Fibrosis Of Extraocular Muscles, Congenital, 1

A number sign (#) is used with this entry because congenital fibrosis of extraocular muscles-1 (CFEOM1) is caused by heterozygous mutation in the KIF21A gene (608283) on chromosome 12q12.

Mutations in the KIF21A gene have also been reported in patients with CFEOM3B.

Description

Congenital fibrosis of the extraocular muscles (CFEOM) encompasses several different inherited strabismus syndromes characterized by congenital restrictive ophthalmoplegia affecting extraocular muscles innervated by the oculomotor and/or trochlear nerves. Classic CFEOM is characterized by bilateral blepharoptosis and ophthalmoplegia with the eyes fixed in an infraducted position about 20 to 30 degrees below the horizontal midline. Involvement of the horizontal extraocular muscles is variable. If all affected members of a family have the classic phenotype with bilateral involvement, the disorder is referred to as 'CFEOM1' (Engle et al., 1997; Heidary et al., 2008).

CFEOM2 (602078), an autosomal recessive disorder caused by mutation in the ARIX gene (602753) on chromosome 11q13, is characterized by bilateral ptosis with eyes fixed in an exotropic position.

The CFEOM3 phenotype shows more variable clinical features: affected individuals may have unilateral eye involvement, may be able raise their eyes above midline, or may not have blepharoptosis. CFEOM3 is diagnosed in a family if even 1 member does not have classic findings of the disorder. CFEOM3 is a genetically heterogeneous disorder; CFEOM3A with or without extraocular involvement (600638) is caused by mutation in the TUBB3 gene (602661) on chromosome 16q24; CFEOM3B is caused by mutation in the KIF21A gene (608283) on chromosome 12q12; and CFEOM3C (609384) maps to chromosome 13q.

CFEOM4 (609428), also known as Tukel syndrome, maps to chromosome 21q.

CFEOM5 (616219) is caused by mutation in the COL25A1 gene (610004) on chromosome 4q25.

See also NOMENCLATURE below.

Clinical Features

Congenital fibrosis of extraocular muscles is characterized clinically by anchoring of the eyes in downward gaze, ptosis, and backward tilt of the head. Although an earlier report of congenital blepharoptosis with markedly restricted eye movements can be identified, the classic report of familial congenital bilateral blepharoptosis with absence of extrinsic ocular muscle function was that of Heuck (1879). In addition to fibrosis of the extraocular muscles, fibrosis of the Tenon capsule and adhesions between muscles, Tenon capsule, and globe are found. There is no elevation or depression of the eyes and little or no horizontal movement. The eyes are fixed 20 to 30 degrees below the horizontal and as a result the patient holds the head tilted back in a 'chin-up' position. The condition, including blepharophimosis, is present from birth. Heuck (1879) showed, in the postmortem examination of one of his patients, and Apt and Axelrod (1978) confirmed at operation that the extraocular muscles are not only fibrotic but also insert anomalously. Laughlin (1956) observed the condition in at least 4 generations of a family. Hansen (1968) described an affected mother, son, and daughter. Harley et al. (1978) traced the disorder through 4 generations. The parents of the first affected person were first cousins, a probably coincidental event; the first affected person may have had his disorder as a result of new mutation. Male-to-male transmission was described. Walther (1983) observed 'a few beautiful autosomal dominant pedigrees containing many instances of father-son transmission.'

Engle et al. (1995) provided a photograph of 3 sibs. The 2 affected children had ptosis and hypotropic strabismus with a compensatory backward tilt to the head. They also showed a horizontal smile in comparison with their unaffected sister.

Gottlob et al. (2002) reported a 9-month-old girl with classic CFEOM who also had elevation of her right eye during tooth brushing. She showed no voluntary ocular elevation above the midline, and her eyes converged on attempted upgaze. However, when her right maxillary teeth or upper gums were touched, her right eye elevated above the midline. This elevation was not elicited by jaw movements, as seen in Marcus Gunn jaw-winking (154600). The authors felt that this represented the first case of CFEOM with aberrant regeneration between the nerve to the superior rectus and the trigeminal nerve. They concluded that this aberrant innervation supports a primary developmental abnormality of the cranial nerves as the cause of CFEOM. The child's exonic and flanking intronic regions of the CFEOM2 ARIX gene (602753) were sequenced and no mutations were found.

Reck et al. (1998) estimated that the minimum prevalence of CFEOM in the Wessex region of England is 1 in 230,000. They identified 4 families in an attempt at total ascertainment. CFEOM had previously been divided into several clinical entities: general fibrosis syndrome, vertical retraction syndrome, and congenital fibrosis of the inferior rectus. In this study, Reck et al. (1998) found that several of the presumably distinct CFEOM entities were present within 1 family, suggesting that these are variants of the same condition and that subclassification is not warranted.

Sener et al. (2000) described the phenotype of a Turkish family with autosomal dominant variably expressed CFEOM that was linked to the FEOM1 locus on chromosome 12. Since the family demonstrated autosomal dominant inheritance with reduced penetrance and variable expressivity, the phenotype was classified as CFEOM3 (Mackey et al. (2002)).

Rudolph et al. (2009) reported 3 families and 2 unrelated patients with CFEOM1 due to a heterozygous R943W mutation in the KIF21A gene (608283.0001). All patients were of German origin, except 1 who was Turkish. The phenotype was relatively homogeneous: affected individuals showed bilateral restricted upgaze with compensatory chin elevation, ptosis, and variable limitations of horizontal gaze motility. Some had esotropia and/or exotropia. Many patients had corrective surgery of the extraocular muscles. In 1 family, affected individuals also had mental disability or mental retardation, which Rudolph et al. (2009) postulated may indicate that the syndrome can be associated with more general neurologic dysfunction in addition to impairment in ocular motility. Haplotype analysis did not indicate a founder effect.

Congenital Fibrosis of Extraocular Muscles 3B

Sener et al. (2000) reported a Turkish family with autosomal dominant inheritance of a variably expressed disorder consistent with congenital fibrosis of extraocular muscles. Eighteen of the 29 affected family members had bilateral congenital ptosis and restrictive infraductive (downward) ophthalmoplegia consistent with classic CFEOM1; however, 11 affected individuals had eye(s) in a neutral primary position, residual upgaze, and/or absence of ptosis, most closely resembling a CFEOM3 phenotype. The mutation in this family appeared to exhibit reduced penetrance and marked variability.

Lin et al. (2005) reported a Taiwanese family with CFEOM3. The phenotype in this family was considered different from classic CFEOM1 because of intrafamilial variation in disease severity. Two members had classic disease with severe ptosis and fixed eyes. Three other members were all affected, but these individuals could still move their eyes, and severity between the 2 eyes also differed.

Lu et al. (2008) reported a Chinese family with a phenotype consistent with CFEOM3. The diagnosis of CFEOM3 was due to variable involvement and severity of ophthalmoplegia and ptosis. Five individuals had a classic phenotype with bilateral severe ptosis, restricted upgaze, and compensatory head position. By contrast, 3 individuals had at least 1 eye with mild ptosis, residual upgaze, or the ability to elevate above the midline. Two additional family members had varying ptosis without compensatory head position. Finally, 1 individual, who was an obligate carrier, had only subtle symptoms with mild limitation of vertical ocular motility without ptosis, strabismus, or compensatory head position.

Pathogenesis

From neuropathologic examination of an individual with CFEOM1, Engle et al. (1997) demonstrated an absence of the superior division of the oculomotor nerve (cranial nerve III) and corresponding oculomotor subnuclei.

Mapping

Engle et al. (1994) mapped the gene responsible for this disorder to an 8-cM interval flanked by D12S87 and D12S85 in 2 unrelated families. Engle et al. (1995) refined the linkage in the 2 families reported by Engle et al. (1994), performed linkage analysis of 5 additional families, and provided a physical map of the critical region for the CFEOM gene. In each of the 7 families, the disease gene was linked to the pericentromeric region of chromosome 12, supporting genetic homogeneity.

Black et al. (1998) reported 3 families with typical CFEOM. One family did not map to the FEOM1 locus on chromosome 12 or to the FEOM2 locus on chromosome 11. The family also did not map to 1p34.1-p32, where the gene for isolated congenital ptosis (PTOS1; 178300) has been mapped. Black et al. (1998) also reported recombinants in 2 families that potentially reduced the candidate region for CFEOM1 to the region flanked by D12S345 and D12S1048, although they emphasized that this regionalization is based on an assumption of locus homogeneity and full penetrance.

In a Turkish family with a CFEOM3 phenotype, Sener et al. (2000) found strong linkage to the CFEOM1 locus on chromosome 12 (maximum lod score of 10.8 at D12S85). These data indicated that there may be greater phenotypic heterogeneity at the CFEOM1 locus than previously reported, and the authors noted that this may blur the ability to distinguish different CFEOM loci based solely on clinical presentation.

Engle et al. (2002) analyzed 11 unpublished CFEOM1 pedigrees and found that 9 were consistent with linkage to the FEOM1 locus on chromosome 12. In the remaining 2 families that were not linked to the FEOM1 locus, the CFEOM1 phenotype cosegregated with the FEOM3 locus (600638) markers on chromosome 16q. These findings suggested that the CFEOM1 phenotype is genetically heterogeneous.

Molecular Genetics

In 31 probands with CFEOM1 from unrelated families and in 13 sporadic cases, Yamada et al. (2003) identified 6 different heterozygous mutations in the KIF21A gene (see 608283.0001-608283.0006).

Tiab et al. (2004) identified the R954W mutation (608283.0001) in all affected members of 3 families of Swiss, Turkish, or French origin with CFEOM1, as well as in a sporadic case of Iranian origin. The R954W mutation was not observed in 100 normal controls from various ethnic origins. Tiab et al. (2004) concluded that mutation analysis in CFEOM1 is important, especially in sporadic cases, to evaluate correctly recurrence and transmission risks.

In affected members of a 4-generation Indian family with CFEOM1, Ali et al. (2004) identified the R954W mutation, which affected the C nucleotide of a CpG dinucleotide. A G-to-A transition at this nucleotide results in the R954Q mutation (608283.0002). Bisulfite genomic sequencing revealed that all the CpG dinucleotides in exon 21 were methylated both in the genomic DNA from blood and sperm. Ali et al. (2004) concluded that the high mutability of this CpG dinucleotide may result, in part, from its methylated state.

To investigate the structural basis of ocular motility abnormalities in patients with CFEOM1, Demer et al. (2005) performed high-resolution orbital MRI in 19 individuals from 6 unrelated CFEOM1 pedigrees, harboring 4 of the 6 reported KIF21A mutations, and 23 normal controls. Patients with CFEOM1 had severe bilateral blepharoptosis, limited supraduction, and variable ophthalmoplegia. In the affected individuals, MRI demonstrated atrophy of the levator palpebrae superioris and superior rectus extraocular muscles (EOMs) and small or absent orbital motor nerves. The oculomotor nerve was most severely hypoplastic, but the abducens was also affected. EOMs exhibited variable atrophy and an abnormally bright T1 signal. Individuals with the arg954-to-trp (R954W; 608283.0001) substitution or the arg954-to-gln (R954Q; 608283.0002) substitution frequently exhibited A-pattern strabismus, with misinnervation of the lateral rectus muscle by an oculomotor nerve branch. Patients with CFEOM1 exhibited subclinical but highly significant reduction from normal in mean optic nerve size (p less than 0.001). Comparing clinical and MRI phenotypes did not reveal distinguishing features among KIF21A mutations. Demer et al. (2005) concluded that orbital imaging in CFEOM1 caused by various amino acid substitutions in the kinesin KIF21A demonstrated consistent abnormalities of motor and sensory innervation in the orbit and that neuronal disease is primary in CFEOM1, with myopathy arising secondary to abnormal innervation and minimal rectus pulley abnormality due to reduced EOM forces.

Congenital Fibrosis of Extraocular Muscles 3B

In affected members of a family with CFEOM3 reported by Sener et al. (2000), Yamada et al. (2004) identified a heterozygous mutation in the KIF21A gene (M947I; 608283.0007). Yamada et al. (2004) stated that the occurrence of a CFEOM3 phenotype rather than a CFEOM1 phenotype in this family may result in part from environmental factors or genetic background. They noted that a subset of individuals within this pedigree did exhibit the classic CFEOM1 phenotype, suggesting that some KIF21A mutations may cause a more variable and milder CFEOM phenotype. Yamada et al. (2004) did not identify KIF21A mutations in 11 additional CFEOM3 pedigrees or in 10 patients with sporadic CFEOM3, suggesting that KIF21A mutations are a rare cause of the CFEOM3 phenotype.

In affected members of a Taiwanese family with CFEOM3, Lin et al. (2005) identified a heterozygous mutation in the KIF21A gene (R943W; 608283.0001). This mutation had been identified in other families with classic CFEOM1. The molecular findings of Lin et al. (2005) thus indicated that the CFEOM3 phenotype can be caused by KIF21A mutations, and that the expression of KIF21A mutations may be variable. However, Lin et al. (2005) suggested that the third family may be better described as CFEOM1 with variability in expression.

In affected members of a Chinese family with CFEOM3, Lu et al. (2008) identified a heterozygous mutation in the KIF21A gene (R954Q; 608283.0002), which had previously been identified in patients with classic CFEOM1.

Heterogeneity

Yoshida et al. (2007) reported a Japanese family in which at least 4 individuals had congenital fibrosis of the extraocular muscles inherited in an autosomal dominant pattern. All affected individuals showed a complete loss of upgaze with ptosis and severe or moderate restriction of downgaze. Horizontal gaze function was relatively well preserved, although horizontal nystagmus was noted in 2 patients. Pupillary reactions were normal, and there was no retinal pigmentary degeneration or optic atrophy. Two middle-aged patients but not 2 younger patients developed a slowly progressive gait ataxia in adolescence. Brain MRI in all patients showed cerebellar atrophy. Mild hearing impairment and learning difficulties were also noted. Although 4 affected individuals shared a common haplotype at the FEOM1 locus at chromosome 12p11.2-q12, direct sequencing of the KIF21A gene failed to identify a pathogenic mutation in the proband.

Nomenclature

The designations CFEOM1, CFEOM2, and CFEOM3 refer to the clinical subtypes of congenital fibrosis of extraocular muscles. The designations FEOM1, FEOM2, FEOM3, and FEOM4 refer to loci on chromosomes 12q12, 11q13, 16q24, and 13q12, respectively (Heidary et al., 2008).