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