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Pediatric Hematology and Oncology, 29:215–219, 2012
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Copyright ISSN: 0888-0018 print / 1521-0669 online
DOI: 10.3109/08880018.2012.657338
HISTIOCYTE DISORDERS
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Primary Hemophagocytic Lymphohistiocytosis in
Iran: Report from a Single Referral Center
Bibi Shahin Shamsian, MD,1 Nima Rezaei, MD, PhD,2 Samin Alavi, MD,1
Mona Hedayat, MD,3 Ali Amin Asnafi, MD,1 Zahra Pourpak, MD, PhD,4
Atoosa Gharib, MD,5 Farzaneh Jadali, MD,5
and Mohammad Taghi Arzanian, MD1
1
Department of Pediatric Hematology-Oncology, Mofid Children’s Hospital, Shahid
Beheshti University of Medical Sciences, Tehran, Iran; 2 Research Center for
Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran
University of Medical Sciences, Tehran, Iran; and Molecular Immunology Research Center
and Department of Immunology, School of Medicine, Tehran University of Medical
Sciences, Tehran, Iran; 3 Research Center for Immunodeficiencies, Pediatrics Center of
Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran;
4
Immunology, Asthma, and Allergy Research Institute, Tehran University of Medical
Sciences, Tehran, Iran; 5 Department of Pediatric Pathology, Mofid Children’s Hospital,
Shahid Beheshti University of Medical Sciences, Tehran, Iran
Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by fever, hepatosplenomegaly, and cytopenia, and widespread accumulation of lymphocytes and histiocytes,
sometimes with hemophagocytosis, primarily involving the spleen, lymph nodes, bone marrow,
and liver. HLH can either occur sporadically (secondary HLH) or as part of a familial syndrome (primary HLH), including familial HLH and the distinct immunodeficiency syndromes. Herein the authors report 6 Iranian patients with primary HLH and their outcome from a single tertiary-care
center.
Keywords familial HLH, Griscelli syndrome type 2, hemophagocytic lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition
characterized by prolonged fever, hepatosplenomegaly, cytopenia, and hemophagocytosis [1–3]. It arises from uncontrolled activation of histiocytes and CD8+ T cells,
with abnormally elevated levels of circulating proinflammatory cytokines leading to
progressive organ dysfunction. HLH can be divided into primary (genetic) and secondary (acquired) forms, the latter being associated with infections, malignancies, or
rheumatologic disorders [1, 4, 5]. Primary HLH with autosomal recessive or X-linked
inheritance can be divided into familial HLH and the distinct immunodeficiency
syndromes Chédiak-Higashi syndrome (CHS), Griscelli syndrome type 2 (GS-2), and
X-linked lymphoproliferative disease (XLP) [1, 4]. The known gene defects causing
familial HLH (PRF1, UNC13D, STX11, and MUNC18-2, also known as STXBP2) and
Received 11 December 2011; accepted 10 January 2012.
Address correspondence to: Bibi Shahin Shamsian, MD, Department of Pediatric
Hematology-Oncology, Mofid Children’s Hospital, Shariati Avenue, Tehran, Iran. Postal Code:
15468-15514. E-mail: [email protected]
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B. S. Shamsian et al.
the related disorders CHS (LYST), GS-2 (RAB27A), and XLP (SAP) result in impaired
natural killer (NK) and cytotoxic T-lymphocyte (CTL) function and a predisposition
to develop HLH.
The clinical syndrome of HLH is the only manifestation of familial HLH, whereas
CHS and GS-2 are distinct immunodeficiency syndromes combined with partial albinism due to defective melanosome transport in melanocytes. XLP is a rare immunodeficiency characterized by fulminant infectious mononucleosis, which may develop
into a hemophagocytic syndrome, dysgammaglobulinemia, and lymphoma [6, 7]. Primary HLH is considered fatal unless treated by hematopoietic stem cell transplantation (HSCT).
Here we report a series of 6 patients diagnosed with primary HLH from independent families, as indicated by parental consanguinity or other infant deaths in the family, who were evaluated at a single tertiary-care center.
RESULTS
Clinical, laboratory, and imaging findings of our patients, establishing the diagnosis
of primary HLH, is summarized in Table 1.
GS-2 was diagnosed in 3 patients based on clinical, laboratory, and microscopic
features of partial albinism and finding of RAB27A mutations in 2 patients tested. DNA
sequencing revealed homozygous missense mutation in exon 5 (A → G) of patient
5 leading to an amino acid change (S115G) [8], and a novel homozygous missense
mutation in exon 3 (A → G) of patient 1 leading to an amino acid change (D74G).
Two patients (patients 1 and 2) were on the HLH-2004 continuation therapy
and 2 patients (patients 4 and 6) died while waiting for a suitable donor. Two patients (patients 3 and 5) underwent HSCT, patient 5 had a human leukocyte antigen
(HLA)-identical sibling donor and patient 3 had a cord-blood, unrelated, 1-antigenmismatched donor. Both patients were treated according to the HLH-2004 treatment
protocol and none had active disease at the time of HSCT. Patient 5 who were diagnosed with GS-2 responded well and remained in remission through 24 months of
follow-up, whereas the other died of acute graft-versus-host disease and infection on
day 136 after HSCT.
DISCUSSION
There is a high prevalence of consanguinity in some parts of Iran, which accounts
for the increased rate of rare primary immunodeficiency diseases in this population
[9]. Our study highlights the importance of considering the diagnosis of GS-2 in Iranian fair-haired individuals with hemophagocytic syndromes, particularly those originating from areas with high rates of consanguineous marriages. However, in patients
without obvious signs of silvery-gray hair, consistent findings on microscopic examination of the hair and, more important, identification of RAB27A mutations should
facilitate prompt diagnosis and treatment [8].
Neurologic involvement is a common finding and found in more than half of patients with HLH at initial clinical presentation [10, 11]. It has been demonstrated that
children with abnormal cerebrospinal fluid (CSF) at diagnosis have increased risk
of mortality and neurological sequelae [10]. We found neurological symptoms (ie,
seizure, ptosis, facial palsy, and hemiplegia) in 3 patients with normal CSF examination and 1 patient had abnormal CSF but no neurological symptoms. The latter died
following HSCT. Although allogeneic HSCT is the only curative treatment available
and has drastically improved survival for patients with primary HLH, persistent neurological sequelae, mostly neurodevelopmental delay and epilepsy, are common in the
Pediatric Hematology and Oncology
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60
0.84
39
684
179
<1.5
700
211
116
3.1, 0.5
14
37
1730
—
Present
46 XX
13
46
820
50/14.8
Present
45 XY t(3q21, 17q21)
Hemoglobin (g/L)
Neutrophils (109 /L)
Platelets (109 /L)
Triglycerides (mg/dL)
Cholesterol (mg/dL)
Fibrinogen (g/L)
Ferritin (µg/L)
SGOT (IU/L)
SGPT (IU/L)
Bilirubin total, direct
(mg/dL)
PT (s)
PTT (s)
LDH (U/L)
Flow cytometry CD4/CD8
(%)
Hemophagocytosis
Cytogenetic study
Yes
Abnormal, compatible
with GS2
84
0.64
530
272
159
0.5
>2000
119
46
5.4, 2
Silvery-gray Hair
Hair microscopy
No
Normal
Yes, first cousins
Fever Splenomegaly
Hepatomegaly
Seizure Pneumonia
Yes, first cousins
Fever Splenomegaly
Hepatomegaly
Seizure Diarrhea
Edema
Consanguinity
Clinical manifestations
Patient 2
Male
Female
9 months
16 months
Yes, the first child died No
at 2 months
Patient 1
Gender
Age
Familial disease
Characteristics
TABLE 1 Characteristics of Patients With Primary HLH.
Patient 4
Present
46 XY
13
43
998
—
100
0.28
251
460
235
0.6
3279
74
38
0.6, 0.1
No
Normal
Yes, first cousins
Fever Splenomegaly
Male
6 months
No
Patient 5
Present
46 XX
24
48
1150
26/31
Present
46 XY
13
32
360
—
18
46
1150
6.3/26.6
86
0.08
43
755
150
1.2
650
35
40
1.5, 0.3
No
Normal
Female
12 years
Yes, the first
child died at
11 months
Yes, first cousins
Fever
Splenomegaly
Lymphadenopathy
Patient 6
Present
46 XX
(Continued on next page)
Yes, first cousins
Yes, first cousins
Fever Splenomegaly
Fever Splenomegaly
Hepatomegaly
Hepatomegaly
Seizure Cranial
nerve palsy Left
hemiplegia
Yes
Yes
Abnormal, compatible Abnormal, compatible
with GS2
with GS2
71
90
0.53
0.01
51
38
750
392
—
—
0.92
1.85
300
4660
247
51
227
41
4,2
1.5, 0.2
Male
Female
5 months
5 months
Yes, the first child died No
at 10 months
Patient 3
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Normal
HLH-2004
Live in 2nd remission Live in remission after
1 year; waiting for
after 1.5 years;
SCT (no available
history of relapse in
donor yet)
maintenance phase
of HLH-2004
protocol; then on
more
immunosuppressive
treatment; waiting
for SCT (no available
donor yet)
Brain MRI
Specific treatment
Outcome
Abnormal
enhancement in
white matter
Steroids, CSA, VP16,
IVIG
Normal
Normal
Not done
Patient 4
HLH-2004 SCT (cord
blood-, unrelated, 1
antigen mismatched
donor)
Dead after 4.5 months Dead after 6 months;
post-SCT
history of recurrent
HLH
Cerebral atrophy
Abnormal
Normal
Not done
Patient 3
Live at 2 years
post-SCT
HLH-2004 SCT
(HLA-identical
sibling donor)
RAB27A mutation,
exon 5, A→G
(S115G)
Normal
Cerebral atrophy,
hypodense lesions
in white matter
—
Patient 5
Dead after 5
years; history
of progression
to T-cell ALL
after 2 years;
and dead due
to relapse of
ALL, sepsis
and DIC
despite
chemotherapy
(no donor at
that time)
Steroids, CSA,
VP-16, 6MP,
MTX
Normal
Normal
Cerebral atrophy
Not done
Patient 6
Note. PT = prothrombin time; PTT = partial thromboplastin time; LDH = lactate dehydrogenase; CSF = cerebrospinal fluid; CSA = cyclosporine; IVIG = intravenous
immunoglobulin; VP-16 = etoposide; 6MP = 6-mercaptopurine; MTX = methotrexate; SCT = stem cell transplantation; GSII = Griscelli syndrome type II; ALL = acute
lymphoblastic leukemia; DIC = disseminated intravascular coagulation.
HLH-2004
—
Normal
Cerebral atrophy
CSF analysis
Brain CT scan
Normal
Normal
RAB27A mutation,
Not done
exon 3, A→G (D74G)
Patient 2
Molecular study
Patient 1
Characteristics of Patients With Primary HLH (Continue).
Characteristics
TABLE 1
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Primary Hemophagocytic Lymphohistiocytosis
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survivors [10, 12]. The neurological complications in GS-2 probably develop in association with the hemophagocytic syndrome itself; therefore, timely initiation of HLH
therapy is imperative to decrease the risk of fatal outcome and long-term HLH-related
neurological sequelae.
Genetic defects leading to hemophagocytic syndromes have recently been described in familial cases of HLH. Therefore, making a definite diagnosis confirmed by
gene mutation studies is helpful to provide genetic counseling and prenatal diagnosis
and, more important, dictate the need for HSCT later in the patient’s course [1]. However, treatment should not be delayed in patients with familial disease or molecular
diagnosis, and patients with severe and persistent, or reactivated, disease pending the
results of gene mutation studies.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the
content and writing of the paper.
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2010;55:725–726.
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