{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T15:48:04Z","timestamp":1764690484599,"version":"3.46.0"},"reference-count":27,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background and Clinical Significance: This case report describes a 46-year-old male with no prior comorbidities who developed progressive neurological symptoms\u2014ataxia and diplopia\u2014shortly after the second Comirnaty (Pfizer-BioNTech) COVID-19 vaccine dose. The aim is to highlight the diagnostic challenges of central nervous system-dominant hemophagocytic lymphohistiocytosis (HLH) and its overlap with neuroinflammatory disorders. Case Presentation: Initial MRI showed demyelinating lesions in the brain and spinal cord, suggesting acute disseminated encephalomyelitis (ADEM). The patient had only transient improvement with corticosteroids and then multiple relapses with expanding CNS lesions despite cyclophosphamide, plasmapheresis, and rituximab. After 27 months, systemic features appeared, including fever, cytopenias, elevated inflammatory markers, and splenomegaly. Bone marrow analysis revealed hemophagocytosis, fulfilling HLH-2004 criteria, with an H-score of 200 supporting secondary HLH. Given consanguinity and persistent immune activation, next-generation sequencing identified two homozygous PRF1 variants\u2014one pathogenic (p.Arg232His) and one of uncertain significance (p.Ala91Val)\u2014consistent with autosomal recessive familial type 2 HLH. The patient underwent matched unrelated donor hematopoietic stem cell transplantation (HSCT) 11 months after HLH diagnosis, achieving initial stabilization, but ultimately died from infectious complications in March 2025 without evidence of HLH relapse. Conclusions: This case illustrates an atypical adult-onset presentation of familial HLH manifesting primarily with recurrent neuroinflammatory symptoms that initially mimicked ADEM. The diagnostic delay reflects the challenge of recognizing CNS-dominant HLH, especially in adults and in the absence of early systemic features. The identification of biallelic PRF1 variants confirmed an underlying genetic predisposition. This is the first reported case of adult-onset familial HLH presenting predominantly with neurological symptoms following COVID-19 vaccination. The case emphasizes the need to consider genetic forms of HLH in relapsing neuroinflammatory disorders and raises the hypothesis that vaccination may unmask subclinical immune dysregulation in genetically susceptible individuals<\/jats:p>","DOI":"10.3390\/diagnostics15233000","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T10:04:57Z","timestamp":1764151497000},"page":"3000","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adult Onset of Type 2 Familial Hemophagocytic Lymphohistiocytosis After SARS-CoV-2 Vaccination with an Unusual Neurological Onset: The Great Mimic"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7730-4262","authenticated-orcid":false,"given":"Flaminia","family":"Bellisario","sequence":"first","affiliation":[{"name":"UOSD Malattie Linfoproliferative Extramidollari, Dipartimento di Scienze di Laboratorio ed Ematologiche\u00a0, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7101-0949","authenticated-orcid":false,"given":"Assunta","family":"Bianco","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"D\u2019Alo\u2019","sequence":"additional","affiliation":[{"name":"UOSD Malattie Linfoproliferative Extramidollari, Dipartimento di Scienze di Laboratorio ed Ematologiche\u00a0, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7919-4626","authenticated-orcid":false,"given":"Chiara","family":"Passarelli","sequence":"additional","affiliation":[{"name":"Unit\u00e0 di Ricerca di Citogenomica Traslazionale, UOC Laboratorio di Genetica Medica, IRCCS Ospedale Pediatrico del Bambino Ges\u00f9, 00165 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1791-5085","authenticated-orcid":false,"given":"Rosellina","family":"Russo","sequence":"additional","affiliation":[{"name":"UOSD Neuroradiologia Diagnostica, Dipartimento di Diagnostica per Immagini e Radioterapia Oncologica,  Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7783-114X","authenticated-orcid":false,"given":"Massimiliano","family":"Mirabella","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"},{"name":"Centro di Ricerca per la Sclerosi Multipla \u201cAnna Paola Batocchi\u201d, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Sica","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze di Laboratorio ed Ematologiche, UOC Ematologia e Trapianto di Cellule Staminali Emopoietiche, Fondazione Policlinico Universitario  A. Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5534-7197","authenticated-orcid":false,"given":"Stefan","family":"Hohaus","sequence":"additional","affiliation":[{"name":"UOSD Malattie Linfoproliferative Extramidollari, Dipartimento di Scienze di Laboratorio ed Ematologiche\u00a0, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Steen, E.A., Hermiston, M.L., Nichols, K.E., and Meyer, L.K. (2021). Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis. Front. 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