PHOX2A – Congenital Fibrosis of the Extraocular Muscles Type 2

Congenital fibrosis of the extraocular muscles type 2 (CFEOM2) is an autosomal recessive disorder characterized by restrictive external ophthalmoplegia and congenital strabismus. CFEOM2 belongs to the congenital fibrosis syndromes, which arise from maldevelopment of cranial nerve nuclei controlling extraocular muscles (MONDO:0011181). The disorder presents at birth with bilateral ptosis, limited vertical and horizontal eye movements, and absence of ocular motility, significantly impacting vision and quality of life.

In 2001, three homozygous PHOX2A variants were identified in four unrelated CFEOM2 pedigrees, confirming the gene’s role in human disease. Affected individuals harbored two splice-site mutations (c.217+1G>A; c.406-1G>A) and one missense variant (c.215C>T (p.Ala72Val)) that segregated with disease in each family (PMID:11600883). A total of four probands from four distinct families were reported, with segregation of homozygosity in parental carriers and concordant clinical findings.

All reported variants are predicted loss-of-function alleles: one missense change within the conserved homeodomain and two consensus splice-site disruptions. No recurrent or founder alleles have been described, and population screening indicates these variants are absent from large control cohorts. The inheritance mode is autosomal recessive with complete penetrance in homozygotes.

Functional studies in mouse and zebrafish models demonstrate that PHOX2A (ARIX) is essential for development of oculomotor (nIII) and trochlear (nIV) nuclei. Knock-out or knock-down of PHOX2A orthologs results in phenotypes analogous to human CFEOM2, including failed innervation of extraocular muscles. These concordant in vivo data support a loss-of-function mechanism underlying the human phenotype.

No conflicting evidence has been reported; subsequent screens of other candidate genes in CFEOM patients have not identified alternative causes in PHOX2A negative families. The available data meet criteria for a strong gene–disease association based on multiple unrelated probands, segregation in consanguineous pedigrees, and robust animal model concordance.

Key Take-home: Biallelic loss-of-function variants in PHOX2A cause CFEOM2, supporting targeted genetic testing for early diagnosis and family planning.

References

• Nature genetics • 2001 • Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. PMID:11600883

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