Congenital fibrosis of the extraocular muscles (CFEOM) is a heterogeneous non-progressive eye movement disorder, which results from the dysfunction of all or part of the oculomotor nerve (cranial nerve III) and/or the muscles this cranial nerve innervates. CFEOM is characterized by a variable restrictive external ophthalmoplegia, ptosis and eyes that are fixed in an abnormal position. The classification of CFEOM is based on clinical manifestations and genetic classification is based on molecular analysis. To date, there are seven forms and four genetic loci for CFEOM. CFEOM1, CFEOM2, CFEOM3 and Tukel syndrome have been mapped, and mutations in KIF21A and PHOX2A have been found to cause CFEOM1 and CFEOM2, respectively.
CFEOM1 is the most common form of the condition affecting at least 1 in 230,000 people worldwide. It is inherited as an autosomal dominant pattern, characterized by bilateral ptosis, ophthalmoplegia, and hypotropic eyes with chin up position. Affected patients may require a stepwise surgical approach to correct strabismus and eyelid position.
Khan et al. (2008) reported two unrelated Saudi families with congenital fibrosis of the extraocular muscles type 1. All affected patients (one child from family A and four adults from family B) had ptosis, hypotropia, and virtually complete ophthalmoplegia. The two families were not consanguineous, but there was endogamy in family B. The affected child from family A developed a moderate esotropia. All patients from family B had high astigmatism, and two sons developed mild esotropia with attempted upgaze. Later, Khan et al. (2010) analyzed a family that had familial congenital fibrosis of the extraocular muscles (CFEOM) with apparent autosomal recessive inheritance. The family consisted of two affected siblings, three asymptomatic siblings, and their two asymptomatic parents. The two affected siblings had large-angle exotropia, moderate bilateral hypotropia, moderate bilateral ptosis, sluggish pupils, and almost complete ophthalmoloplegia with some abnormal synkinesis. The asymptomatic parents were not related and had unremarkable ophthalmic examinations. Four other siblings were normal by history; three underwent venous blood sampling for confirmatory testing. Sequencing of the KIF21A gene revealed heterozygous p.R954L in both affected individuals, but not in their parents or three asymptomatic siblings, consistent with parental germline mosaicism. Haplotype analysis suggested paternal inheritance but was not conclusive. Khan et al. (2010) noted that parental germline mosaicism can mimic recessive inheritance in CFEOM and likely is underrecognized. They also recommended that ophthalmologists should be aware of this phenomenon when counseling parents of children with apparent recessive (or de novo) hereditary eye disease. In 2011, Khan et al. sequenced the KIF21A gene in five probands with classic CFEOM1. None of the probands had mutations in KIF21A. Khan et al. (2011) speculated that the lack of KIF21A mutations in CFEOM1 patients exclusively from consanguineous families, most of whom had siblings with CFEOM, is strong evidence for a recessive form of CFEOM1.
Khan et al. (2011) studied a cohort of ten patients from eight families ranging from 5–23 years of age. Seven of the eight families were consanguineous. Five patients were diagnosed with CFEOM1 and five had CFEOM3. Five patients had notable disc cupping (three asymmetric, two bilateral) and five had optic nerve head hypoplasia (four bilateral, one unilateral). The presence of optic nerve head abnormalities in CFEOM is consistent with the concept of orbital dysinnervation having an effect on developing sensory nerves/tracts from the brainstem. All patients underwent CFEOM candidate gene testing and a causative mutation (heterozygous p.R954W in KIF21A) was only found in the one patient from a nonconsanguineous family. The study was limited by a lack of objective imaging analysis of the optic nerve head. The notable cupping in five patients from the cohort may have been physiological (as often occurs in myopia) or related to reduced optic nerve tissue. The authors concluded that optic nerve head findings could be part of the underlying dysinnervation process in CFEOM and may be under-recognized during clinical examination of patients with large angle incomitant strabismus, particularly if they are young children.