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Clinical and Laboratory Observations

Erdheim-Chester Disease in Childhood: A Challenging Diagnosis and Treatment

Tran, Tu-Anh MD, PhD; Fabre, Monique MD; Pariente, Daniele MD; Craiu, Irina MD; Haroche, Julien MD, PhD; Charlotte, Frederic MD; Eid, Pierre MD, PhD; Durrbach, Antoine MD, PhD; Taoufik, Yassine PD, PhD; Kone-Paut, Isabelle MD

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Journal of Pediatric Hematology/Oncology: October 2009 - Volume 31 - Issue 10 - p 782-786
doi: 10.1097/MPH.0b013e3181b76827
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Erdheim-Chester disease (ECD) is a rare, non-Langerhans systemic histiocytosis of unknown origin.1 It is characterized by xanthomatous or xanthogranulomatous infiltration of tissues by spumous histiocytes, a CD68 positive, CD1a negative, and S100-protein negative phenotype (in 50% of cases), and the presence of pathognomonic Touton giant cells.1 To date, about 250 cases have been reported.1–3 ECD mainly occurs in adults and involves bilateral symmetric sclerosis of the metaphyseal regions of long bones and infiltration of other organs. Its diverse presentations depend on the organ involved1: exophthalmos, diabetes insipidus, xanthelasma, interstitial lung disease, bilateral adrenal enlargement, retroperitoneal and perirenal fibrosis, and/or ureteral stenosis, renal impairment, testis infiltration, and central nervous system and/or cardiovascular involvement. ECD is rare in children, with only 5 cases reported.4–10 There is no standard treatment and 60% of adult patients die within 32 months of presentation.1 Treatment options include corticosteroids, chemotherapy, radiotherapy, surgery, and immunotherapy.1 Interferon-α (IFN-α) has been increasingly used for adult ECD.11,12 Here, we report a case of ECD in a 10-year-old girl with visceral and bone involvement in whom treatment with IFN-α was successful within 6 months.


A 10-year-old girl was followed up for 3 years for daily fever spikes of up to 40°C. She was initially admitted to our hospital, at 7-years-old, for recurrent fever. Clinical examination revealed hepatosplenomegaly. Biologic investigation showed inflammatory syndrome with an erythrocyte sedimentation rate (ESR) of 105 mm/h (N <10) and a C-reactive protein (CRP) level of 97 mg/L (N <5 mg/L). Other laboratory tests, including liver tests, were normal. An abdominal ultrasound and a computed tomography scan showed multiple enlarged peritoneal and retroperitoneal lymph nodes. Bone marrow aspiration was normal. Histologic analysis of a biopsied lymph node indicated a reactive adenitis with fibrosis consistent with an infection. Tc-99 m hydroxydiphosphonate bone scintigraphy was normal. Tests for infectious and autoimmune diseases were negative. The patient was treated with corticosteroids. Although the fever stopped, the hepatosplenomegaly and inflammatory parameters remained. One year later, when corticosteroids were discontinued, the symptoms reappeared and a bone defect was detected on chest x-ray in the 2 humeri, fibula, and in the first rib. There were also multiple osteolytic and osteosclerotic lesions in the femurs, tibias, and pelvis (Fig. 1). Bone biopsy analysis identified epithelioid granulomas, prompting the diagnosis of atypical bone sarcoidosis. Although a new abdominal ultrasound showed multiple micronodules in the liver, a liver biopsy indicated an active chronic liver disease with lymphocytic infiltration of the portal tract and septa and without abnormal cells. No treatment was given. A year later, fever resumed with headaches, fatigue, bone pain of the lower limbs, and growth retardation. Skeletal radiography showed an overall regression of osteolytic lesions but an increase in osteosclerotic lesions in the pelvis, lower limbs, and skull. Tc-99 m hydroxydiphosphonate bone scintigraphy was normal. A whole-body magnetic resonance imaging (MRI) showed hyperintensity of the skeletal bone marrow in T2-weighted images with fat suppression, retroperitoneal infiltration from the renal pedicles to the aortic bifurcation, and multiple adenomegalies (Fig. 2). Coronal T1-weighted MR images showed diffuse low-intensity signal in the metadiaphyses. Both T1-weighted and T2-weighted images showed heterogeneous signal intensity in the epiphyses. Computed tomography scan-guided pelvic bone biopsies identified pathognomonic ECD lesions within the bone marrow. One nodule comprised an infiltrate of eosinophilic and spumous macrophages and pathognomonic CD68+, CD1a- Touton giant cells intermixed with PS100+ dendritic cells and CD3+ T lymphocytes (Fig. 3). An epithelioid granuloma was also identified near this nodule. As atypical mycobacteria infection can present with the same clinical pictures as ECD,13 we performed investigations to rule out this etiology. Mycobacteria serology was negative. Atypical mycobacteria polymerase chain reaction analysis (M. tuberculosis complex, M. kansasii, M. avium-intracellulare complex, M. malmoense) in bone and liver biopsies were both negative. Genetic macrophage dysfunction was also examined. Lymphocytes of the patient normally produced IFN-γ in response to interleukin-12 (IL-12) and PMA+ ionomycin. Expression of IL-12R in the surface of lymphocytes was normal. Sequencing of all exons of IL-12Rβ did not show any gene mutation. Therefore the exploration of the IL-12/IFN-γ axis failed to show any genetic anomaly involved in the IFN-γ signaling pathway. The patient was treated with 3 million units of subcutaneous IFN-α2a thrice weekly. The fever disappeared after several weeks. ESR and CRP normalized after 4 months and a whole-body MRI showed normal liver and spleen volumes, significant regression of retroperitoneal infiltration, and altered bone marrow intensity, which looked more heterogeneous in T2-weighed images (Fig. 2). Treatment tolerance was excellent. At month 10, the patient experienced a relapse with fever, bone pain, hepatosplenomegaly, and increased blood inflammatory markers (ESR and CRP). IFN-α2a was increased up to 6 millions units 3 times a week without any efficacy before being stopped. Induction of chemotherapy was then started with vinblastin 6 mg/m2/wk during 6 weeks and corticosteroids (prednisone 2 mg/kg/d) during 1 month. When corticosteroids were stopped, symptoms reappeared. Chemotherapy was discontinued and prednisone was given at the dosage of 1 mg/kg/d with inability to decrease the doses. The presence of an induced antibody against IFN-α2a was suspected as the patient's serum was able to inhibit the IFN-α2a-induced STAT1 activation, by contrast to the control serum. Pegylated-IFN-α2b was then started at the dose of 50 μg/wk subcutaneously with efficiency. Prednisone was then gradually decreased without any clinical relapse. Currently, the patient is on 0.25 mg/kg/d of prednisone after 5 months treatment with pegylated-IFN-α2b.

A, Conventional radiograph of the skeleton shows a bone defect in the humerus and fibula, symmetric osteolytic and osteosclerotic lesions in the femurs and tibias. B, Computed tomographic scan shows multiple osteosclerotic lesions involving both the mediaphyseal and the epiphyseal regions of the femurs, tibias, and pelvis.
Whole-body magnetic resonance imaging. Before treatment: A, On coronal fat-suppressed T2-weighted images: symmetrical high-signal intensity in the bone marrow. B, Hepatosplenomegaly and infiltration of the retroperitoneum from renal pedicles to the aortic bifurcation and multiple adenomegalies. Four months after treatment with interferon-α: C, Decrease of the signal intensity in the bone marrow of the long bones. D, Complete regression of the hepatosplenomegaly and partial regression of the infiltration in the retroperitoneum.
Microscopic findings of bone biopsy: A, Diffuse infiltration of foamy histiocytes, which have round nuclei and vacuolated cytoplasms (×40) with (B) a Touton giant cell (arrow) with a ring of nuclei surrounding foamy cytoplasm (×40). C, Negative CD1a labeling of histiocytes (×10). D, Diffuse CD68 positivity of histiocytes (×20).


ECD occurs mainly in adults,1 with only 5 cases reported in children (Table 1). As systemic pediatric histiocytic diseases are generally viewed as Langerhans cell histiocytoses in children, ECD is usually not suspected upon the initial clinical, radiographic, and histological workup. Accordingly, the diagnosis may be delayed for years, which has also been observed in adults.1 Unlike in adults,1 there is a female predominance1,2 in pediatric cases (Table 1).

Clinical Features and Outcomes of 6 Reported Pediatric Patients

The initial clinical presentation may be variable in children (Table 1): diabetes insipidus, mandibular lesions, brain or neck masses, knee and elbow swelling, pain associated with fever or hepatosplenomegaly. However, the radiographic bone presentations are constant and similar in all cases and should raise suspicions of ECD. Only 50% of the bone involvement is symptomatic.1 Typical ECD exhibits bilateral and symmetric involvement of the long bones, predominating around the knee (lower femurs and upper tibiae).14 The upper limbs, axial skeleton, and flat bones are less frequently involved.14 However, skull, rib, mandibular, and vertebral involvement have been described in children (Table 1). ECD typically affects the metadiaphyseal regions of the long bones with lesions of osteosclerosis. Osteosclerosis of the cancellous bone is heterogeneous, with multiple lucent foci of less than 1 cm in diameter disseminated throughout the sclerotic bone.14 In our patient, there were some isolated osteolytic lesions in the long bone at different stages of evolution, possibly reflecting the recent involvement of histiocytes, giant cells, and unossified fibroses.4,15,16

In noninvasive MRIs of long bones, the normal fatty bone marrow of the diaphyseal and metaphyseal bone segments is typically replaced by a markedly low-intensity signal and a heterogeneous high-intensity signal on fat-suppressed T2-weighted images.14 MRI can also reveal mass formation in various tissues. In our case, the initial whole-body MRI was of interest, providing an inventory of all the bone and tissue lesions and allowing follow-up after therapy initiation.

Given its nonspecific clinical presentation, a diagnosis of ECD relies exclusively upon the correlation between radiographic and pathologic findings. Histology must be examined from a biopsy performed at a florid lesion. Histologically, the xanthogranulomatous lesions in ECD show medullary fibrosis and accumulated lipid-laden, non-Langerhans cell histiocytes that lack grooved nuclei. In our patient, we twice detected epithelioid granulomas in a bone biopsy, the first time falsely orienting the diagnosis toward an atypical bone sarcoidosis. The presence of epithelioid granulomas, which has been described,17 probably reflected immune dysfunction linked to ECD infiltration resulting from an abnormal interaction between T-lymphocytes and macrophages, similarly to the macrophage activation syndromes18,19; it was probably not ECD-specific.

No clinical trials have investigated treatments for ECD, and therapeutic options are based on anecdotal experience. Although corticosteroids are the traditional first-line treatment, they are generally ineffective or only transiently effective.1 Although corticosteroids may slow growth in children, their long-term use is necessary because no current treatments can cure ECD.4 Chemotherapy, for example, with vinca alkaloids, anthracyclin, or cyclophosphamide, has also been used, usually combined with steroids1; it can induce transient partial responses but is often ineffective.1 Radiation, methotrexate, cyclosporine, and azathioprine have not yielded sustained clinical responses.1 As IFN-α can modulate the maturation and activation of dendritic cells, affect the immune-mediated (eg, through natural killer cells) destruction of histiocytes, and inhibit proliferation, it has been used in adult ECD patients with success especially in ECD without central nervous system or cardiovascular involvement.11,12 In our case, the effect of IFN-α was significant and well tolerated, meaning that it can be used as a first-line therapy in pediatric ECD.

In summary, although exceptional in children, this disease should be evoked in the presence of non-Langerhans histiocytosis with typical bone lesions upon imaging. We have reported here the first pediatric ECD case successfully treated with IFN-α and propose of this treatment as a first-line therapy in children. Additional studies are needed to confirm our initial observation.


The authors thank Pr J. C. Piette, Internist in La Pitié-Salpêtrière hospital, Dr A. Miquel, radiologist in Bicêtre hospital, and Dr C. Picard in Necker-Enfants-Malades hospital, Paris, for their precious help. The authors also thank Dr R. Bourayou for his assistance in editing this manuscript.


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Erdheim-Chester disease; childhood; histiocytosis; interferon-α

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