PHOX2A – Congenital Fibrosis of the Extraocular Muscles

PHOX2A (formerly ARIX) has been proposed as the gene underlying the autosomal recessive form of congenital fibrosis of the extraocular muscles (CFEOM2). Comprehensive sequencing in a sporadic 9-month-old patient with classic CFEOM features revealed no pathogenic PHOX2A variants (PMID:12208268). Subsequent analysis of 11 CFEOM1 pedigrees (nine linked to FEOM1 and two to FEOM3) and five sporadic classic CFEOM cases likewise failed to identify ARIX/PHOX2A mutations (PMID:11882252, PMID:15747768). Screening of 12 CFEOM3 families and 10 sporadic CFEOM3 probands also detected no PHOX2A variants, despite uncovering KIF21A mutations in some pedigrees (PMID:15223798).

The absence of pathogenic PHOX2A variants across diverse familial and sporadic CFEOM1–3 cohorts argues against a major role for PHOX2A in classic CFEOM presentations. These negative findings underscore significant genetic heterogeneity and point to unidentified loci underlying recessive CFEOM2 and related phenotypes. Currently, clinical testing of PHOX2A for CFEOM lacks support until bona fide pathogenic variants are discovered.

References

• American journal of ophthalmology • 2002 • Elevation of one eye during tooth brushing. PMID:12208268
• BMC genetics • 2002 • CFEOM1, the classic familial form of congenital fibrosis of the extraocular muscles, is genetically heterogeneous but does not result from mutations in ARIX. PMID:11882252
• Transactions of the American Ophthalmological Society • 2004 • Congenital abnormalities of cranial nerve development: overview, molecular mechanisms, and further evidence of heterogeneity and complexity of syndromes with congenital limitation of eye movements. PMID:15747768
• Investigative ophthalmology & visual science • 2004 • Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3). PMID:15223798

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