A case report of adult type 2 familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is a fatal autosomal recessive disorder that often occurs in infants and young children, and rarely reported in adults. In this paper, we retrospectively reported an elderly woman with recurrent fever, this patient was diagnosed with familial hemophagocytic syndrome by perfecting relevant examinations after admission, improvement was observed after standard chemotherapy. In order to further determine the possible underlying genetic causes, we performed gene mutation analysis and found that there were compound heterozygous missense mutations c.133G > A (p.Gly45Arg) and c.147C > A (p.Asp49Glu) on the exon2 of PRF1 gene in this patient. According to the clinical manifestations and test results, the patient was further confirmed as late‐onset FHL‐2 type. Without a suitable donor, the patient did not perform hematopoietic stem cell transplantation. Therefore, the relevant genetic examination should be performed as early as possible in young patients with a family history of hemophagocytic lymphohistiocytosis, and it can provide a basis for etiological diagnosis and radical treatment by hematopoietic stem cell transplantation. It is essential to further study the molecular mechanism and clinical application value for late‐onset elderly FHL patients without appropriate donors.


| INTRODUCTION
Hemophagocytic syndrome (HPS), also known as hemophagocytic lymphohistiocytosis (HLH), shows the typical feature of the massive secretion of inflammatory cytokines form uncontrolled activation of macrophages and lymphocytes, ultimately forming a severe hyperinflammatory state. 1,2Its incidence is rare, occult, rapidly progressive, and extremely fatal.The clinical characteristics of HLH contain high fever, pancytopenia, hepatosplenomegaly, and hemophagocytosis in the bone marrow and lymphoid tissues, often leading to death due to multiple organ failures.HLH includes primary hemophagocytic lymphohistiocytosis (PHLH) and secondary hemophagocytic lymphohistiocytosis.PHLH mainly contains three types: familial HLH, immunodeficiency syndrome HLH, and Epstein-Barr virus (EBV)-driven HLH, 3 most PHLH caused by gene mutation such as PRF1, UNX13D, STX11, and STXBP2. 4breviations: CMV, Cytomegalovirus; EBV, Epstein-Barr virus; FHL, Familial Familial hemophagocytic lymphohistiocytosis (FHL), is referred to as familial HPS. 5 FHL is a rare autosomal recessive immunodeficiency disorder that usually presents in children and extremely rare occurs in adults. 6Based on different genetic mutations, FHL is divided into five types: FHL-1, FHL-2, FHL-3, FHL-4, and FHL-5.No relevant pathogenic gene has been identified for FHL-1, and the remaining four types of corresponding gene mutations are PRF1 (FHL-2), UNC13D (FHL-3), STX11 (FHL-4), and STXBP2 (FHL-5), 7,8 of which PRF1 and UNC13D are the most common gene mutations in FHL. 9 Most primary FHL occurred at childhood caused by gene defect, secondary HLH happened both in children and adult owing to virus infection or hematological diseases.A retrospective study analyzed 15 adult-onset primary FHL with gene mutation, but most patients were youth except one.According to previous reports, most FHL patients over 50 years are male. 10,11Here, we present a case of a woman (Chinese) aged 58 with late-onset FHL due to PRF1 gene site mutation.on Exon2 of the PRF1 gene, and that was confirmed by the first generation sequencing (Figure 3).After discussion by the consulting expert, considering that the patient had repeated fever, long history, long-term febrile state, and multi-system involvement, the diagnosis of primary HLH with insidious onset was planned.Because there was no suitable donor, hematopoietic stem cell transplantation could not be completed.After discharge, the patient continued to orally take methylprednisolone tablets 4 mg bid.Then the patient was treated with long-term oral Chinese medicine in the outpatient department.

| CASE PRESENTATION
At present, the patient is in stable condition and still complained of intermittent fever.

| DISCUSSION
According to previous studies, primary HLH in adults is rare and usually occurs in youth.It has been reported that a 27 year old male FHL2 patient who was admitted due to persistent fever and pancytopenia.Although this patient did not receive hematopoietic stem cell transplantation, he achieved complete remission after receiving the HLH-2004 treatment regimen. 12In our case, the elderly female ized by the release of a large cytokine storm. 12After the treatment based on HLH-1994 and HLH-2004 regimens for our patient, her condition maintained stable with no worsening trend.
Based on physical examination and long-term treatment, we ruled out the caused by infection, malignant tumors, and immune diseases.Taken together, these results support the view that this patient might not be a secondary HPS.
According to the International Histiocytic Association, patients with FHL account for only 5% of patients after the age of 5 years, and F I G U R E 1 FDG PET/CT abdominal transverse section (A) CT (B) PET/CT fusion image).On both sides of the neck, the axilla sees multiple small lymph node shadows, part of the radioactive uptake is slightly higher, SUV max was 1.35, whole body bone visible diffuse, symmetrical radioactive uptake is slightly higher, SUV max was 4.26, CT image of bone showed no obvious abnormality.The spleen volume increased, and there was no obvious abnormal density shadow.The radioactive uptake was slightly higher, and the SUV max was 3.28.Bilateral adrenal gland and kidney size showed no obvious abnormalities, no obvious abnormal density.Small omental bursa, peripancreatic, retroperitoneal lymph nodes seen multiple shadows, larger 1.6 cm*1.1 cm, some radioactive uptake.the maximum age is 62 years. 13From the previous reports, FHL-2 accounts for about 20%-50%, and FHL-3 accounts for about 25% of cases. 13The FHL2 (PRF1) type is rare in adults, the majority of patients are mainly young people in their 20s depending on existing data, 14 but elderly patients are poorly understood.Consistent with this, studies in China have shown that FHL2 is mostly under 18 years old in FHL patients, while FHL3 is more common in adults. 15e treatment of HLH remains a major challenge, and few reports focus on the treatment of refractory HLH.At present, the treatment of HLH mainly includes corticosteroids, chemotherapy, immunosuppressive therapy, hematopoietic stem cell transplantation (HSCT), and supportive care, and chemotherapy mainly includes HLH-94 and HLH-04 regimens. 16Although chemotherapy can control the excessive inflammatory state of HLH patients, hematopoietic stem cell transplantation is the best way to treat FHL. 17 Hematopoietic stem cell transplantation can restore the normal immune response of HLH patients, with a 5-year survival rate of 71% after transplantation. 18Clinical research demonstrated that transplantation is generally performed on the basis of HLH94/04 regimen to achieve and maintain the control of excessive inflammatory status. 19Among them, fully matched siblings without HLH-related genes are the best donors for hematopoietic stem cell transplantation, and haploid-unrelated donors without HLH-related genes are also suitable. 20Currently, there are relatively few studies on the survival rate of patients who have not undergone hematopoietic stem cell transplantation.Therefore, it is worthwhile to further explore adjuvant therapy for FHL adult patients with PRF1 gene who have not yet found a suitable donor for hematopoietic stem cell transplantation.

A
58-year-old Chinese female patient was admitted to the Department of Infectious Diseases in Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine on September 1, 2020 due to "recurrent fever for 1 week".On admission, the patient had fatigue, occasional dizziness, fair appetite, poor sleep, and without other discomforts.No immediate family members have a similar history.All vital signs are normal.Auxiliary examination: (1) laboratory examinations (Table 1).(2) Peripheral blood smear: decreased total white blood cell count, band nucleated cell increased, occasional lymphocytes; mature red blood cell morphology was fair; platelets were scattered.(3) Bone marrow cytology: Consider HPS.(4) Detection of Ig gene rearrangement: No monoclonal rearrangement of the gene was detected.(5) Abdominal CT showed intrahepatic calcifications, splenomegaly, and multiple small lymph nodes in bilateral axillae and retroperitoneum.(6) PET-CT showed (Figure 1): The lymph node metabolism was slightly higher, the liver and spleen volume increased, and the spleen FDG metabolism increased.(7) Immunophenotyping of hematological tumors: lymphocytes accounted for about 10.5% of nuclear cells, the proportion decreased, and the distribution of each lymphoid subset was approximately normal (Figure 2).Primitive zone cells occupy about 1% of nuclear cells and are scattered.Monocytes occupy about 3.5% of nuclear cells and are phenotypically mature.Granulocytes accounted for about 73% of the nuclear cells and were high in proportion, and no significant developmental abnormalities were observed.(8) No obvious virus infection (including EBV and cytomegalovirus) was detected.According to the above examination, the diagnosis of the HPS was confirmed, and the patient was treated with an HLH-2004 regimen.Specifically, etoposide injection 0.1 g biw intravenous drip of 2 weeks and methylprednisolone 80 mg qd intravenous drip of 5 days, combined with immunoglobulin 20 g qd intravenous drip of 5 days blocking antibody, after treatment for 14 days.After treatment, the patient was recovered from her fever and discharged.On April 23, 2021, the patient still had fever and was hospitalized in the Department of Infectious Diseases, in Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, with body temperature of 37.5 C, accompanied by upper abdominal distention.To this end, the patient was tested for HLH secondgeneration sequencing, and the results showed that the patient had mutations at some sites of the PRF1 gene, including the compound heterozygous missense mutation c.133G > A (p.Gly45Arg) and the compound heterozygous missense mutation c.147C > A (p.Asp49Glu) FDG PET/CT Vertebral Sagittal Tomography/PET MIP Imaging (C/D) Radioactive uptake of multiple lymph nodes in hilum and mediastinum increased, about 1.8*0.8cm, SUV max 3.84.Calcification was seen in the left hilum.The heart shadow is not big, the pericardium sees an arc low-density shadow.Cardiac density was decreased.more than 90% of patients develop FHL before the age of 2 years.In recent years, Wang et al. confirmed many cases of adult FHL through genetic testing.The minimum age of adult patients is 18 years old and Distribution of FCM lost cells.(A) Negative control; (B) Whole blood cell; (C) White blood cell; (D) T lymphocyte cell; (E) Blast cells region (F) Monocytes; (G) Granulocytes; (H) Nucleated erythrocytes region.F I G U R E 3 First-generation sequencing results for the patient c.133G > A (p.Gly45Arg) and c.147C > A (p.Asp49Glu).

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CONCLUSIONAppropriate donor and transplantation schedules are necessary to improve the therapeutic effect in gene mutated-HLH patients.In our case report, this patient could not perform hematopoietic stem cell transplantation without an appropriate donor from the Chinese bone marrow donor program or the patient's sibling donor.Chemotherapy with HLH-94 and HLH-2004 regimens, the patient's temperature returned to normal, splenomegaly, and laboratory parameters gradually improved, but intermittent fever was still present after discharge, currently in good condition.Further research on the molecular mechanism and clinical application value for patients with FHL without suitable donors is needed in the future.

1
Laboratory test results on admission.
c.133G > A (p. Gly45Arg) and c.147C > A (p. Asp49Glu) of exon 2 of PRF1 gene in this patient.FHL is caused by gene mutations that impair the cytotoxic function of natural killer cells and cytotoxic T cells.The defective allele in the PRF1 gene encodes porin, which, in combination with environmental factors, leads to