. McKusick : 10/24/1997

Edit History:
alopez : 07/13/2021
carol : 10/10/2019
ckniffin : 03/01/2010
carol : 2/3/2010
ckniffin : 2/1/2010
carol : 6/10/2005
wwang : 5/24/2005
alopez : 6/13/2002
alopez : 11/21/2001
alopez : 10/15/2001
terry : 10/12/2001
carol : 11/17/1999
carol : 11/17/1998
carol : 9/16/1998
terry : 9/11/1998
terry : 10/28/1997
jenny : 10/24/1997