New Phenotype in Two Siblings with Familial FLVCR1 Mutation: Neurotrophic Keratopathy

The feline leukemia virus subgroup C receptor (<i>FLVCR1</i>) gene plays a role in heme, choline, and ethanolamine transport. In biallelic pathogenic <i>FLVCR1</i> variants, macrocytic anemia may be associated with childhood- or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. In patients with <i>FLVCR1</i> variants, optic atrophy and retinitis pigmentosa are previously described ocular findings, but neurotrophic keratopathy has not been reported. In this study, we describe two patients with homozygous novel likely pathogenic variants in terms of their clinical findings, including neurotrophic keratopathy. On examination, the 2-year-old sister had bilateral central corneal clouding, leukoma, absent corneal reflexes, normal fundus findings, and protruding ears. The 5-year-old sister exhibited significant bilateral corneal leukoma and scarring, optic disc pallor, absent corneal reflexes, and autoamputation-like defects on the fingertips of both hands. Next-generation sequencing analysis of the 5-year-old patient revealed a homozygous likely pathogenic c.160dup p.Arg54ProfsTer36 variant of the <i>FLVCR1</i> gene that was not listed in the GnomAD, ESP6500, ExAC, or Clinvar databases. <i>FLVCR1</i> mutations can disrupt choline transport and therefore acetylcholine production. Acetylcholine increases cGMP in the cornea, promoting epithelial growth. A lack of this neurotransmitter in the cornea leads to epithelial destruction. The development of neurotrophic keratopathy in this patient and her sibling may be a new phenotypic feature of this novel variant.