Peripheral T-cell lymphoma in adult-onset familial hemophagocytic lymphohistiocytosis type 2 and heterozygous LRBA mutation

Here, we present an unusual case of a patient with late-onset familial hemophagocytic lymphohistiocytosis (FHL) type 2 and concurrent heterozygous LRBA mutation presenting with hemophagocytic lymphohistiocytosis (HLH), peripheral T-cell lymphoma, severe infectious complications with atypical pathogen spectrum and progressive hyperbilirubinemia.

FHL is a rare and life-threatening disorder characterized by uncontrolled immune activation leading to hyperinflammation and hemophagocytosis. In most cases, patients develop FHL, also called primary HLH, in the first 2 years after birth, although a subset of patients develop symptoms of FHL later (late-onset FHL). FHL-associated inflammation is often triggered by infection. In adults HLH usually develops secondary to viral infections, neoplasia, most commonly lymphoma or autoimmune disorders.^1,2 The most common FHL subtype FHL2 is caused by hereditary biallelic mutations of the perforin gene PRF1. Perforin is involved in the immune system’s cytotoxic function and plays a crucial role in the elimination of infected or abnormal cells by pore formation, facilitating the entry of cytotoxic molecules leading to cell death. Mutations in PRF1 disrupt the function of perforin, impairing the cytotoxic activity of T lymphocytes and natural killer (NK) cells.^3,4

Until now, best treatment option for patients with clinically manifested FHL remains allogenic hematopoietic stem cell transplantation (alloHSCT), with survival rates after alloHSCT of ~70%.⁵

Mono- and biallelic PRF1 mutations were associated with the development of lymphoma with or without concurrent clinical evidence of FHL.⁶ Homozygous lipopolysaccharide-responsive beige-like anchor protein (LRBA) mutations lead to a rare immune disorder known as LRBA deficiency. Some cases may present with an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. LRBA is involved in regulating immune cell function and mutations lead to immune dysregulation, autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenia (ITP), autoimmune enteropathy, and susceptibility to infections. AlloHSCT may be considered in severe cases.⁷, ⁸ A 31-year-old male patient was administered to our tertiary care center with suspected HLH. In the previous 4 weeks the patient had shown recurrent episodes of fever and malaise. Histopathologically confirmed linear IgA dermatosis was known for 3 years and treated with dapsone. The patient’s sister showed multiple demyelinating manifestations of the central nervous system (CNS) at adult-onset of unclear origin and was diagnosed with recurring episodes of ITP, AIHA, direct hyperbilirubinemia, and lymphoproliferation. In childhood, she developed prolonged infectious mononucleosis with large cervical histologically benign lymph nodes, that showed spontaneous regression. ALPS was suspected; in vitro apoptosis reaction test was positive; sequencing of the FAS gene showed no pathogenic mutations. She died at the age of 26 of fungal sepsis confirmed post mortem from gastric autopsy. A second sister was diagnosed with oligoclonal band negative multiple sclerosis at the age of 30 and was alive 16 years later under immunosuppression. Currently, a third sister of similar age showed no symptoms. Both non-consanguineous parents did not show any phenotype. HLH was diagnosed according to the HLH-2004 criteria, characteristics are summarized in Table 1.

Table 1.Patient characteristics according to the hemophagocytic lymphohistiocytosis-2004 diagnostic criteria.

The patient underwent broad virology, autoimmunology, and morphological screening. Epstein-Barr virus viral reactivation with low viral load of 795 units/mL was detected. Autoimmunological assessment showed weakly positive antinuclear antibodies (1:160). Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging revealed multiple lymph nodes with high glycolytic activity (Figure 1A-D). Furthermore, a diffuse intensive glucose utilization of the bone marrow was found. A CNS lesion on the right cerebellar side was found as focal hypometabolism and showed enhancement of gadolinium in magnetic resonance imaging (MRI). Microbiological and virological cerebrospinal fluid findings were unremarkable, oligoclonal bands were negative, meningeosis lymphomatosa was excluded. After laparoscopic retroperitoneal lymphadenectomy histology confirmed peripheral T-cell lymphoma, not further specified according to latest World Health Organization 2022 classification with an EBER^-/CD3⁺/CD5⁺/CD30^-/CD56^-/TCL1^-/ bF1⁺/partial PD1⁺ immune-phenotype (Figure 1E, F). Bone marrow aspiration and biopsy showed hemophagocytosis and 30% infiltration of the lymphoma with concurrent monoclonal VJ-recombination of the TRG locus. Flow cytometry showed 30% CD3⁺/CD4⁺ lymphocytes. Peripheral blood showed 65% lymphocytes with a concurrent immunophenotype. Chromosomal banding analysis showed a normal 46,XY karyotype in 27 metaphases.

Figure 1.Diagnostic findings: imaging, tissue histology, and molecular genetic results. (A-D) Positron emission tomography-computed tomography imaging demonstrating increased fluorodeoxyglucose uptake in lymph nodes along the right thoracic internal mammary chain, hepatic hilum, portal venous system, retroperitoneum, and mesentery, with concomitant diffuse bone marrow uptake. (E, F) Histopathology of T-cell lymphoma in (E) hematoxylin and eosin stain and (F) anti-CD3-immunhistochemistry. (G) Schematic representation of PRF1 mutations both detected in exon 3 by whole-exome seuquencing. (H) Confirmation of the compound heterozygous PRF1 genotype by allele specific polymerase chain reaction with gel electrophoresis, products amplified with Amplitaq-Gold (1: 253Glu/356Arg [negative], 2: 253Glu/356Trp [positive], 3: 253Lys/356Arg [positive], 4: 253Lys/356Trp [negative], C1-4: negative controls of 1-4). The figure was created in BioRender (https://BioRender.com/xabycto and /r1w4pz4).

Whole-exome sequencing (WES) (Twist Human Core Exome, Ilumina NextSeq) was performed from whole blood and genes associated with FLH (14 genes), ALPS or ALPSlike phenotype (14 genes) and neurofibromatosis (NF1, NF2) were assessed. WES analyzed gene panels included (i) HLH: CD27, HAVCR2, IFNGR1, LYST, PRF1, RAB27A, RAG1, RAG2, SLC29A3, SLC7A7, STX11, STXBP2, UNC13D, XIAP; (ii) ALPS: CASP10, CASP8, CTLA4, FADD, FAS, FASL, ITK, KRAS, LRBA, MAGT1, NRAS, PIK3CD, PRKCD, RASGRP1 and (iii) NF: NF1, NF2; whereas the lymphoma somatic next-generation sequencing panel included (i) full sequences of ASXL1, BCOR, CALR, CEBPA, ETV6, EZH2, IKZF1, NF1, PHF6, PRPF8, RB1, RUNX1, SH2B3, STAG2, TET2, TP53, and ZRSR2; (ii) mutational hot spots of ABL1, BRAF, CBL, SF3R, DNMT3A, FLT3, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, MYD88, NPM1, NRAS, PTPN11, SETBP1, SF3B1, SRSF2, U2AF1, and WT1.

Two heterozygous pathogenic and likely pathogenic missense variants in PRF1 were detected (NM_001083116.3:c.757G>A and NM_001083116.3:c.1066C>T) leading to the amino acid substitutions p.Glu253Lys and p.Arg356Trp detected in variant allele fractions (VAF) of 47 % and 52% likely reflecting a germline heterozygous state (Figure 1G). Allele-specific polymerase chain reaction confirmed compound heterozygosity of the PRF1 mutations (Figure 1H). PRF1 p.Ala91Val polymorphism was excluded. Additionally, a likely pathogenic heterozygous LRBA missense variant NM_006726.4:c.3913C>G leading to the amino acid change p.Arg1305Gly was present in VAF of 41 % without signs of copy number loss in exome-based copy number variant analysis.

Treatment according to the HLH-94 protocol was initiated (Figure 2).⁹ Initially, laboratory findings improved during the first 4 weeks of treatment. However, the patient developed severe infectious complications consisting of recurring neutropenic fever with blood stream infections of S. haemolyticus and E. faecium, prolonged diarrhea, progressive dysphagia with diffuse distal esophagitis detected by esophagogastroduodenoscopy (EGD), PAS-positive signs of fungal infection in EGD biopsies and diffuse upper gastrointestinal bleeding. Endoscopic biopsies from the latest EGD showed caspofungin-resistant Saccharomyces cerevisiae besides Candida species (C. crusei/albicans) and Bacterioides caccae. Additionally, Herpes simplex virus 1 DNA was found in these biopsies but not prior to that in oropharyngeal washes and swabs. Later, the patient developed clinical jaundice, progressive ascites, and direct hyperbilirubinemia up to total bilirubin serum levels of 21.8 mg/dL. Cholestasis was excluded by sonography and MR-cholangiopancreatography. Ascites punctures excluded spontaneous bacterial peritonitis. Consecutive hepatitis testing remained negative. During the whole treatment, the patient was highly transfusion dependent. After diagnosis of peripheral T-cell lymphoma was confirmed, intensity reduced treatment with cyclophosphamide, etoposide and prednisolone was initiated. The patient rapidly developed a fulminant septic shock with multi organ failure, and died 3 days after admission to the intensive care unit. The study was performed in accordance with the ethical standards and regulations of the country in which it was conducted and in adherence to the Declaration of Helsinki. Consent for publication was not obtained because the patient deceased. Formal ethics committee approval was not obtained, as this is a descriptive single-patient case report.

Figure 2.Clinical course of the patient. (A) Timeline from initial diagnosis till death including treatment regimens. (B) Selected laboratory parameters (serum ferritin, soluable interleukin 2 receptor [sIL2R], total bilirubin). HLH: hemophagocyitc lymphohistiocytosis; FHL: familial hemophagocyic lymphohistiocytosis subtype 2; Cyclo: cyclosporin; R-CEP: Rituximab, Cyclosporin, Etoposide. The figure was created in BioRender (https://BioRender.com/xabycto and /r1w4pz4).

FHL2 is associated with a wide spectrum of PRF1 mutations. Our patient carried compound heterozygous PRF1 mutations (Glu253Lys/Arg356Trp), a genotype not previously described, though both variants have been individually linked to FHL2. The Arg356Trp mutation has been associated with late-onset FHL2 and cases of peripheral T-cell lymphoma, with some patients initially presenting with neurological symptoms.^6,10 In contrast, the Glu253Lys variant has been predominantly described in early-onset cases of FHL2, often accompanied by CNS involvement and rapid progression.^11,12 The identification of compound heterozygous PRF1 mutations in this 31-year-old patient aligns with increasing evidence regarding the genetic landscape of adult-onset HLH. Bloch et al.¹³ recently demonstrated that variants of uncertain significance and pathogenic variants in FHL-related genes, such as PRF1, are significantly enriched in adults presenting with severe HLH, suggesting that these genetic predispositions may remain clinically silent until triggered by a secondary insult like malignancy or infection.

In addition, our patient harbored a previously unreported heterozygous LRBA^Arg1305Gly variant. However, a pathogenic variant at the same residue Arg1305His has been linked to LRBA deficiency, supporting a functional relevance in this highly conserved position.¹⁴

The complexity of our patient’s genetic profile, involving both PRF1 and LRBA, supports the ‘synergistic defect’ model proposed by Zhang et al.,¹⁵ which illustrates how compound heterozygosity or multiple defects in cytotoxic pathways can converge to cross the threshold for clinical FHL.

The previously unreported genotype found in our patient may point toward a synergistic effect contributing to immune dysregulation and progression to lymphoma. Our findings underscore the clinical relevance of comprehensive genetic testing in atypical HLH presentations and highlight the need for further investigations into potential pathogenetic interactions between PRF1 and LRBA variants in immune-mediated disorders and lymphomagenesis. As commercial panels for autoinflammatory and immunodeficiency syndromes become increasingly accessible, we anticipate that findings in multiple converging pathways of HLH and lymphoproliferation will become more frequently recognized. Our case adds to this growing body of literature and reinforces the argument that widespread HLH genetic testing is warranted in young adults with hyperinflammatory presentations.

Footnotes

• Received January 10, 2026
• Accepted March 5, 2026

Correspondence

M. TEMBRINK - marco.tembrink@uk-essen.de

Disclosures

MT received financial support from Abbvie Inc. for educational activities. HCR received consulting and lecture fees from Abbvie, Roche, KinSea, Vitis, Cerus, Lilly, Novartis, Takeda, AstraZeneca, Vertex, and Merck; received research funding from AstraZeneca and Gilead Pharmaceuticals; and is a co-founder of CDL Therapeutics GmbH. MH and TH have no conflicts of interest to disclose.

Contributions

Funding

MT is funded by a UMEA Junior Clinician Scientist research grant of the Medical Faculty, University Duisburg-Essen.

Acknowledgments

We are grateful to Prof. Dr. Wolfram Klapper and Dr. Karoline Koch (Institute for Pathology, University Clinic Schleswig-Holstein, Campus Kiel) for providing histopathological figures, and to Prof. Dr. med. Ken Herrmann and Dr. Francesco Barbato (Clinic for Nuclear Medicine, University Clinic Essen) for providing high-resolution PET images.