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Vandœuvre-lès-Nancy, France

Strullu M.,University Paris Diderot | Caye A.,University Paris Diderot | Lachenaud J.,University Paris Diderot | Cassinat B.,University Paris Diderot | And 20 more authors.
Journal of Medical Genetics | Year: 2014

Background: Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia ( JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS. Methods and results: Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/ 12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/ JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation. Conclusions: JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.

Favier R.,Assistance Publique | Kheyar T.,Assistance Publique | Renolleau S.,Service de reanimation pediatrique | Tabone M.D.,Service dOnco Hematologie pediatrique | And 2 more authors.
Annales de Biologie Clinique | Year: 2012

We report a case of lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) in an 11 year old girl initially hospitalized for bleeding. The patient presented with petechia, persisting bleeding after tooth extraction performed two days before, nephritic syndrome (renal failure, proteinuria and macroscopic hematuria), severe anemia, thrombocytopenia, lymphopenia. The association of these abnormalities suggested LAHPS secondary to severe systemic lupus. Immediate treatment with fresh frozen plasma and intravenous immunoglobulins (400 mg/kg/5d) was started and followed by steroid (500 mg/d) and cyclophosphamide (800 mg/m 2) pulse therapy leading to rapid improvement of bleeding, renal involvement and prothrombin levels within 13 days. Lupus diagnosiswas confirmed by immunological investigations and renal biopsy. Two early relapses occurred despite adequate treatment. After a followup of two years, no further disease activity is noted while the patient is treated only by mycophenolate mofetil (1 200 mg/m2/d). LAHPS did not relapse during this follow-up.

Perez B.,University Paris Diderot | Perez B.,French Institute of Health and Medical Research | Mechinaud F.,Service dOncologie Hematologie Pediatrique | Galambrun C.,Service dHematologie pediatrique | And 20 more authors.
Journal of Medical Genetics | Year: 2010

Background: CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multiadaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types. Methods and results: CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype. Conclusion: A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.

Godot C.,Service dOnco Hematologie pediatrique | Patte C.,Institute Gustave Roussy | Blanche S.,Service dImmuno hematologie Pediatrique | Rohrlich P.,Hopital University | And 3 more authors.
Journal of Pediatric Hematology/Oncology | Year: 2012

Chronic HIV infection leads to increased risk of non-Hodgkin B-cell lymphoma. However, only few recent data are available about their current management and prognosis in HIV-infected children since the advent highly active antiretroviral therapy (HAART). This multicenter retrospective study describes the 12 cases of B-cell non-Hodgkin lymphoma diagnosed in HIV-infected children in France between 1996 and 2009. All children had moderate to severe immunosuppression and high viral load at the time of diagnosis. Nine children had extracerebral primary sites and 3 had a primary central nervous system lymphoma. Eight patients had Burkitt lymphoma; 4 had diffuse large B-cell lymphoma. Concomitantly with HAART, all children with extracerebral lymphoma received intensive chemotherapy according to LMB protocol, those with primary central nervous system lymphoma received high-dose methotrexate. No toxicity-related deaths occurred. Ten patients entered complete remission (CR), 2 died of tumor progression despite a second line of therapy. No relapses occurred after CR (median follow-up, 72 mo). Thus, prognosis of patients unresponsive to first-line lymphoma treatment remains poor, but relapse seems to be rare when CR is achieved. Children without severe comorbidities can tolerate intensive chemotherapy with a mandatory HAART treatment, taking into account drug interactions. Copyright © 2012 by Lippincott Williams &Wilkins.

Lebot A.-C.,Service dOnco Hematologie pediatrique | Pastorelli C.,Service dOnco Hematologie pediatrique | Tessier E.,Service dOnco Hematologie pediatrique | Edelga L.,Service dOnco Hematologie pediatrique | Rialland F.,Service dOnco Hematologie pediatrique
Soins Pediatrie/Puericulture | Year: 2015

Summary Each year in France, 500 children and their family are faced with a diagnosis of leukaemia. Their lives then become centred on this disease. From diagnosis to cure, and over the following years, a special relationship is established between the child, their family and the staff of the paediatric haemato-oncology department.

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