Case Report: Late-onset primary hemophagocytic lymphohistiocytosis leading to the diagnosis of Griscelli Syndrome Type 2 in a young woman with phenotypically inapparent partial albinism

Johanna Rausch^1,2*Stephanie Herold^1*Simone Liebhäuser¹Yagmur Bülbül¹Edite Antunes Ferreira¹Wenz Till³Kevin Jan Legscha^1,2Matthias Bros⁴Florian Butsch⁴Oliver Kriege¹Klaus Warnatz^5,6Miriam Groß^6,7Kai Lehmberg⁸Helena Clara Lichtenfeld⁸Paul La Rosée⁹Markus Philipp Radsak^1,10Matthias Theobald^1,11,2Hakim Echchannaoui^1,2Markus Munder^1,11,12

• ¹Department of Hematology and Oncology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
• ²German Cancer Consortium (DKTK), Partner site Frankfurt/Mainz, Mainz, Rhineland-Palatinate, Germany
• ³Department of Hematology and Medical Oncology, Johanniter Hospital Bonn, Bonn, Germany
• ⁴Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
• ⁵Department of Rheumatology and Clinical Immunology, University Medical Center, University of Freiburg, Freiburg, Germany
• ⁶Center for Chronic Immunodeficiency, University Medical Center, University of Freiburg, Freiburg, Germany
• ⁷Institute of Immunodeficiency, University Medical Center, University of Freiburg, Freiburg, Germany
• ⁸Division for Pediatric Stem Cell Transplantation and Immunology, Clinic and Polyclinic for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany
• ⁹Department of Internal Medicine II, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
• ¹⁰Department of Hematology and Oncology, Donau-Isar Hospitals, Deggendorf, Germany
• ¹¹Research Center for Immunotherapy, Johannes Gutenberg University Mainz, Mainz, Rhineland-Palatinate, Germany
• ¹²Department of Hematology and Medical Oncology, Diakonissen-Stiftungs-Krankenhaus Speyer, Speyer, Germany

Griscelli syndrome type 2 (GS-2) is a rare congenital immune dysfunction characterized by partial albinism and recurrent episodes of hemophagocytic lymphohistiocytosis (HLH). It is caused by a variant in the gene encoding Rab27a leading to a degranulation defect in melanocytes, natural killer (NK)-and T cells. Prognosis of patients with GS-2 is limited by repetitive episodes of life-threatening HLH with onset in early childhood. The only curative treatment is an allogeneic hematopoietic stem cell transplantation (cCT).Here, we report on an 18 year old female patient with a homozygous missense p.Arg50Glnfs*35 variant in exon 2 of RAB27A who presented with an exceptionally late onset of severe HLH. Her phenotypically inapparent albinism complicated to correctly diagnose GS-2. Immune function assays confirmed a T-and NK cell degranulation deficiency characteristic for patients with primary HLH, while microscopic hair analysis revealed melanin clumps secondary to melanocyte functional impairment.To understand why disease onset occurred unusually late in this patient, we investigated the patient's T cell and polymorphonuclear neutrophil (PMN) function in more detail. We could show that intracellular granzyme B storage in cytotoxic T cells was increased compared to healthy donors and that the patient's T cells maintained some degranulation activity. Both, antigen-specific cytotoxic response and proliferation capacity of the patient's T cells were preserved. We demonstrate for the first time that also PMN degranulation, assessed as stimulation-induced CD66b and CD11b cell membrane expression, is dysfunctional in patients with Rab27a deficiency-associated primary HLH.The patient was treated with steroids and cyclosporine A for immunosuppression to control the HLH.After two severe episodes within only a few months, she eventually received an allogeneic HSCT and has not experienced further HLH episodes for now more than 3 years after the HSCT procedure. This case should raise awareness for the possibility of initial manifestation of primary, geneticallydetermined HLH even in adult patients.