ObjectiveTo explore the clinical characteristics of children with primary hemophagocytic lymphohistiocytosis (pHLH) and gene mutations of their families.
MethodsFrom November 2016 to January 2017, three children with pHLH from the Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University were selected as probands, and the 3 probands and their 16 family members were taken as the study objects. Complete blood count test, coagulation, serum ferritin, natural killer (NK) cell, soluble CD25, morphology of bone marrow cell of 3 probands were tested. And HLH related gene mutation screening were preformed among patients and their family members. The patients were treated with HLH-94 and HLH-2004 scheme. The medical history and related examination results, diagnosis, treatment and outcome of 3 probands were analyzed retrospectively. This study was in line with the requirements ofWorld Medical Association of Helsinkirevised in 2013.
Results① Case 1, female, 4 months old, was hospitalized in our hospital on November 4, 2016 due to " fever for 7 d, thrombocytopenia for 6 d" . Her clinical manifestations were fever, hepatosplenomegaly. Results of complete blood count test showed that all blood count were significantly reduced. The hemophagocytosis was observed by bone marrow puncture. NK cell activity decreased, serum ferritin increased and soluble CD25 levels increased. Brain MRI showed that the right posterior part of the pons, the left cerebellopontine combined arm, the bilateral basal ganglia, the left thalamus, the bilateral frontal parietal occipital lobes had multiple abnormal signals, the brain parenchyma was not fully developed, and the bilateral frontal temporal subarachnoid space was widened. The results of cerebrospinal fluid examination showed that the total protein and albumin levels were increased. The results of HLH related genes screening and pedigree analysis showed that this proband′s c. 272delA(p.Asp91ValfsTer11) (heterozygous) in exon 5 and c. 121delA(p.Thr41GlnfsTer44) (heterozygous) in exon 3 were found in RAB27A gene, which were double heterozygous and originated from her parents. She was diagnosed as Griscelli syndrome(GS)-2 related HLH with central nervous system disease. After more than one month′s regular treatment with HLH-2004 scheme, HLH of the probomd was not controlled. Her guardian gave up treatment and left hospital. ② Case 2, male, 8 years old, was hospitalized in our hospital on November 14, 2016 due to " fever for 27 d " . His clinical manifestations were fever, hepatosplenomegaly and neck lymphnodes. Results of complete blood count test showed that all blood count were significantly reduced. Fibrinogen level and NK cell activity decreased, serum ferritin and soluble CD25 levels increased. EB virus (EBV)-DNA was 1.42 ×106copies/mL. The pathological results of cervical lymph node biopsy and immunohistochemical showed classic Hodgkin lymphoma(HL) (mixed cell type). The results of HLH related genes screening and pedigree analysis showed that c. 65delC(p.Pro22ArgfsX29) (heterozygous) and c. 503G>A(p.Ser168Asn) (heterozygous) were found in exon 2 of PRF1 gene, which were double heterozygous and originated from his parents. He was diagnosed as family pHLH (FHL), typical HL (mixed cell type), EBV infection. The proband was treated with HLH-94 scheme, and the disease was initially controlled. After that, the patient was treated with regimen of HL. When the disease course was more than 2 months, the proband died after aggravation. ③ Case 3, male, 13 years old, was hospitalized in the our hospital on January 5, 2017 due to " initial diagnosis of HLH in local hospital, intermittent fever for more than 4 months" . His clinical manifestations were fever, hepatosplenomegaly. The results of bone marrow examination showed that hemophagocytosis was occasionally seen. NK cell activity decreased, serum ferritin increased, the degranulation function of CD107a decreased. The pathological results of cervical lymph node biopsy showed reactive hyperplasia of lymph nodes. The results of HLH related genes screening and pedigree analysis showed that c. 503G>A(p.Ser168Asn) (heterozygous) was found in exon 2 of PRF1 gene, which was a heterozygous mutation and originated from his father. He was diagnosed as FHL. The treatments were not effect in local hospital, so the proband transfer to our hospital and receive treatment of HLH-2004 scheme for 27 d. Then he discharged after his condition was under control. The hematopoietic stem cell transplant(HSCT) were suggested to use. After that, the proband did not return to the hospital for reexamination, and died of FHL recurrence after 7 months later.
ConclusionsIn order to improve the survival rate of children with pHLH, early lymph node biopsies should be carried out in HLH patients with large lymph nodes and EBV infection at the initial diagnosis. And early detection of HLH related gene mutations should be proceed in patients with abnormal NK cell activity and CD107a degranulation function. On this basis, the pedigree of analysis should be carried out to provide genetic counseling.
