Homozygous DIAPH1 Deficiency Without Cortical Blindness Presenting with EBV-Associated Hodgkin Lymphoma

Abstract

Background:

Diaphanous-related formin 1 (DIAPH1) is a cytoskeletal protein belonging to the formin family. Homozygous loss-of-function variants in DIAPH1 have been associated with seizures, cortical blindness, mitochondrial dysfunction, and combined immunodeficiency. Here, we report a rare case of homozygous DIAPH1 deficiency presenting with the classical clinical features of the disorder but without cortical blindness.

Case Presentation:

An 11-year-old male patient presented with a productive cough. His computed tomography scan revealed diffuse bronchiectasis and chronic parenchymal infiltrative lesions. Respiratory examination revealed bilateral crackles. Ophthalmologic examination and visual field testing were normal. Laboratory evaluation showed elevated serum IgG and IgE levels, whereas the IgA level was within the normal reference range and the IgM level was decreased for his age. Vaccine responses to hepatitis B and rubella were adequate; however, the isohemagglutinin titer against the blood group was insufficient. Lymphopenia was detected in the complete blood count. Although CD3⁺, CD4⁺, and CD8⁺ T cell, B cell, and natural killer cell counts were within normal ranges, class-switched memory B cells and recent thymic emigrants (CD4⁺CD45RA⁺CD31⁺) were significantly reduced. Next-generation sequencing-based targeted gene panel analysis, performed with a preliminary diagnosis of immunodeficiency, identified a homozygous nonsense variant, c.1051C > T (p.Arg351*), in exon 11 (11/15) of the DIAPH1 (NM_005219) gene. Epstein–Barr virus (EBV)-associated classical Hodgkin lymphoma subsequently developed in the patient, and chemotherapy was initiated.

Conclusions:

This is the first case of homozygous DIAPH1 deficiency presenting without cortical blindness. Homozygous DIAPH1 deficiency may present with a broad clinical spectrum and phenotypic variability, highlighting an increased susceptibility to EBV infection and virus-associated malignancies. Comprehensive immunological evaluation and close, long-term follow-up are essential for affected patients.