Familial fleck corneal dystrophy caused by complete deletion of the PIKFYVE gene.

BACKGROUND: Fleck corneal dystrophy (FCD) is a rare autosomal dominant disease that affects exclusively the corneal stroma. The disease is caused by heterozygous variants in PIKFYVE, a gene encoding a lipid kinase involved in multiple cellular pathways, primarily participating in membrane dynamics and signaling. This report describes a familial case of FCD caused by a complete deletion of the PIKFYVE gene. MATERIAL AND METHODS: A clinical ophthalmic examination was performed on the proband and family members. Genetic testing included next-generation sequencing (multigene panel), and chromosomal microarray analysis. A quantitative PCR assay was designed in order to segregate the deletion. RESULTS: A 19-year-old male, with no family or personal history of ocular disease, presented for evaluation due to an acute illness consisting of burning, foreign body sensation, and red eye. Slit lamp biomicroscopy revealed bilateral small pterygia and scattered bilateral white opacities in the corneal stroma, a very similar corneal phenotype was found in the 47-year-old father, who was asymptomatic. NGS detected a heterozygous deletion of the entire PIKFYVE coding sequence. CMA in DNA from the propositus indicated a 543 kb deletion in 2q33.3q34 spanning the entire PIKFYVE gene. The deletion was confirmed in the father. CONCLUSIONS: We add to the molecular spectrum of FCD by describing a familial case of a whole PIKFYVE gene deletion in affected subjects. Our findings support that normal expression of PIKFYVE is necessary for corneal keratocytes homeostasis and normal corneal appearance. We conclude that PIKFYVE haploinsufficiency is the molecular mechanism underlying this familial case of FCD.

Mutational Profile and Retinal Phenotypes of PCARE-Related Cone-Rod Dystrophies in a Mexican Cohort.

Purpose: The aim of the study is to describe the genotype and phenotype of a Mexican cohort with PCARE-related retinal disease. Methods: The study included 14 patients from 11 unrelated pedigrees with retinal dystrophies who were demonstrated to carry biallelic pathogenic variants in PCARE. Visual assessment methods included best corrected visual acuity, color fundus photography, Goldmann visual field test, kinetic perimetry, dark/light adapted chromatic perimetry, full-field electroretinography, autofluorescence imaging, and spectral domain-optical coherence tomography imaging. Genetic screening was performed either by gene panel sequencing or by exome sequencing. Results: According to the results of multimodal imaging and functional tests, all 14 patients were diagnosed with cone-rod dystrophy. Six different PCARE pathogenic alleles were identified in our cohort, including three novel mutations: c.3048_3049del (p.Tyr1016∗), c.3314_3315del (p.Ser1105∗), and c.551A > G (p.His184Arg). Notably, alleles p.His184Arg, p.Arg613∗, and p.Arg984∗ were present in 18 of the 22 (82%) PCARE alleles from probands in our cohort. Conclusion: Our work expands the PCARE mutational profile by identifying three novel pathogenic variants causing retinal dystrophy. While phenotypic variations occurred among patients, a cone-rod dystrophy pattern was observed in all affected individuals.

USH2A mutational spectrum causing syndromic and non-syndromic retinal dystrophies in a large cohort of Mexican patients.

Background: Mutations in the USH2A gene are the leading cause of both non-syndromic autosomal recessive retinitis pigmentosa (RP) and Usher syndrome, a syndromic form of RP characterized by retinal dystrophy and sensorineural hearing loss. To contribute to the expansion of the USH2A-related molecular spectrum, the results of genetic screening in a large cohort of Mexican patients are presented. Methods: The study population comprised 61 patients with a clinical diagnosis of either non-syndromic RP (n = 30) or Usher syndrome type 2 (USH2; n = 31) who were demonstrated to carry biallelic pathogenic variants in USH2A in a three-year period. Genetic screening was performed either by gene panel sequencing or by exome sequencing. A total of 72 available first- or second-degree relatives were also genotyped for familial segregation of the identified variants. Results: The USH2A mutational spectrum in RP patients included 39 distinct pathogenic variants, most of them of the missense type. The most common RP-causing variants were p.Cys759Phe (c.2276G>T), p.Glu767Serfs*21 (c.2299delG), and p.Cys319Tyr (c.956G>A), which together accounted for 25% of all RP variants. Novel USH2A mutations included three nonsense, two missense, two frameshift, and one intragenic deletion. The USH2A mutational spectrum in USH2 patients included 26 distinct pathogenic variants, most of them of the nonsense and frameshift types. The most common Usher syndrome-causing variants were p.Glu767Serfs*21 (c.2299delG), p.Arg334Trp (c.1000C>T), and c.12067-2A>G), which together accounted for 42% of all USH2-related variants. Novel Usher syndrome USH2A mutations included six nonsense, four frameshift, and two missense mutations. The c.2299delG mutation was associated with a common haplotype for SNPs located in exons 2-21 of USH2A, indicating a founder mutation effect. Conclusions: Our work expands the USH2A mutational profile by identifying 20 novel pathogenic variants causing syndromic and non-syndromic retinal dystrophy. The prevalent c.2299delG allele is shown to arise from a founder effect. Our results emphasize the usefulness of molecular screening in underrepresented populations for a better characterization of the molecular spectrum of common monogenic diseases.

Positron emission tomography in subcutaneous panniculitis-like T-cell lymphoma.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL), an uncommon disorder, was diagnosed in a 17-year-old female when she presented with multiple hard subcutaneous masses that developed over 3 years. She was treated on chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone. Pre- and post-treatment positron emission tomography study demonstrated dramatic resolution of the subcutaneous lesions indicating its usefulness in SPTCL staging and treatment response monitoring.