Alternative titles; symbols
HGNC Approved Gene Symbol: HPLH1
SNOMEDCT: 398250003; ICD10CM: D76.1; ORPHA: 540; DO: 0110921;
Cytogenetic location: 9q21.3-q22 Genomic coordinates (GRCh38) : 9:78,500,001-99,800,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q21.3-q22 | Hemophagocytic lymphohistiocytosis, familial, 1 | 267700 | Autosomal recessive | 2 |
Zur Stadt et al. (2005) summarized the clinical features of hemophagocytic lymphohistiocytosis (HLH), a rare autosomal recessive disorder characterized by massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently central nervous system involvement. In FHL, the familial form of the disease, first episodes occur mostly during infancy, with a rapidly fatal outcome if untreated. Diagnostic criteria also include low fibrinogen and high triglyceride and ferritin levels. Chemoimmunotherapy based on corticosteroids, epipodophyllotoxins, and cyclosporin succeeds in controlling the disease in the majority of patients, although remission is rarely obtained (Henter et al., 2002). Most patients suffer an early death unless they are treated by hematopoietic stem cell transplantation (Durken et al., 1999).
Genetic Heterogeneity of Familial Hemophagocytic Lymphohistiocytosis
Familial hemophagocytic lymphohistiocytosis (FHL1) has been mapped to chromosome 9q. Also see FHL2 (603553), caused by mutation in the PRF1 gene (170280) on chromosome 10q22; FHL3 (608898), caused by mutation in the UNC13D gene (608897) on chromosome 17q25; FHL4 (603552), caused by mutation in the syntaxin-11 gene (STX11; 605014) on chromosome 6q24; and FHL5 (613101), caused by mutation in syntaxin-binding protein-2 (STXBP2; 601717), which is an interaction partner of STX11, on chromosome 19p13.
Before the identification of mutations in the RAG1 (179615) and RAG2 (179616) genes, both of which map to 11p, Omenn syndrome (familial reticuloendotheliosis with eosinophilia; 603554) was not thought to be clearly distinct from other reported cases of hemophagocytic lymphohistiocytosis.
Mutation in the HAVCR2 gene (606652) on chromosome 5q23 causes an inflammatory disorder that is sometimes associated with HLH (SPTCL; 618398). Mutation in the RC3H1 gene (609424) on chromosome 1q25 causes a hyperinflammatory disorder with HLH-like features (IMDYSHI; 618998).
Anemia, granulocytopenia, and thrombocytopenia are produced in part by phagocytosis of blood cells, and in part by replacement of the marrow by histiocytic infiltration. Families have been reported by Marrian and Sanerkin (1963) and by Farquhar and Claireaux (1952) and Farquhar et al. (1958). In the latter family 4 sibs were affected. The father showed autoantibody and shortened red cell life span. Farquhar et al. (1958) concluded that the minor changes observed in the father and one sib represented the heterozygous state. They were not concerned about the lack of changes in the mother since expression in the heterozygote is often variable. Miller (1966) described 5 sisters--a complete sibship, including a pair of twins--with clinical features of failure to thrive, recurrent infections, lymphadenopathy, hepatosplenomegaly, pulmonary infiltration, and terminal pancytopenia and hypergammaglobulinemia. Death occurred between ages 20 months and 57 months. Autopsy showed diffuse reticulum cell infiltration of most organs including the central nervous system, obliteration of architecture of lymph glands and marked plasmacytosis. The family reported by Farquhar and Claireaux (1952) and Farquhar et al. (1958) was Scottish. Another Scottish family, with 3 affected sibs, was reported by Goodall et al. (1965). Bell et al. (1968) described affected brothers born 11 years apart. Meningoencephalitis during infancy was a feature in each. Hemophagocytosis in bone marrow preparations made the diagnosis.
Donohue (1968) had autopsy information on 6 cases that occurred in an inbred Mennonite group in Ontario. De Veber (1974) provided further information on these cases, which he considered to be in the general group of histiocytoses. (These cases are also discussed in entry 246400.) A major difference from other reported families was raised platelet counts. Cutbush et al. (1974) identified 22 cases in an inbred Mennonite kindred. Six of them were still living. The disease presented at about 3 months of age with hepatomegaly and variable lymphadenopathy, and untreated cases died rapidly with high fever, hemolytic anemia, and a picture resembling acute leukemia. Some cases responded to prednisone. Others died despite prednisone and cytotoxic agents. Healthy relatives may have high platelet counts.
The familial histiocytoses are nosologically confused. Even the terminology, based on histopathology, is confusing: lymphohistiocytic, erythrophagocytic, lymphoreticular, etc. The confused group of histiocytoses includes monocytic leukemia, histiocytic lymphoma, Letterer-Siwe disease, malignant histiocytosis, Hand-Schuller-Christian disease, eosinophilic granuloma, histiocytosis X, reticuloendotheliosis, histiocytic reticulosis, disseminated lipogranulomatosis, and familial hemophagocytic reticulosis. Newton and Hamoudi (1973) gave a useful review, but a convincing classification has not been achieved. Confusion is compounded by failure to distinguish infectious diseases such as histoplasmosis and graft-versus-host reaction such as occurs in infants with severe combined immunodeficiency transfused with fresh whole blood or receiving maternal blood transplacentally. Some authors have suggested that familial erythrophagocytic lymphohistiocytosis, familial reticuloendotheliosis with eosinophilia, and Letterer-Siwe disease (246400) can be lumped together, whereas other authors have considered them to be separate entities. Nelson et al. (1961) claimed that the disorder they described was quite different from Letterer-Siwe disease and presumably also from the disorder described here.
Mozziconacci et al. (1965) described 2 brothers, aged 6 and 8, with this fatal disease characterized by a high and irregular fever, hepatosplenomegaly, purpura, and, later, jaundice, polyneuritis, meningeal reaction, choked disks, moderate anemia, and severe granulocytopenia. A possible relationship to ceroid storage disease (256730) is only speculative. Price et al. (1971) described 4 of 12 sibs with a progressive neurologic disease characterized by diffuse lymphohistiocytic infiltrations of the central nervous system in association with multiple foci of parenchymal destruction. The range of age at death was 15 months to 12 years. The spinal fluid showed pleocytosis and increased protein. Histologically the disorder resembled familial hemophagocytic reticulosis or familial erythrophagocytic lymphohistiocytosis but unlike these conditions the process was largely confined to CNS. Since lymphocytic and histiocytic infiltration of viscera was present in some of the patients and leukopenia with hypocellular bone marrow was described, most would consider this the same as familial histiocytic reticulosis.
Nemoto and Ohnishi (1987) reported histologic studies of the spleen, liver, and mesenteric lymph nodes from a patient in whom splenectomy and biopsy of the other tissues were performed. They described lymphoid cells of various sizes, with atypical features including mitotic figures and convoluted nuclei; these were suspected to be T cells on the basis of immunohistochemical findings. The authors suggested that this may be a special type of lymphoproliferative disease accompanied by severe proliferation of erythrophagocytic histiocytes rather than being a true histiocytic disease.
Ladisch et al. (1978) demonstrated abnormal lipid metabolism and defects in both humoral and cellular immunity, together with a plasma inhibitor of in vitro lymphocyte blastogenesis. Because a component of the immunodeficiency is plasma-mediated inhibition of lymphocyte proliferation, Ladisch et al. (1982) tested whether repeated plasma or blood exchange would help in FEL. Clinical improvement was complete in 2 and partial in 1 of 3 patients studied. Laboratory values also improved. Relapse, which was ultimately fatal, was accompanied by recurrence of the immune defects.
Stark et al. (1984) studied 11 patients in 4 Jewish families of Iranian and Iraqi origin. Parental consanguinity was found in 3. The age of onset varied from 6 weeks to 36 months. All had fever, wasting, and hepatosplenomegaly. Lymph node enlargement and neurologic abnormalities were common. Pancytopenia, atypical lymphomonocytoid cells in the peripheral blood, abnormal liver function tests, and increased CSF protein were the most consistent laboratory findings. In 9 patients death occurred in 2 weeks to 3 months after presentation. The longest survival was 2 years after presentation.
Janka (1983) reviewed 121 cases, and Henter and Elinder (1991) provided a clinical review based on the findings in 7 children.
The excessive immune activation that occurs in FHL is characterized by uncontrolled T lymphocyte and macrophage activation (Henter et al., 1991; Hirst et al., 1994). Infiltration of the liver, spleen, bone marrow, and central nervous system by activated T cells and macrophages results in a multisystem disorder with onset in early infancy, which, in the absence of treatment with epipodophyllotoxins, immunosuppressive agents, or bone marrow transplantation, progresses rapidly, with a median survival of 2 months. In Sweden, Henter et al. (1991) studied the incidence of hemophagocytic lymphohistiocytosis in children during a 16-year period, 1971-1986; the incidence was 1.2 per 1 million children per year. One child per 50,000 live births developed the disorder during this period. The sex ratio was approximately 1:1. Prominent early clinical signs were fever, splenomegaly, hepatomegaly, rash, and lymph node enlargement. Neurologic symptoms, which developed in 47%, could totally dominate the clinical picture and develop before other symptoms and signs. In only 11 of 32 children was the diagnosis made during their lifetime.
Henter et al. (1991) demonstrated elevated levels of circulating interferon-gamma (147570), tumor necrosis factor (191160), and interleukin-6 (147620) in children during active phases of FHL. Soluble CD8 was also increased in all of 7 children tested. Henter et al. (1991) suggested that a genetic defect in cytokine regulation underlies this disorder.
The entity described here should not be confused with Langerhans cell histiocytosis, which has little or no tendency to familial aggregation; see 604856 for evidence to the contrary. The Langerhans cell, a dendritic cell of the epidermis, was described by medical student Paul Langerhans, who thought that it was part of the nervous system (Langerhans, 1868). Birbeck et al. (1961) found that the Langerhans cell displays a unique electron-microscopic morphology. The discoveries that these cells are not confined to skin and that they make up a sizable portion of the cellular infiltrate in histiocytosis X, along with other evidence, suggest that they play an immunologic role in protecting against environmental antigens. Egeler and D'Angio (1995) presented a classification of histiocytosis syndromes in children: class I, Langerhans cell histiocytosis; class II, histiocytosis of mononuclear macrophages other than Langerhans cells, including familial hemophagocytic lymphohistiocytosis; and class III, malignant histiocytic disorders, including histiocytic lymphoma.
Henter and Elinder (1995) pointed out that hemophagocytic lymphohistiocytosis can be divided into 2 categories, a primary and a secondary form. The primary form is hereditary, whereas the secondary form is a reactive condition, commonly associated with immunosuppressive therapy, malignancies and/or infections, which often are of viral origin. Henter et al. (1991) published diagnostic guidelines for hemophagocytic lymphohistiocytoses. Henter and Elinder (1995) pointed out that a viral infection may elicit a bout of familial hemophagocytic lymphohistiocytosis in a genetically predisposed child.
Dufourcq-Lagelouse et al. (1999) pointed out that other causes of inherited hemophagocytic lymphohistiocytosis include Chediak-Higashi syndrome (214500) and Griscelli syndrome (214450), both associated with partial albinism, and X-linked lymphoproliferative syndrome (308240). Acquired forms of lymphohistiocytosis, such as Letterer-Siwe disease (246400), usually occur later in childhood. The diagnosis of hemophagocytic lymphohistiocytosis depends on both positive and negative criteria, including the early occurrence and severity of the hemophagocytic syndrome, the occurrence of relapse, evidence of autosomal recessive inheritance, and the absence of associated albinism.
Janka and Schneider (2004) summarized revised diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH).
Henter et al. (2007) reviewed the diagnostic and therapeutic guidelines for HLH and stated that the 5 criteria from the 1991 guidelines remained valid: fever, splenomegaly, cytopenia affecting at least 2 of the 3 cell lineages in the peripheral blood, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis in bone marrow, spleen, or lymph nodes. In addition, 3 more criteria had been introduced: low or absent natural killer cell activity, hyperferritinemia, and high levels of soluble IL2RA (147730). Henter et al. (2007) noted that 5 of the 8 criteria must be fulfilled, but that patients with a molecular diagnosis consistent with HLH do not necessarily need to fulfill the diagnostic criteria.
The review of Henter and Elinder (1991) indicated successful results with chemotherapy.
Bergholz et al. (1978) reviewed the evidence that 'congenital allogeneity' with graft-versus-host reaction might be involved. Nespoli et al. (1991) treated 3 patients, aged 6 to 20 months, with allogeneic bone marrow transplantation (BMT). They concluded that when an HLA-identical family donor exists, the BMT followed by intensive chemotherapy can produce a stable remission.
Mache et al. (1994) reported 2 sibs who were thought to have disseminated T-cell lymphoma at the time of diagnosis of familial hemophagocytic lymphohistiocytosis. DNA hybridization studies provided evidence of a monoclonal T-cell receptor beta-chain gene rearrangement. One sib received an allogeneic bone marrow transplant from a related healthy donor.
Allogeneic bone marrow transplantation (BMT) from an HLA-identical related donor is the treatment of choice in patients with familial hemophagocytic lymphohistiocytosis. However, fewer than 20% of patients have a disease-free HLA-identical sib. Jabado et al. (1997) described BMTs from 13 HLA-nonidentical related donors and from a matched unrelated donor that were performed in 2 centers and 14 consecutive cases of this disorder. Remission of disease was achieved before BMT in 10 patients. Marrow was T-cell-depleted to minimize graft-versus-host disease (GVHD; see 614395). In addition to a conditioning regimen of cytotoxic drugs or antithymocyte globulin (ATG), antiadhesion antibodies specific for the alpha chain of the leukocyte function-associated antigen-1 (ITGAL; 153370) and CD2 (186990) were infused pre-BMT and post-BMT to help prevent graft rejection. Acute GVHD greater than stage 1 was not observed, and 1 patient had mild cutaneous chronic GVHD that resolved. Sustained engraftment was obtained in 11 of 17 transplants (3 patients had 2 transplants), and disease-free survival in 9 patients, with a follow-up period of 8 to 69 months (mean, 33), was observed.
Locatelli et al. (2020) investigated the efficacy and safety of emapalumab, a human anti-interferon-gamma (147570) antibody, administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving previously treated and untreated patients with primary hemophagocytic lymphohistiocytosis 18 years of age or younger. A total of 34 patients, 27 previously treated and 7 previously untreated, received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40%. In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. The authors concluded that emapalumab is an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis.
By homozygosity mapping in 4 inbred families of Pakistani descent, Ohadi et al. (1999) demonstrated linkage of familial hemophagocytic lymphohistiocytosis to markers in the 9q21.3-q22 region (FHL1). In an additional kindred of Arab origin, linkage to this interval could not be demonstrated; the maximum multipoint lod score was -0.12. All affected children in the 5 kindreds exhibited typical features of FHL, which included fever, liver and spleen enlargement, bi- or pancytopenia, hypertriglyceridemia, and hypofibrinogenemia. Hemophagocytosis was identified on examination of bone marrow and, in 2 cases, cerebrospinal fluid. All patients received treatment with etoposide and cortical steroids alone or in combination with cyclosporin A. One individual subsequently underwent successful allogeneic bone marrow transplantation from an HLA-identical sib donor and remained disease free 54 months after diagnosis. One patient survived in partial remission with continuing therapy for 15 months. The remaining 3 patients died 9 to 17 months after diagnosis because of disease progression despite treatment.
Dufourcq-Lagelouse et al. (1999) likewise found evidence for genetic heterogeneity in familial hemophagocytic lymphohistiocytosis. In studies of 17 families with FHL, they found that 10 showed no recombination with 3 tightly linked markers in the proximal region of 10q (see 603553). The maximum multipoint lod score was 11.22 at D10S1650. They established D10S206 and D10S1665 as the telomeric and the centromeric flanking markers, respectively. In the other 7 families, FHL was not linked to 10q21-q22.
Further genetic heterogeneity in familial hemophagocytic lymphohistiocytosis was suggested by a study in which FHL in 2 unrelated Canadian families with affected first cousins was not linked to 9q21.3-q22 or 10q21-q22 (Graham et al., 2000).
Although the genes encoding granulysin (188855) and granzyme B (123910) had been considered reasonable candidates for the site of mutations causing FHL, Ericson et al. (2003) found no mutations in either gene in 16 well-defined FHL families.
Zur Stadt et al. (2006) performed mutation analysis of the STX11 (605014), PRF1 (170280), and UNC13D (608897) genes in 63 unrelated patients with FHL of different geographic origins: Turkey, 32; Germany, 23; others, 8. They identified mutations in 38 of 63 samples: 20 in PRF1, 12 in UNC13D, and 6 in STX11. Of the 32 patients from Turkey, 14 had mutations in PRF1, 6 had mutations in UNC13D, and 6 had mutations in STX11. The mutation trp374 to ter in PRF1 (170280.0002) was found in 12 patients from Turkey and was associated with a very early onset of the disease, below the age of 3 months in all cases. In contrast, 3 of the 23 and 4 of the 23 patients from Germany, and 3 of 8 and 2 of 8 from other origins, showed mutations in PRF1 and UNC13D, respectively, but none in STX11. Thus, FHL2, and FHL3, and FHL4 account for 80% of the hemophagocytic lymphohistiocytosis cases of Turkish origin, and for 30% of German patients.
Zur Stadt et al. (2006) identified mutations in RAB27A (603868) in 3 patients with Griscelli syndrome type 2 (607624), the presentation of which can include typical signs of FHL. In functional studies using a mammalian 2-hybrid system, they found that the ala87-to-pro mutation in RAB27A (603868.0010) and leu403 to pro in UNC13D (608897.0007) each prevented the formation of a stable UNC13D/RAB27A complex in vitro. The findings of Zur Stadt et al. (2006) demonstrated extensive genetic and allelic heterogeneity in FHL and delineated an approach for functionally characterizing missense mutations in RAB27A and UNC13D.
Among 76 FHL patients from 65 unrelated families, Horne et al. (2008) found that 13 (18%) of 74 had PRF1 mutations, 6 (10%) of 61 had UNC13D mutations, and 14 (20%) of 70 had STX11 mutations. No molecular diagnosis was found in 27 (45%) of 60 patients. STX11 mutations were most common in Turkish families (7 of 28, 25%), whereas PRF1 mutations were most common in Middle East families (6 of 13, 46%). No biallelic mutations were identified in most families of Nordic origin (13 of 14, 93%). Patients carrying PRF1 mutations had higher risk of early onset before age 6 months compared to patients carrying STX11 mutations. Patients without identified mutations had increased risk of pathologic cerebrospinal fluid at diagnosis compared to patients with STX11 mutations. The results revealed some genotype/phenotype correlations among FHL patients with different disease-causing mutations.
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