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Blood, 15 September 2002, Vol. 100, No. 6, pp. 2266-2266
CORRESPONDENCE
To the editor:
Adult onset and atypical presentation of
hemophagocytic lymphohistiocytosis in siblings carrying
PRF1 mutations
Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of
early infancy characterized by fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia, and hemophagocytosis, which
represent the diagnostic criteria.1,2 In the absence of a
specific marker, differential diagnosis may be difficult, especially in
patients without familial recurrence. Mutations in PRF1, a
gene relevant for cellular cytotoxicity mechanisms whose mutations
result in impaired antiviral defense and dysregulation of the apoptotic
mechanisms, have been first documented in patients with HLH
(HLH2; Online Mendelian Inheritance in Man #603553) by Stepp et
al.3 The same clinical picture is apparently shared by patients with HLH due
to PRF1 mutations or any other cause.4-6 Most
patients develop HLH within the first few months of age. In the series of 122 patients collected by the International HLH Registry, most patients were diagnosed between 1 and 6 months.1
Exceptions to this general rule have been observed, as in the past
there have been reports of familial cases with an age at onset of up to
8 years.1,7 Furthermore it has been observed that the age
at onset for affected siblings is usually comparable and often coincides;1 discordant and later onset has been
exceptionally reported.8 Clementi et
al4 reported a PRF1 mutation in a 6-year-old
patient, an age at which onset of HLH is rarely observed, and discussed
whether adult forms of HLH2 may exist. We report 2 siblings
sharing the same mutations in the PRF1 gene, who developed HLH at 22 and 21 years, respectively. Case 1 is a white 27-year-old male, the son of unrelated
parents from southern Italy. In 1996 at age 22, an occasional finding of hypertransaminasemia was reported, in the absence of any other clinical signs. A few months later, left arm weakness appeared, lasting
one month. On July 1, 1998, he was admitted to the hospital because of
spiking fever, cough, lymphadenopathy, pancytopenia, and neurologic
symptoms (hemiplegia and somnolence). A brain magnetic resonance (MR)
scan showed multifocal demyelination, but no clonal immunoglobulines
were found in the cerebrospinal fluid (CSF). Neurosarcoidosis
was suspected, and therapy with high doses of intravenous
glucocorticoid was started, with good clinical response. Oral
methylprednisolone was progressively tapered, but a minimal dose of 40 mg daily was required to control fever and asthenia; while
pancytopenia persisted, the patient suffered recurrent respiratory and
urinary infections, which required frequent hospitalizations. We first saw the patient 2 years later, with fever, cough, dyspnea,
herpes simplex lesions in nasal and perioral skin, marked hepatosplenomegaly, and severe cushingoid features. Laboratory findings
showed pancytopenia, hypofibrinogenemia, hypertriglyceridemia, high
levels of transaminases, colestatic indexes, and ferritin. Upper and lower respiratory infection by S aureus and
P aeruginosa, together with septicemia by S hominis,
were present. Re-evaluation of the bone marrow biopsy that had
been performed elsewhere ruled out any malignancy; 8 months after this
first one, a bone marrow biopsy was repeated with a liver biopsy, and
both showed hemophagocytic features. Serologic tests for Epstein-Barr
virus (EBV), cytomegalovirus (CMV), and adenovirus (IgM and
IgG) were all negative, while a high IgG titer for herpes virus 1 and
parvovirus B19 were found. In spite of the age of the patient,
HLH was suspected. Natural killer (NK) cell activity was found
completely absent, as was perforin expression by peripheral blood
lymphocytes. Thus, starting in May 2000, the patient was treated with
oral cyclosporin, with good clinical response. At the time of writing,
he remains asymptomatic and laboratory values are normal except for hypertriglyceridemia. Case 2 is the only sister of case 1 and is 25.5 years old at the time
of writing. At 21 years, she was admitted to the hospital for
spiking fever, weight loss, weakness, and hepatosplenomegaly. Pancytopenia, hypertriglyceridemia, hypofibrinogenemia and high levels
of ferritin were observed. Neither superficial nor deep lymph nodes
were enlarged, and an abdominal computed tomographic (CT) scan only
showed moderate splenomegaly (19 cm) and mild hepatomegaly. Initial
bone marrow biopsy showed a T-cell infiltrate with no evidence for
clonal proliferation; this finding was confirmed at repeated biopsies.
A T-cell lymphoblastic lymphoma was diagnosed, and the patient was
treated with combination chemotherapy including vincristine,
cyclophosphamide, asparaginase, doxorubicin, and intrathecal
methotrexate; cranial irradiation was also given. One year later she
underwent autologous bone marrow transplantation (BMT). In the
follow-up mild cytopenia persisted for a few months. At the time of
writing, 4 years after autologous BMT, she remains asymptomatic except
for chronic fatigue. Laboratory tests only show mild leucopenia. When
HLH was diagnosed in her brother, she also was tested for NK cell
activity and perforin expression, both of which were found depleted. Molecular analyses were performed as reported by Stepp et
al,3 sequencing exons 2 and 3 of the PRF1
gene. The BLASTN program was used to compare the obtained
sequences to the reported gene structure and to PRF1 genes
of other species. The mutations found were tested for confirmation in
the parents of the patients and in a group of 25 controls. Sequencing of the coding exons of PRF1 disclosed the same
mutations in both siblings: each of them carried both the Ala91Val and
the Trp374Stop mutations (Figure 1). Each
parent carried 1 of the 2 mutations in the heterozygous condition. The
first mutation changes a small (alanine) into a larger (valine)
hydrophobic amino acid and has not been reported previously. As the
alanine at position 91 is conserved between human, mouse, and rat
perforin and has not been found in either heterozygous or homozygous
form in any other sequenced control (n = 31), it was inferred to be a
pathogenic mutation. The second, truncating mutation was first reported
by Stepp et al3 in families of Turkish origin and later
found in patients from the same ethnic background by Goransdotter et al.5 In all cases it was present as homozygous mutation;
it falls in an EGF domain, and the trypsin at position 374 is
conserved between human, rat, and mouse perforin. It is a pathogenic
mutation.
View larger version (11K):
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| Figure 1.
Structure of the
PRF1 gene and electropherograms of the mutations
identified. TM indicates transmembrane domain; EGF, epidermal
growth factor; and C2, domain sharing similarities with the C2
complement factor.
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The presenting clinical picture of HLH is rather uniform, characterized
by fever and hepatosplenomegaly with cytopenia and signs of
hyperactivation and infiltration by lymphocytes and macrophages, these
last often engaged in hemophagocytosis.1,2 The central nervous system (CNS) is variably involved, with symptoms that range
from irritability, bulging fontanel, and neck stiffness to seizures,
cranial nerve palsies, ataxia, psychomotor retardation, and coma.
Markedly different presenting pictures are not described in the
available series.1,5 Adult onset of familial HLH, never reported before, is the most
prominent feature in this family. Their presenting features were
different, with a prominent CNS involvement9 in one case and a diagnosis of non-Hodgkin lymphoma (NHL) in the other. Remarkably, in both cases the final diagnosis was delayed by about 3 years from the
onset of symptoms; both achieved an adequate disease control when
treated and did not show disease reactivation for more than one year
after the diagnosis. Given the limited potential for antiviral defense
in patients with PRF1 mutations,10 the prolonged absence of clinical manifestations due to macrophage activation following common viral infections in these subjects is
unexpected. In case 2 the diagnosis of NHL led to polychemotherapy followed by autologous BMT. Her prolonged remission is also unexpected, as an autologous BMT consolidation has no potential to restore the
genetically determined immune deficiency of the patient. We have
previously observed in one HLH patient, after acute graft rejection, an
18-month disease-free interval before overt disease reactivation (M.A.
and F.L., unpublished observation, 1998). The mechanism by which
massive immune suppression associated with the pre-BMT conditioning
regimen may result in a prolonged disease control remains to be elucidated. Even in the presence of quite different clinical presentations,
both patients carried the same mutations. The Trp374Stop mutation has
been previously reported in 9 patients always as a homozygous mutation.
All these patients showed a homogeneous phenotype with a
severe clinical course and an early age of onset, within the first
months of life in 8 of 9 cases, with the ninth presenting at 39 months.
This mutation was always found in subjects of Turkish origin;
historical data are available that may support the hypothesis of
migration of the mutation from Turkey to southern Italy in ancient
times. Further research will clarify whether this mutation originated
in the same haplotype both in the Italian and Turkish population. We confirm that Trp374Stop appears to be the most frequently reported
mutation in HLH and suggest that Ala91Val (which we found also in 4 other Italian patients; Clementi et al, in preparation) may be an
"Italian mutation." Thus the knowledge of the ethnic background of HLH patients may usefully address
mutation analysis. In our patients the genotype Trp374Stop/Ala91Val results in an atypical
presentation and milder clinical course, which is possibly attributed
to the latter mutation. Identification of patients with milder clinical
course and Ala91Val/Ala91Val genotype will confirm this hypothesis;
whether they indeed share the usual HLH phenotype remains to be demonstrated. The presence of patients with atypical presentation makes differential
diagnosis in hemophagocytic syndromes more difficult. We suggest that
HLH is included in the differential diagnosis of such patients not only
in infants and children but also in adults. In the attempt to
facilitate the diagnostic approach, we have recently proposed a flow
chart, which includes testing for perforin expression, to improve the
procedure.11
Rita Clementi, Lorenzo Emmi, Rita Maccario, Francesco Liotta, Lorenzo Moretta, Cesare Danesino, and Maurizio Aricò
Correspondence: Maurizio Aricò, Oncoematologia
Pediatrica, Ospedale
dei Bambini "G. Di Cristina," Palermo,
Italy; e-mail: arico{at}proxy.ospedalecivicopa.org
Acknowledgments
R.C., L.E., C.D., and M.A. contributed equally to
this work. This work was supported in part by the following grants:
Telethon Italy, Grant C30 (C.D.) and E755 (M.A.); IRCCS Policlinico San Matteo, Pavia, Italy (Ricerca Corrente) and 80291 (M.A.); the "Associazione Antonio Pinzino" (Petralia, Palermo, Italy); and by
IRCCS G. Gaslini Institute (L.M.).
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