Alternative titles; symbols
ORPHA: 540; DO: 0110922;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q22.1 | Hemophagocytic lymphohistiocytosis, familial, 2 | 603553 | Autosomal recessive | 3 | PRF1 | 170280 |
A number sign (#) is used with this entry because familial hemophagocytic lymphohistiocytosis-2 (FHL2) is caused by homozygous or compound heterozygous mutation in the gene encoding perforin (PRF1; 170280) on chromosome 10q22.
Familial hemophagocytic lymphohistiocytosis-2 (FHL2) is an autosomal recessive disorder of immune dysregulation with onset in infancy or early childhood. It is characterized clinically by fever, edema, hepatosplenomegaly, and liver dysfunction. Neurologic impairment, seizures, and ataxia are frequent. Laboratory studies show pancytopenia, coagulation abnormalities, hypofibrinogenemia, and hypertriglyceridemia. There is increased production of cytokines, such as gamma-interferon (IFNG; 147570) and TNF-alpha (191160), by hyperactivation and proliferation of T cells and macrophages. Activity of cytotoxic T cells and NK cells is reduced, consistent with a defect in cellular cytotoxicity. Bone marrow, lymph nodes, spleen, and liver show features of hemophagocytosis. Chemotherapy and/or immunosuppressant therapy may result in symptomatic remission, but the disorder is fatal without bone marrow transplantation (summary by Dufourcq-Lagelouse et al., 1999, Stepp et al., 1999, and Molleran Lee et al., 2004).
For a general phenotypic description and a discussion of genetic heterogeneity of FHL, see 267700.
Goransdotter Ericson et al. (2001) reported 7 unrelated families with FHL2 confirmed by genetic analysis. Four of the families were consanguineous: 3 from Turkey and 1 from Sweden. The patients presented between ages 1 and 58 months with fever, splenomegaly, cytopenia affecting at least 2 lineages, and hypertriglyceridemia and/or hypofibrinogenemia. All had hemophagocytosis on bone marrow, splenic, or lymph node biopsy. Five patients died without bone marrow transplant. Two with bone marrow transplant were alive at the time of the report, although 1 had mild retardation.
Clinical Variability
Chiapparini et al. (2011) reported a 13-year-old girl who presented with ataxia, headache, double vision, vomiting, and a progressive increase in intracranial pressure. She had papilledema, and brain MRI showed a swollen cerebellum with tonsillar herniation and signal abnormalities; some T2 hyperintensities were also present in supratentorial areas. CSF showed protein, IgG, and IgM levels consistent with blood-brain barrier damage. She was treated with steroids, but developed fever, worsening ataxia, and decreased sensation in the lower limbs after interruption of steroids. She also had organomegaly. Laboratory studies showed increased triglycerides and ferritin, anemia, elevated liver enzymes, and decreased NK activity. Bone marrow biopsy showed hypoplasia of the myeloid line with adequate erythropoiesis and an infiltration of lymphocytes and histiomonocytoid cells; hemophagocytosis was rare. She underwent bone marrow biopsy and was in good condition after 18 months. Genetic analysis identified a homozygous mutation in the PRF1 gene (R225W; 170280.0004). Chiapparini et al. (2011) noted the unusual but prominent neurologic presentation in this patient.
The transmission pattern of FHL2 in the families reported by Goransdotter Ericson et al. (2001) was consistent with autosomal recessive inheritance.
Arico et al. (2002) proposed a clinical diagnostic algorithm for the diagnosis of FHL2 based on the absence of perforin expression as determined by flow cytometric analysis of NK cells. Using this algorithm in 19 patients diagnosed with FHL by other criteria, they identified 7 with absent perforin expression; all 7 patients were subsequently found to have mutations in the PRF1 gene. The remaining 12 patients were determined to have other forms of FHL or associated infections.
Trizzino et al. (2008) analyzed data from 124 FHL patients with known mutations in the PRF1 gene. Flow cytometry showed that perforin expression was absent in 40 patients, reduced in 6, and normal in 4; natural killer cell activity was absent or severely reduced (less than 2%) in 54 (77%) of the 70 patients in which it was reported. The authors stated that thrombocytopenia was by far the most sensitive of diagnostic parameters, being present in all cases; fever and splenomegaly were present in 96% and 98% of cases, respectively, and anemia and hyperferritinemia were present in 90%. Lymphadenopathy and central nervous system involvement were found in 35% and 36% of cases, respectively, and skin rash in 24% of cases.
Locatelli et al. (2020) investigated the efficacy and safety of emapalumab, a human anti-interferon-gamma 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.
In a genetic linkage study of 17 families with familial hemophagocytic lymphohistiocytosis, Dufourcq-Lagelouse et al. (1999) mapped a locus for this disorder to chromosome 10q21-q22. Ten families showed no recombination with 3 tightly linked markers, with a maximum multipoint lod score of 11.22 at the D10S6050 locus. Haplotype analysis of these 10 families allowed them to establish D10S206 and D10S1665 as the telomeric and centromeric flanking markers, respectively. Heterogeneity analysis and haplotype inspection of the remaining families confirmed that in 7 families familial hemophagocytic lymphohistiocytosis was not linked to 10q21-q22.
In 8 unrelated patients with familial hemophagocytic lymphohistiocytosis linked to 10q21-q22, Stepp et al. (1999) sequenced the coding region of the PRF1 gene and identified homozygous nonsense mutations in 4 patients (170280.0001-170280.0003) and missense mutations in the other 4 patients (170280.0004-170280.0009). Cultured lymphocytes from these patients had defective cytotoxic activity, and immunostaining revealed little or no perforin in the granules. Thus, defects in perforin are responsible for 10q21-q22-linked FHL.
In 2 sibs with adult-onset hemophagocytic lymphohistiocytosis, diagnosed at ages 22 and 21 years, respectively, Clementi et al. (2002) identified compound heterozygosity for a trp374-to-ter (W374X; 170280.0002) mutation and an ala91-to-val (A91V; 170280.0011) substitution in the PRF1 gene. The unrelated parents from southern Italy were each heterozygous for 1 of the substitutions. The patients had an atypical presentation and unusually mild course of the disease, despite absence of perforin expression in one and 'depleted' expression in the other.
In 25 (58%) of 43 unrelated North American families with children diagnosed with primary hemophagocytic lymphohistiocytosis, Molleran Lee et al. (2004) identified mutations in the PRF1 gene. There was no significant difference in median age at diagnosis when comparing patients with and without perforin mutations (6 months vs 7 months, respectively); however, comparing patients with PRF1 mutations who expressed low levels of perforin to those with no detectable perforin, the median age at onset was 54 months versus 3 months, respectively (p less than 0.001).
Lipton et al. (2004) described the clinical course and laboratory findings in monozygotic twin male infants with familial hemophagocytic lymphohistiocytosis in whom compound heterozygosity for a missense mutation on the maternal allele and a polymorphism on the paternal allele of the PRF1 gene was identified and reported by Molleran Lee et al. (2004).
Arico, M., Allen, M., Brusa, S., Clementi, R., Pende, D., Maccario, R., Moretta, L., Danesino, C. Haemophagocytic lymphohistiocytosis: proposal of a diagnostic algorithm based on perforin expression. Brit. J. Haemat. 119: 180-188, 2002. [PubMed: 12358924] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.03773.x]
Chiapparini, L., Uziel, G., Vallinoto, C., Bruzzone, M. G., Rovelli, A., Tricomi, G., Bizzi, A., Nardocci, N., Rizzari, C., Savoiardo, M. Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss (sic) diagnosis. Neurol. Sci. 32: 473-477, 2011. [PubMed: 21234777] [Full Text: https://doi.org/10.1007/s10072-010-0467-2]
Clementi, R., Emmi, L., Maccario, R., Liotta, F., Moretta, L., Danesino, C., Arico, M. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. (Letter) Blood 100: 2266-2267, 2002. [PubMed: 12229880] [Full Text: https://doi.org/10.1182/blood-2002-04-1030]
Dufourcq-Lagelouse, R., Jabado, N., Le Deist, F., Stephan, J.-L., Souillet, G., Bruin, M., Vilmer, E., Schneider, M., Janka, G., Fischer, A., de Saint Basile, G. Linkage of familial hemophagocytic lymphohistiocytosis to 10q21-22 and evidence for heterogeneity. Am. J. Hum. Genet. 64: 172-179, 1999. [PubMed: 9915956] [Full Text: https://doi.org/10.1086/302194]
Goransdotter Ericson, K., Fadeel, B., Nilsson-Ardnor, S., Soderhall, C., Samuelsson, A., Janka, G., Schneider, M., Gurgey, A., Yalman, N., Revesz, T., Egeler, R. M., Jahnukainen, K., Storm-Mathiesen, I., Haraldsson, A., Poole, J., de Saint Basile, G., Nordenskjold, M., Henter, J.-I. Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. Am. J. Hum. Genet. 68: 590-597, 2001. [PubMed: 11179007] [Full Text: https://doi.org/10.1086/318796]
Lipton, J. M., Westra, S., Haverty, C. E., Roberts, D., Harris, N. L. Case 28-2004: Newborn twins with thrombocytopenia, coagulation defects, and hepatosplenomegaly. New Eng. J. Med. 351: 1120-1130, 2004. Note: Erratum: New Eng. J. Med. 351: 2025 only, 2004. [PubMed: 15356310] [Full Text: https://doi.org/10.1056/NEJMcpc049019]
Locatelli, F., Jordan, M. B., Allen, C., Cesaro, S., Rizzari, C., Rao, A., Degar, B., Garrington, T. P., Sevilla, J., Putti, M. C., Fagioli, F., Ahlmann, M., Dapena Diaz, J.-L., Henry, M., De Benedetti, F., Grom, A., Lapeyre, G., Jacqmin, P., Ballabio, M., de Min, C. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. New Eng. J. Med. 382: 1811-1822, 2020. [PubMed: 32374962] [Full Text: https://doi.org/10.1056/NEJMoa1911326]
Molleran Lee, S., Villanueva, J., Sumegi, J., Zhang, K., Kogawa, K., Davis, J., Filipovich, A. H. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J. Med. Genet. 41: 137-144, 2004. [PubMed: 14757862] [Full Text: https://doi.org/10.1136/jmg.2003.011528]
Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Cartain, S., Mathew, P. A., Henter, J.-I., Bennett, M., Fischer, A., de Saint Basile, G., Kumar, V. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286: 1957-1959, 1999. [PubMed: 10583959] [Full Text: https://doi.org/10.1126/science.286.5446.1957]
Trizzino, A., zur Stadt, U., Ueda, I., Risma, K., Janka, G., Ishii, E., Beutel, K., Sumegi, J., Cannella, S., Pende, D., Mian, A., Henter, J.-I., Griffiths, G., Santoro, A., Filipovich, A., Arico, M. Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations. J. Med. Genet. 45: 15-21, 2008. [PubMed: 17873118] [Full Text: https://doi.org/10.1136/jmg.2007.052670]