Erdheim Chester DiseaseErdheim Chester DiseasePaediatric casesPaediatric cases
Stéphanie Eyssette-GuerreauStéphanie Eyssette-GuerreauPédiatrie Générale Pédiatrie Générale Rhumathologie PédiatriqueRhumathologie PédiatriqueCHU LE KREMLIN BICETRECHU LE KREMLIN BICETRE
Rare form of non-Langerhans cell histiocytosis Rare form of non-Langerhans cell histiocytosis Unknown origin Unknown origin Xanthogranulomatous infiltration, spumous Xanthogranulomatous infiltration, spumous
CD68+ CD1a- histiocytes CD68+ CD1a- histiocytes Touton giant cellsTouton giant cells Heterogeneous systemic manifestationsHeterogeneous systemic manifestations Bilateral and symmetrical osteosclerosis in the Bilateral and symmetrical osteosclerosis in the
metaphyseal portions of long bones sparing the metaphyseal portions of long bones sparing the axial skeleton, hands and feet axial skeleton, hands and feet
Extraskeletal manifestationsExtraskeletal manifestations
Extraskeletal manifestationsExtraskeletal manifestations
ExophthalmosExophthalmos Diabetes insipidusDiabetes insipidus Xanthelasma Xanthelasma Interstitial lung disease Interstitial lung disease Bilateral adrenal enlargement Bilateral adrenal enlargement Retroperitoneal fibrosis with perirenal and ureteral Retroperitoneal fibrosis with perirenal and ureteral
obstruction, renal impairmentobstruction, renal impairment Testis infiltrationTestis infiltration Central nervous systemCentral nervous system Cardiovascular involvementCardiovascular involvement
Loddenkemper, 2008
Haroche, 2004
Adem, 2005
Haroche, 2007
Chung, 2005
Paediatric onsetPaediatric onset
ECD is a disease of the 5ECD is a disease of the 5thth decade decade
Rheumatology and oncology centers in France Rheumatology and oncology centers in France Three cases of ECD identified Three cases of ECD identified database MEDLINE: 5 patientsdatabase MEDLINE: 5 patients
First symptoms appear in a 17 months old girlFirst symptoms appear in a 17 months old girl Painful bone crisis of lower limbsPainful bone crisis of lower limbs Inflammatory biological syndrome Inflammatory biological syndrome Radiographies: metaphyseal long bone periostitisRadiographies: metaphyseal long bone periostitis Facial MRI shows thickening anterior wall of right maxillary sinus Facial MRI shows thickening anterior wall of right maxillary sinus Evoked diagnoses: infectious osteitis and LCH Evoked diagnoses: infectious osteitis and LCH Chemotherapy and corticoids do not permanently control Chemotherapy and corticoids do not permanently control
symptoms symptoms Recurrent painful bone crisis persist and become corticosteroids Recurrent painful bone crisis persist and become corticosteroids
dependentdependent At the age of three, headaches: intracranial hypertension without At the age of three, headaches: intracranial hypertension without
causescauses Diagnosis at the age of 4 after the biopsy of retro-orbital Diagnosis at the age of 4 after the biopsy of retro-orbital
infiltration because of right exophthalmos infiltration because of right exophthalmos Interferon Interferon αα (IFN (IFNαα), partially effective (good effectiveness on bone ), partially effective (good effectiveness on bone
pain but mild effectiveness on peri-orbital infiltration and pain but mild effectiveness on peri-orbital infiltration and headaches)headaches)
Patient n°1Patient n°1
Since age of 7, a young girl, recurrent fever, biological Since age of 7, a young girl, recurrent fever, biological inflammatory syndrome inflammatory syndrome
Hepatosplenomegaly, retroperitoneal infiltration and Hepatosplenomegaly, retroperitoneal infiltration and osteosclerosis of lower limbs, skull and pelvisosteosclerosis of lower limbs, skull and pelvis
Fewer biopsies (nodes, bone, and liver) without Fewer biopsies (nodes, bone, and liver) without diagnosis diagnosis
Corticoids, mild amelioration Corticoids, mild amelioration Diagnosis at the age of 10 years after a new bone biopsy Diagnosis at the age of 10 years after a new bone biopsy
with typical ECD results with typical ECD results INFINFαα with regression of biological inflammatory with regression of biological inflammatory
syndrome, hepatosplenomegaly, and retroperitoneal syndrome, hepatosplenomegaly, and retroperitoneal infiltrationinfiltration
Patient n°2Patient n°2
Touton giant cells
CD68+ staining
CD1a- staining
MRI total body
Retroperitoneal infiltrationAnd hepatosplenomegalyBone marrow T2 hypersignal
Bone CT
A 6 years old girl, diabetes insipidus, growth hormone deficiencyA 6 years old girl, diabetes insipidus, growth hormone deficiency Cerebral MRI: hypophyseal stalk short and thick with filling tissue Cerebral MRI: hypophyseal stalk short and thick with filling tissue
of indeterminate nature of indeterminate nature Recurrent purulent rhinopharyngitis, with at the age of 11, Recurrent purulent rhinopharyngitis, with at the age of 11,
shrinkage of external auditory canals, right transmission deafness shrinkage of external auditory canals, right transmission deafness and a tissue that infiltrate sphenoidal and maxillary sinusand a tissue that infiltrate sphenoidal and maxillary sinus
At 16 years, acute renal failure, retroperitoneal fibrosis with At 16 years, acute renal failure, retroperitoneal fibrosis with hydronephrosis hydronephrosis
Diagnosis made after sinusal biopsyDiagnosis made after sinusal biopsy Vinblastine and corticoids, then Purinethol with good effectiveness Vinblastine and corticoids, then Purinethol with good effectiveness Years after, asthenia, with recurrent rhinopharyngitis, infiltration Years after, asthenia, with recurrent rhinopharyngitis, infiltration
of temporal bone, and peri-splenic infiltrationof temporal bone, and peri-splenic infiltration In a second time, INFIn a second time, INFαα with good effectiveness on sinusal with good effectiveness on sinusal
symptomssymptoms
Cas n°3Cas n°3
Patient
Sex Age at onset (years)
A g e a t diagnosis (years)
Symptoms Bone pain
1 F 1.5 4 -Statural growth retardation-Exophthalmos
-Yes(lower limbs)
2 F 7 10 -Recurrent Fever -Hepatosplenomegaly-Retroperitoneal Infiltration
-No
3 F 6.5 16 -Diabetes insipidus-Growth hormone deficiency-Recurrent purulent Rhinopharyngitis -Retroperitoneal Fibrosis -Hydronephrosis with acute renal failure
-No
4 (Globerman)
M 6 7 -Neck mass-Diabetes insipidus-GH deficiency-Hyperprolactinemia
-No
5(Clerico)
F 13 14 -Fever-Omentum-breast-lungs
-Yes(knees and right elbow)
6(Nagatsuka)
F 13 13.5 -Epileptic attacks -Abdominal involvement
-Yes(jaws)
7(Joo)
F 10 10 -Fever, fatigue, weight loss -Yes(elbows and knees)
8(Kumandas)
M 4 10 -Diabetes insipidus-cerebellar syndrome-sellar cavity mass
-No
Radiography CT MRI Scintigraphy Histology Treatments
-left lower limb-radius, ulna
Not Done -Bone MRI: abnormality of tibial epiphysis-Abdominal MRI: normal
Metaphyseal tracer uptake
periorbital Infiltration typical histology
Corticoids chemotherapyIFNa
Typical Bone CT: gaps and bone sclerosis of metaphysis and epiphysis of long bones
-Bone MRI: T2 hypersignal bone marow, metadiaphysis T1 hyposignal
Normal Bonetypical histology
Corticoids IFNa
Normal Facial CT: maxillary sinus and nasal cavity infiltration
-Bone MRI: normal-Abdominal MRI: retroperitoneal fibrosis-Brain MRI:??
Normal Mucous membrane sinusal typical histology
Vinblastine Corticoids purinetholIFNa
-long bones sclerosis -skull
Mediastinum mass Lung infiltratreVertebral bodies, ribsLiver, kidney retroperitoneum
-Brain MRI: normal supraclavicular knee anklecalariumright tibia
Bonemediastinum
Surgery
-long bones lysis and sclerosis-skull
Bone CT: Femur, humerus, tibia lesions
-Brain MRI: multiple expansive lesions
-multiple s i t e s o f uptake
-Bone-Abdomen
ImmunoglobulinsChemotherapy/corticoidsSomatostatin
-Jaws-lower extremities
Bone CT: jaws, lower extremities
-Brain MRI: brain lesion NR -Mandibular lesions-Maxillary lesions
-Surgery
-Tibia and fibula -Bone scan: femur, tibia, fibula, radius, mandibule
-Bone MRI: T1 hyposignal, T2 heterogeneous
-long bones -Bone-Bone marrow
-prednisolone
-left femur -Bone scan: cranium, pelvis, left femur
Brain MRI: sellar cavity mass, hyposignal in basal ganglia, capsule and periventricular white matter-Bone MRI: T1 hyposignal and T2 hypersignal of femur
-cranium-pelvis-left femur
-Extra axial mass -Surgery-Steroid
EpidemiologyEpidemiology
Frequency of ECD compared to other forms of Frequency of ECD compared to other forms of histiocytosis is unknown but near 300 cases have histiocytosis is unknown but near 300 cases have been described in the literature been described in the literature
In the largest review of cases (59), the mean age at In the largest review of cases (59), the mean age at the time of diagnosis was 53 years with a slight the time of diagnosis was 53 years with a slight male predominancemale predominance
In the 8 paediatric cases, precocious onset is In the 8 paediatric cases, precocious onset is remarkable, and the age at diagnosis goes to 4 to remarkable, and the age at diagnosis goes to 4 to 16 years16 years
X-RaysX-Rays
Typical findings in 6 patients, one presented Typical findings in 6 patients, one presented asymmetric lesions and one patient had normal asymmetric lesions and one patient had normal bone radiographs bone radiographs
Other localisations like ribs, vertebrae and skull are Other localisations like ribs, vertebrae and skull are described in 4 of the patientsdescribed in 4 of the patients
Scintigraphs are normal in two patients Scintigraphs are normal in two patients Bone MRI : classical involvement in 4 patientsBone MRI : classical involvement in 4 patients In conclusion, bone lesions can be missing or be In conclusion, bone lesions can be missing or be
atypical, and bone MRI seems to be a more atypical, and bone MRI seems to be a more sensible exam to search lesions than Scintigraphysensible exam to search lesions than Scintigraphy
EtiopathogenesisEtiopathogenesis
Patients with both conditions, ECD and LCH, have been reported Patients with both conditions, ECD and LCH, have been reported suggesting ►links between the two diseasessuggesting ►links between the two diseases
Neoplastic or cytokine-driven reactive processes? Neoplastic or cytokine-driven reactive processes? Clonality has been confirmed in some cases of ECD whereas some articles Clonality has been confirmed in some cases of ECD whereas some articles
defend cytokine-driven reactive processesesdefend cytokine-driven reactive processeses High serum levels of IL-6 and IL-6 soluble receptor (sIL-6R) and high High serum levels of IL-6 and IL-6 soluble receptor (sIL-6R) and high
levels of bone turnover markers is found during the acute phase of the levels of bone turnover markers is found during the acute phase of the diseasedisease
Interleukin 1a (IL-1a), IL-1b, IL-2, and IL-8 all had raised expression Interleukin 1a (IL-1a), IL-1b, IL-2, and IL-8 all had raised expression compared with controls, consistent with monocyte activation compared with controls, consistent with monocyte activation
Various chemokines and interferon-Various chemokines and interferon-γγ –inducible 10-kd protein, which is –inducible 10-kd protein, which is specifically induced by interferon-specifically induced by interferon-γγ , and interleukin-6 and RANKL, which , and interleukin-6 and RANKL, which are both implicated in bone remodelingare both implicated in bone remodeling
Chemokine network, histiocyte activation and accumulation, autocrine Chemokine network, histiocyte activation and accumulation, autocrine loop loop
SymptomsSymptoms
Bone pain, most frequent symptom in adult (4 of the 8 patients)Bone pain, most frequent symptom in adult (4 of the 8 patients) Exophthalmos, retroperitoneal infiltrationExophthalmos, retroperitoneal infiltration Diabetes insipidus, growth hormone deficiency Diabetes insipidus, growth hormone deficiency ↑ (↑ (symptomatic contrary symptomatic contrary
to the adult)to the adult) ECD is a rare but classical cause of renal failure because of the ECD is a rare but classical cause of renal failure because of the
hydronephrosis secondary to the retroperitoneal infiltration hydronephrosis secondary to the retroperitoneal infiltration Heart’s involvement is frequent in adult and affects the aorta (“coated Heart’s involvement is frequent in adult and affects the aorta (“coated
aorta”) ►one third of the deaths related to this diseaseaorta”) ►one third of the deaths related to this disease No cardiac involvement in our 8 young patientsNo cardiac involvement in our 8 young patients No xanthelasma (11/59 in the Veyssier-Belot series) No xanthelasma (11/59 in the Veyssier-Belot series) Hepatosplenomegaly (rarely reported) Hepatosplenomegaly (rarely reported) Five of the 8 patients cerebral symptoms plus one with abnormal cerebral Five of the 8 patients cerebral symptoms plus one with abnormal cerebral
MRI MRI In the young patient, cerebral involvement is very frequent and brain MRI In the young patient, cerebral involvement is very frequent and brain MRI
seems to beseems to be interesting interesting because they can show asymptomatic lesions because they can show asymptomatic lesions
TreatmentsTreatments Corticoids, fewer chemotherapy, biphophonates and radiotherapyCorticoids, fewer chemotherapy, biphophonates and radiotherapy No randomised controlled trials No randomised controlled trials Cladribine (a purine analogue toxic to monocytes) : 2 patients, one of whom Cladribine (a purine analogue toxic to monocytes) : 2 patients, one of whom
responded responded INFINFαα (Braiteh in 2005 ,IFN (Braiteh in 2005 ,IFNαα was known to result in terminal differentiation of was known to result in terminal differentiation of
histiocytes and dendritic cells) Effective on exophthalmos, general signs, bone histiocytes and dendritic cells) Effective on exophthalmos, general signs, bone pains, bilateral hydronephrosis but not with severe exophthalmia and cerebral pains, bilateral hydronephrosis but not with severe exophthalmia and cerebral central infiltration central infiltration
Imatinib mesylate (Imatinib mesylate (a tyrosine kinase inhibitor, which selectively inhibits bcr-a tyrosine kinase inhibitor, which selectively inhibits bcr-abl, KIT and platelet-derived growth factor), abl, KIT and platelet-derived growth factor), very partial efficacityvery partial efficacity
One case of treatment of refractory ECD with double autologous One case of treatment of refractory ECD with double autologous hematopoietic stem cell transplantation reported hematopoietic stem cell transplantation reported
In our 8 patients, 3 underwent surgery, 6 steroids, 3 chemotherapy (always with In our 8 patients, 3 underwent surgery, 6 steroids, 3 chemotherapy (always with steroids) and three with IFNalpha. Variable outcome steroids) and three with IFNalpha. Variable outcome
INFINFαα can be considered as a first line treatment in multisystemic disease can be considered as a first line treatment in multisystemic disease
PrognosisPrognosis
In a review of 59 patients, Veyssier-Belot reported death In a review of 59 patients, Veyssier-Belot reported death related to disease in 59% of the cases, with an average related to disease in 59% of the cases, with an average survival of 32 months survival of 32 months
The most common causes of death were respiratory and The most common causes of death were respiratory and heart failures heart failures
In the same study, the authors suggested that patients with In the same study, the authors suggested that patients with ECD have a worse prognosis than patients with LCH ECD have a worse prognosis than patients with LCH
In our cases, prognosis seems to be less poor than In our cases, prognosis seems to be less poor than classically described in the literatureclassically described in the literature
Probably it’s because our patient do not have cardiovascular Probably it’s because our patient do not have cardiovascular involvement that make the gravity in the adults. Progress in involvement that make the gravity in the adults. Progress in the new treatment can helpthe new treatment can help
ConclusionsConclusions
Although exceptional, paediatric ECD can be evoked in Although exceptional, paediatric ECD can be evoked in case of NLH with long bone osteosclerosis and/or visceral case of NLH with long bone osteosclerosis and/or visceral involvementinvolvement
ECD seems to be a large clinical spectrumECD seems to be a large clinical spectrum Interest for Bone and total Body MRIInterest for Bone and total Body MRI Endocrine and cerebral involvementEndocrine and cerebral involvement Treatment needs to be considered case by case with special Treatment needs to be considered case by case with special
interest in IFNinterest in IFNaa Prognosis depends of disease localisations and their Prognosis depends of disease localisations and their
consequences consequences Physiopathology of histiocytes activation needs to be Physiopathology of histiocytes activation needs to be
elucidated to progress in the management of the diseaseelucidated to progress in the management of the disease