Abstract
Familial Hemophagocytic lymphohistiocytosis (FHL) is a rare immune deficiency with defective cytotoxic function. The age at onset is usually young and the natural course is rapidly fatal if untreated. A later onset of the disease has been sporadically reported even in adolescents and adults. We report the results of our retrospective data collection of all cases diagnosed with FHL at an age of 18 years or older and enrolled in the Italian Registry of HLH. All cases were diagnosed with FHL based on evidence of genetic defect in one FHL-related gene. A total of 11 patients were diagnosed with FHL. They were 9 males and 2 females, from 10 unrelated families; their age ranged between 18 and 43 years (median, 23 years). Family history was unremarkable in eight families at the time of the diagnosis. Their genetic diagnoses are: FHL2 (n = 6), FHL3 (n = 2), FHL5 (n = 1), XLP1 (n = 2). Clinical, molecular and functional data are described. These data confirm that FHL may present beyond the pediatric age and up to the fifth decade. FHL2 due to perforin defect is the most frequently reported subtype. Adult specialists should consider FHL in the differential diagnosis of patients with cytopenia and liver or central nervous system disorders, especially when a lymphoproliferative disease is suspected but eventually not confirmed. FHL may turn to be fatal within a short time course even in adults. This risk, together with the continuous improvement in the transplant technique, especially in the area of transplant from matched unrelated donor, resulting in reduced treatment related mortality, might suggest a wider use of SCT in this population. Current diagnostic approach allows prompt identification of patients by flow-cytometry screening, then confirmed by the genetic study, and treatment with chemo-immunotherapy followed by stem cell transplantation.
Highlights
Familial Hemophagocytic lymphohistiocytosis (FHL, OMIM 267700) is a genetically heterogeneous disorder characterized by a hyper-inflammatory syndrome with fever, hepatosplenomegaly, cytopenia and sometimes central nervous system involvement
In most cases the natural course of FHL is rapidly fatal within a few weeks, unless appropriate treatment, including corticosteroids, cyclosporine, etoposide, anti-thymocyteglobulin, can obtain transient disease control
Most of the available information on the clinical spectrum and natural course of FHL derives from reports of children diagnosed by a few referral centres in Europe, North America or Japan [1,2]
Summary
Familial Hemophagocytic lymphohistiocytosis (FHL, OMIM 267700) is a genetically heterogeneous disorder characterized by a hyper-inflammatory syndrome with fever, hepatosplenomegaly, cytopenia and sometimes central nervous system involvement. Patients with Chediak-Higashi syndrome have biallelic mutations of the gene encoding the cytoplasmic protein lysosomal trafficking regulator (LYST;OMIM*606897) and have granulated cells with giant intracytoplasmic lysosomal structures. Since the original report of two affected siblings aged nine weeks by James Farquhar in 1952 [20], FHL has widely been considered as a disease characteristic of the first two years of age. This may mislead the clinician into conclude that a patient with a clinical constellation resembling HLH is considered to be ‘‘too old’’ for this diagnosis. We report a series of patients with FHL due to a documented genetic defect who developed the disease during adulthood
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