Purpose: To report the clinical and genetic study of one family and one isolated case of Egyptian origin with clinical anophthalmia. To further determine the role of RAX in anophthalmia and associated cerebral malformations.
Methods: Three patients with clinical anophthalmia and first-degree relatives from 2 consanguineous families of Egyptian origin underwent full ophthalmologic, general and neurological examination, and blood drawing. Cerebral MRI was performed in the index case of the family and in the isolated case. Genomic DNA was prepared from venous leukocytes and direct sequencing of all the exons and intron-exon junctions of the RAX gene was performed after PCR amplification
Results: Clinical bilateral anophthalmia was observed in all three patients. General and neurological examination was free in the family; obesity and psychomotor developmental delay was noticed in the isolated case. Orbital MRI showed the presence of cystic remnants and reduced optic nerves. Thin optic chiasm was the only observed cerebral malformation on MRI in the index case while the isolated case harboured diffuse cerebral atrophy and absence of the pituitary gland in addition. The three patients carried a novel homozygous mutation (IVS2-3G>A) in the RAX gene, while their parents were heterozygous healthy carriers.
Conclusions: To our knowledge, only two isolated cases of anophthalmia have been found to be caused by compound heterozygote RAX mutations, three null and one missense, affecting nuclear localization or DNA-binding homeodomain. We identified a novel homozygous RAX mutation in three patients with bilateral anophthalmia from Northern Egypt. The mutation potentially affects splicing of the last exon and, if not submitted to non-stop decay, could result in a protein that has an aberrant homeodomain and no paired-tail domain. Functional consequences of this change still need to be characterized. This is the first report of homozygous RAX mutation associated with autosomal recessive bilateral anophthalmia