Extraocular muscles congenital fibrosis

(CFEOM, acronym for Congenital Fibrosis of the ExtraOcular Muscles)

Estimated prevalence of 1/230,000. Congenital and non-progressive restrictive ophthalmoplegia, with or without blepharoptosis, secondary to the fibrosis of the oculomotor muscles due to their primary dysinnervation following an abnormality of a nucleus of the brainstem or of the axons of these muscles. The characteristic sign is a significant decrease in vertical eye movements, leading to a compensatory elevation of the chin.

From a genetic point of view, several forms have been identified:

Gene	transmission	penetrance	phenotype	Details
KIF21A	A dominant	complete sometimes mosaicism	CFEOM 1 (rare: CFEOM 3)	Markus Gunn
PHOX2A or ARIX	A recessive	complete	CFEOM 2	Pupillary abnormalities
TUBB3	A dominant	variable	CFEOM 3 (rare: CFEOM 1)	Cortical malformations, developmental delay, peripheral axonal neuropathy, E410K or R262H syndrome
TUBB2B	A dominant	complete	CFEOM 3	Polymicrogyria, developmental delay
TUBA1A	A dominant	unknown	CFEOM 1 or 3	Polymicrogyria, developmental delay
ECEL1	A recessive	variable	ill-defined	Congenital multiple arthrogryposis
COL25A1 (muscle pathology)	A recessive	unknown	CFEOM 5	Congenital multiple arthrogryposis
Locus in 21 qter	A recessive	unknown	CFEOM 4 (Tuckel syndrome)	Oligodactyly of the hands

There are 5 clinical subtypes:

- CFEOM-1 [MIM 135 700]: most common form (> 50 %); congenital, non-progressive restrictive ophthalmoplegia with blepharoptosis and often Marcus Gunn syndrome (see this term)

- CFEOM-2 [MIM 602 078]: congenital and non-progressive restrictive ophthalmoplegia, with blepharoptosis accompanied by pupillary abnormalities (weak or absent oculomotor reflex)

- CFEOM-3 [MIM 600 638]: congenital restrictive ophthalmoplegia but asymmetric and non-progressive, with blepharoptosis of varying importance; there are other neurological signs and often mental retardation

- CFEOM-4 [MIM 609428]: or Tuckel syndrome! CFEOM 3 with hand oligodactyly

- CFEOM-5 [MIM 616219]: still poorly defined: congenital and non-progressive restrictive ophthalmoplegia, with blepharoptosis and, often, eye retraction

In the context of CFEOM 3, 2 types have been identified:

TUBB3-E410K syndrome where oculomotor abnormalities are associated with pyloric stenosis, hypogonadotrophic hypogonadism and cyclic vomiting
TUBB3-R262H syndrome, where oculomotor abnormalities are associated with congenital joint contractures, early peripheral neuropathy, and basal ganglia abnormalities

Differential diagnosis:

- progressive oculomotor palsy, often due to mitochondrial cytopathy (see this term)

- complete ophthalmoplegia syndrome, "facial weakness", and malignant hyperthermia due to a mutation in the RYR1 gene also described as atypical Moebius syndrome or variant of multiminicores syndrome with external ophthalmoplegia [MIM 255 320]

Anesthetic implications:

eye protection (risk of lagophthalmos); depending on the associated abnormalities; strabismus repair is often difficult and with a high failure rate

References :

Xia W, Wei Y, Wu L, Zhao C.
Congenital Fibrosis of the Extraocular Muscles: an overview from genetics to management.
Children 2022, 9, 1605. https:// doi.org/10.3390/children9111605
Shaaban S, Ramos-Platt L, Gilles FH, Chan WM, Andrews C, De Girolami U, Demer J, Engle EC.
RYR1 mutations as a cause of ophthalmoplegia, facial weakness, and malignant hyperthermia.
JAMA Ophthalmol. 2013, 131, 1532–40

Updated: December 2022