Navigating classical Hodgkin lymphoma in a patient with DIAPH1 deletion syndrome: Diagnostic and therapeutic challenges in a rare immuno-genetic context

Abstract

Abstract DIAPH1 encodes for formin diaphanous homolog 1, a protein fundamental to cytoskeletal organisation, cell division, neurodevelopment and T cell function. Recent in vitro studies show DIAPH1's importance in DNA double-strand break (DSB) repair via homologous recombination (HR), critical for maintaining genomic stability (Woodward et al., 2025). Billallelic loss of function mutations in DIAPH1 cause DIAL syndrome, a rare autosomal recessive condition associated with progressive microcephaly, cortical blindness, intellectual disability, epilepsy and variable immunodeficiency or immune dysregulation (Kaustio et al., 2021). Until now, there are approximately 20 patients with DIAL syndrome reported in the literature, at least 2 of them diagnosed with classical Hodgkin and Diffuse Large B Cell Lymphoma (cHL, DLBCL), highlighting the interplay between immune defects and genomic fragility (Kaustio et al., 2021, Azizoglu et al., 2024, Miao et al., 2022). Chemotherapy and radiation tolerance have yet to be clinically established in this patient group. Here, we describe an 8-year-old monozygotic twin boy born to non-consanguineous parents with severe microcephaly, cortical blindness, global developmental delay, and epilepsy on antiepileptic treatment (carbamazepine and valproate). Comprehensive diagnostic work-up performed since birth for both twins did not identify a genetic cause. Our patient presented with a 2-month history of cervical lymphadenopathy, persistent fevers and 15% weight loss during this period. Staging scans revealed extensive lymphadenopathy and extranodal PET uptake, with positive serum EBV PCR. Excisional node biopsy confirmed EBV-positive cHL, Stage IV-E. Our patient was enrolled in a Precision Oncology Program (ZERO2 Trial, NCT05504772) which enabled rapid genomic diagnosis of a homozygous DIAPH1 loss of function germline variant, consistent with DIAL syndrome. Based on the diagnosis, further immunological assessment was performed which showed evidence of defective T-cell maturation with very low naïve T cell populations and preserved B cell function. He was commenced on full dose OEPA (vincristine, etoposide, prednisolone, doxorubicin) after histopathologic confirmation of cHL, and following 2 cycles his early response assessment PET showed complete metabolic response. Due to concerns about hepatic enzyme induction and mitochondrial toxicity, anti-seizure therapy was changed to levetiracetam and clobazam, as carbamazepine is a potent CYP3A4 inducer that may decrease exposure to drugs like methylprednisolone (Bartoszek et al., 1987). Our patient tolerated his OEPA cycles well with expected cytopenias, grade 3 febrile neutropenia and need for parenteral nutrition. His oral mucositis was complicated by HSV-1 stomatitis. With robust supportive care, he achieved full recovery from these complications and was discharged post cycle 2. Consolidation therapy with DECOPDAC21 is planned, with discussion regarding role of radiotherapy pending MDT review, given potential DSB repair defect related radiosensitivity. Our patient's treatment with standard dose chemotherapy achieved early complete metabolic response, with full recovery from multiple grade 3 toxicities including myelosuppression, mucositis, and infectious complications. Management of Hodgkin lymphoma (HL) in patients with DIAPH1 deletion syndrome presents unique challenges, particularly with emerging preclinical evidence implicating DIAPH1 deficiency as a potential DSB repair disorder. However, to date, no clinical evidence defines how this translates into chemotoxicity or radiosensitivity in patients with DIAL syndrome. The intermediate severity of DNA repair impairment in individuals with DIAL syndrome suggested by laboratory data adds uncertainty regarding chemotherapy tolerance (Woodward et al., 2025). Consequently, rationale exists both for cautiously pursuing full dose curative intent chemotherapy, given the curability of HL and the known risks of undertreatment, and for considering dose reductions to minimise potentially life-threatening toxicities. This is the first report showing feasibility of full dose induction therapy for cHL with intensive supportive care in DIAPH1 deficiency. Nonetheless, ongoing careful individualised dosing, vigilant toxicity monitoring, and multidisciplinary input remain essential.