PURPOSE:

To describe the clinical features of two affected members of an Iranian family with autosomal recessive congenital fibrosis of the extraocular muscles (CFEOM2) and to report their novel mutation in the PHOX2A/ARIX gene.

DESIGN:

Experimental study.

METHODS:

Setting: Institutional practice. patient population:Six members of an Iranian family with CFEOM underwent complete ocular examinations including assessment of ocular motility, visual acuity, slit-lamp biomicroscopy, tonometry, and ophthalmoscopy. Experimental procedure: Mutation analysis of the PHOX2A gene was performed using polymerase chain reaction amplification of the coding exons and direct sequencing of polymerase chain reaction products. Main outcome measure: Presence or absence of mutation in PHOX2A gene in two siblings with exotropia and recessive CFEOM. Exotropia and ptosis were corrected surgically in one of the two siblings.

RESULTS:

The two affected siblings had bilateral ptosis and exotropia and severe limitation of all extraocular movements. One patient underwent strabismus surgery and ptosis repair. PHOX2A mutation analysis revealed a novel nonsense mutation in exon 2 (439C-->T). Both parents and the unaffected siblings were heterozygous,and the two affected siblings were homozygous for this mutation.

CONCLUSIONS:

The 439C-->T mutation in this family changes a glutamine to a stop codon (Q90X) at the beginning of the PHOX2A homeodomain region. This is the fourth CFEOM2 mutation in PHOX2A and the first nonsense mutation to be identified. It confirms PHOX2A as the autosomal recessive CFEOM2 disease gene and provides evidence that the phenotypic differences between PHOX2A mutations in man and mouse do not result from hypomorphic PHOX2A alleles in humans.