家族性噬血细胞综合征1例报告

家族性噬血细胞综合征(familial hemophagocytic lymphohistiocytosis,FHL)临床上较少见,现报告1例患儿的临床资料,并结合文献复习,探讨其诊断要点及分类,以提高对该病的认识.     

Familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is probably a genetically transmitted disease affecting infants and very young children. Cardinal symptoms are fever, hepatosplenomegaly, and pancytopenia. Frequently meningeal involvement is seen, manifested by neurologic symptoms and a lymphohistiocytic pleocytosis with increased protein levels in the cerebrospinal fluid. Characteristic laboratory findings in FHL are hypertriglyceridemia and hypofibrinogenemia, which are reversible with treatment. The disease has been rapidly fatal in most patients, but recently longterm remissions have been achieved with cytotoxic agents. Pathohistologic examination shows a widespread infiltrate of lymphocytes and mature macrophages with prominent hemophagocytosis affecting especially liver, spleen, lymph nodes and the central nervous system. Atrophy of the lymphatic tissue is a common finding. From the histologic picture FHL has to be grouped among the histiocytoses of reactive origin since the cells involved show no signs of malignancy. The etiology and pathogenesis of FHL are not known at present. Immunologic studies present evidence for a disturbed function of T lymphocytes, but a secondary immune defect seems to be more likely than primary immune deficiency. Among the broad clinical spectrum of histiocytic disorders especially histiocytic reactions due to infection, histiocytosis X and malignant histiocytosis have to be considered in the differential diagnosis of FHL.     

家族性噬血细胞性淋巴组织细胞增生症伴胸腺发育不良1例

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Familial and acquired hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of severe hyperinflammation caused by the uncontrolled proliferation of activated lymphocytes and histiocytes secreting high amounts of inflammatory cytokines. Cardinal signs and symptoms are prolonged fever, hepatosplenomegaly and pancytopenia. Characteristic biochemical markers include elevated triglycerides, ferritin and low fibrinogen. HLH occurs on the basis of various inherited or acquired immune deficiencies. Impaired function of natural killer (NK) cells and cytotoxic T-cells (CTL) is shared by all forms of HLH. Genetic HLH occurs in familial forms (FHLH) in which HLH is the primary and only manifestation, and in association with the immune deficiencies Chédiak-Higashi syndrome 1 (CHS 1), Griscelli syndrome 2 (GS 2) and x-linked lymphoproliferative syndrome (XLP), in which HLH is a sporadic event. Most patients with acquired HLH have no known underlying immune deficiency. Both acquired and genetic forms are triggered by infections, mostly viral, or other stimuli. HLH also occurs as a complication of rheumatic diseases (macrophage activation syndrome) and of malignancies. Several genetic defects causing FHLH have recently been discovered and have elucidated the pathophysiology of HLH. The immediate aim of therapy in genetic and acquired HLH is suppression of the severe hyperinflammation, which can be achieved with immunosuppressive/immunomodulatary agents and cytostatic drugs. Patients with genetic forms have to undergo stem cell transplantation to exchange the defective immune system with normally functioning immune effector cells. In conclusion, awareness of the clinical symptoms and of the diagnostic criteria of HLH is crucial in order not to overlook HLH and to start life-saving therapy in time.     

Familial hemophagocytic lymphohistiocytosis with the MUNC13-4 mutation: a case report

A 44-day-old male infant with familial hemophagocytic lymphohistiocytosis (FHL) associated with the MUNC13-4 mutation is reported. He presented with fever and poor feeding, lymphocytosis with thrombocytopenia and CSF pleocytosis without virological explanation. On the basis of progressive hyperferritinemia (1323 ng/ml), anemia (hemoglobin: 5.2 g/dl), hypertriglyceridemia (547 mg/dl) and increased LDH (1063 IU/l) with hemophagocytosis in the bone marrow, hemophagocytic lymphohistiocytosis was diagnosed. He showed a good response to corticosteroid therapy and the disease was stable for more than 5 months. Thereafter, he suffered from central nervous system complications, and successfully underwent unrelated cord blood stem cell transplantation. A remission was observed for more than 2 years, with mild mental retardation. Genetic analysis revealed that he had a compound heterozygous mutation of MUNC13-4; namely a novel 2163G>A mutation resulting in W721X, and 754-1G>C resulting in a premature stop codon in this gene. Western blot analysis showed the complete loss of the MUNC13-4 protein, whereas other molecules associated with the SNARE systems were detected at normal levels. Conclusion. FHL may have a broad clinical spectrum, and further analysis on its phenotype-genotype association is required to establish an appropriate treatment strategy, including immunochemotherapy and stem cell transplantation in the future.     

Familial hemophagocytic lymphohistiocytosis and viral infections

A retrospective study was performed in 32 children with hemophagocytic lymphohistiocytosis, 16 of whom had affected siblings. Altogether 22 of these children, of whom the majority (13/22) were familial cases, had clinical or laboratory signs of infection. Laboratory analysis demonstrated Epstein-Barr virus in five children, cytomegalovirus in three and human parvovirus in two. Two siblings with onset of familial hemophagocytic lymphohistiocytosis within one month of each other, both of whom demonstrated serological indications of a recent human parvoviral infection at onset, are described. It is concluded that a viral infection cannot serve as the sole criterion for distinguishing a virus-associated hemophagocytic syndrome as an entity separate from familial hemophagocytic lymphohistiocytosis. Instead, it is suggested that viral infections may elicit a bout of the familial hemophagocytic lymphohistiocytosis disorder in genetically predisposed individuals.     

Familial hemophagocytic lymphohistiocytosis in two brothers with X-linked agammaglobulinemia

Hemophagocytic lymphohistiocytosis (HLH) is often familial and is associated with high mortality. Primary (familial) HLH is known to occur in children with mutations in perforin, Munc13-4, or syntaxin 11. We describe a case series of two brothers who developed HLH in the setting of X-linked agammaglobulinemia (XLA, Bruton's disease) and adenovirus infection. Further studies revealed absence of Bruton's tyrosine kinase (BTK) protein expression and a novel BTK mutation.     

Familial hemophagocytic lymphohistiocytosis: report of four cases in two families and review of the literature

Four cases of familial hemophagocytic lymphohistiocytosis (FHL) from two families with first cousins affected in family and siblings in another are presented. The pathological findings, including neuropathology, transmission (TEM), and scanning electron microscopy (SEM), are discussed. This is the first study of this condition to include TEM and SEM. One hundred and fifty-nine cases from the literature, including the author's four cases, are reviewed. The familial occurrence in 116 instances in sibships and consanguinity in 13 of the 73 families support autosomal-recessive inheritance. In five families there were affected first cousins--an observation not readily explained by autosomal-recessive transmission. We suggest that the genetic aspects of FHL be more fully explored and that in future cases parents and other relatives be included in the hematologic, immunologic, and genetic evaluation.     

家族性噬血细胞性淋巴组织细胞增生症伴胸腺发育不良1例

<正>患儿,男性,1岁,因发热、咳嗽1月余,当地基层医院诊断为肺炎,经抗感染治疗无明显效果,后又出现右下肢无力,转入上级医院,查脑脊液、头颅MRI、脑电图均无异常发现,血常规示嗜酸性粒细胞0.28,骨髓细胞学检查示嗜酸性粒细胞增多症而转来我院。既往无特殊病史,体查:T37.5℃,R30     

Familial hemophagocytic lymphohistiocytosis. Clinical review based on the findings in seven children

Clinical, laboratory, and histological findings in FHL of diagnostic importance were intermittent fever, hepatosplenomegaly, peripheral blood cytopenia, hypertriglyceridemia, hypofibrinogenemia, and a lymphohistiocytic accumulation with hemophagocytosis in the mononuclear phagocytic system. Fine-needle aspiration biopsy from the spleen appeared to be a useful method for revealing hemophagocytosis. The treatment of induction and relapses, as well as the maintenance therapy, included administration of teniposide, etoposide, and corticosteroids. The regimen had to be individualized for each child since the clinical course was highly variable. Half of the children given successful induction therapy (3/6) are still alive with over a 3-year survival after diagnosis.     

Sensorineural hearing loss in a case of familial hemophagocytic lymphohistiocytosis

Severe sensorineural hearing loss (bilateral >80 dB) was diagnosed in a case of familial hemophagocytic lymphohistiocytosis (FHL). The female patient developed HLH at 3 months of age and underwent allogeneic cord blood transplantation at 11 months of age following 7 months of immuno-chemotherapy. The type 2 FHL patient had a homozygous perforin gene mutation of 1090-1091delCT, and was noted to have hearing loss at 3.5 years of age. Retrospective evaluation did not clarify the exact causes of hearing loss. Reports on Kawasaki disease, suggesting a correlation between severe inflammatory status in infancy and the development of sensorineural hearing loss, may shed some light on this rare complication in this case of FHL. Considering the markedly improved prognosis of FHL due to recent advances made in the molecular diagnosis and in the management including allogeneic hematopoietic stem cell transplantation, auditor by screening might be warranted for surviving FHL patients.     

Imaging characteristics of hemophagocytic lymphohistiocytosis

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a nonmalignant disorder of immune regulation, with overproduction of cytokines and diminished immune surveillance. Symptoms are nonspecific and may affect multiple organs, including the central nervous system. Neuroimaging findings have been described in case reports and small series; body imaging findings have not been described extensively. OBJECTIVE. To summarize findings of the most frequently performed imaging studies of the brain, chest and abdomen in patients with HLH. MATERIALS AND METHODS: Retrospective review of chest radiographs and CT, abdominal ultrasound and CT, brain CT and MRI, skeletal surveys, and autopsy data. RESULTS: Twenty-five patients were diagnosed and treated for HLH at our institution over an 11-year period; 15 patients (60%) died. Common chest radiograph findings included alveolar-interstitial opacities with pleural effusions, often with rapid evolution and resolution. Hepatosplenomegaly, gallbladder wall thickening, hyperechoic kidneys and ascites were common abdominal findings, which resolved after therapy in some cases. Brain-imaging studies revealed nonspecific periventricular white-matter abnormalities, brain-volume loss and enlargement of extra-axial fluid spaces. Three infant cases, one with intracranial hemorrhage, one with multiple pathologic rib fractures and one with diaphyseal periosteal reaction involving multiple long bones on skeletal survey, raised suspicion of child abuse at presentation. Abuse was not substantiated in any case. CONCLUSIONS: Clinicians and radiologists should be aware of the radiographic manifestations of HLH, which are nonspecific and overlap with infectious, inflammatory and neoplastic disorders. Findings in the chest (similar to acute respiratory distress syndrome) and abdomen may progress rapidly and then regress with institution of appropriate anti-HLH therapy. CNS findings may be progressive. In some infants, initial imaging findings may mimic nonaccidental trauma.     

儿童内脏利什曼病相关性噬血细胞性淋巴组织细胞增生症四例临床分析

目的 总结分析4例内脏利什曼病(VL)相关性噬血细胞性淋巴组织细胞增生症(HLH)患儿的临床资料,提高继发性HLH诊治水平.方法 回顾性总结两家医院近期诊断的4例VL-HLH患儿的临床特征及诊治经过.结果 本组4例患儿男3例、女1例,均来自于明确VL疫区或具有明确疫区生活史.以长期发热、肝脾肿大、外周血全血细胞减少为显著临床表现,结合相关实验室检查均符合HLH诊断标准.2例患儿接受HLH化疗并有效,表现为体温恢复正常和脾脏回缩等,但持续贫血为突出临床特征.病程早期骨髓检查和(或)rk39免疫试纸条法检测均无阳性发现,是导致漏诊和误诊的重要原因.结论 VL是导致继发性HLH的1种少见基础疾病.对来自VL疫区或具有疫区生活史的患儿,HLH鉴别诊断时应充分考虑VL可能性,需反复骨髓检查和(或)免疫学检查,早期诊断,及时予VL特异性治疗.

Abstract：

Objective The clinical features of four cases of visceral leishmaniasis (VL)-associated hemophagocytic lymphohistiocytosis(VL-HLH)were retrospectively analyzed for the purpose of helping the diagnosis of secondary HLH. Method Clinical data of three childhood cases of VL-HLH documented in our hospital and one case diagnosed in the Capital Institute of Pediatrics was reviewed retrospectively,with particular emphasis on peculiar clinical manifestations and on clues to the diagnosis of this relatively rare disease entity.Result Three children were from endemic areas of VL, and the other one had lived in endemic area for one year,which was revealed by detailed history-taking.Clinically,VL-HLH is characterized by persistent fever, hepatosplenomegaly and pancytopenia, which is similar to those of HLH, and is one of the important reasons of delayed diagnosis or misdiagnosis. Based on the HLH-2004 protocol, all the four cases met the diagnostic criteria of HLH. In addition, bone marrow aspirate and immunologic detection of VL-specific antibody via rk39 dipstick test during the early disease course of VL-HLH yielded negative results.Two cases who received HLH-targeted therapy responded reasonably well, with rapid temperature normalization and spleen retraction. Nevertheless,Hb remained lower than normal,which we believed to be related to persistent red cell destruction by the invading parasite Leishmania donovani. Conclusion VL,a parasitic disease caused by Leishmania donovani, which is currently endemic just in 6 provinces in China, shares similar clinical picture of HLH and is an easily ignored underlying cause of secondary HLH.We suggest that VL should be in the list of differential diagnosis for any patients with HLH who lives in or has a definite travel history to endemic areas.Repeated bone marrow studies are highly warranted to make a definite diagnosis of VL, because bone marrow aspirate or rk39 dipstick test during early disease course might yield negative results.Although VL-HLH responds quite well to HLH-tailored chemotherapy,specific therapy against VL must be given to prevent disease recurrence, and HLH-targeted chemotherapy might be discontinued to prevent chemotherapy-related toxicities.     

Further evidence for genetic heterogeneity in familial hemophagocytic lymphohistiocytosis (FHLH)

Familial hemophagocytic lymphohistiocytosis (FHLH; MIM #267700) is an autosomal recessive disorder of immune regulation characterized by fever, hepatosplenomegaly, and cytopenia that is fatal without bone marrow transplantation. Recent studies have suggested the existence of FHLH loci at 9q21.3-22 and t0q21-22 in Asian and European/African/Australian families, respectively. We studied two unrelated Canadian families in which first cousins were affected with FHLH. In an effort to localize the causative gene, we completed a genome-wide screen for homozygosity by descent by using an automated system to genotype 400 highly polymorphic dinucleotide repeat markers covering the genome with an average resolution of 10 centiMorgans (cM). We identified a total of three candidate loci that met the combined criteria for homozygosity by descent in one family and shared maternal alleles in the other family. One of these, D9S1690, had a cytogenetic localization (9q22.33) proximal to a previously reported inversion of chromosome 9 in an FHLH patient. However, additional closely linked flanking markers within 1-2 cM of all three candidates did not conform to the criteria for linkage in either family. Similarly, we excluded the linked 9q21.3-q22 and 10q21-22 regions recently reported in Asian and European/African/Australian families, respectively. The two families were then analyzed independently to encompass the possibility that they were segregating separate genes. Six additional candidate loci were identified on the basis of homozygosity for the same allele in all affected members of one family, but further analysis of closely linked flanking markers did not demonstrate similar homozygosity. Our data provide further evidence of genetic heterogeneity in FHLH and suggest the existence of at least a third locus for this disease.