Unmistakable Morphology? Infantile Malignant Osteopetrosis Resembling Juvenile Myelomonocytic Leukemia in Infants

Strauss, Anne; Furlan, Ingrid; Steinmann, Sandra; Buchholz, B.; Kremens, Bernhard; Corbacioglu, Selim; Rajagopal, Revathi; Lahr, Georgia; Yoshimi, Ayami; Strahm, Brigitte; Niemeyer, Charlotte M.; Schulz, Ansgar

doi:10.1016/j.jpeds.2015.04.064

Cited by 18 publications

(19 citation statements)

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“…Conclusions regarding the optimal conditioning regimen are limited by small numbers, possible imbalances in disease severity between the arms, and differing approaches to pre‐HCT chemotherapy; the latter two potentially having a substantial impact on post‐HCT outcomes. Nevertheless, ASCT1221 is the first prospective trial wherein all transplanted patients were molecularly characterized and confirmed to have JMML, an important consideration given that there are known mimics of the disease, such as Wiskott–Aldrich Syndrome and Infantile Osteopetrosis …”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, ASCT1221 is the first prospective trial wherein all transplanted patients were molecularly characterized and confirmed to have JMML, an important consideration given that there are known mimics of the disease, such as Wiskott-Aldrich Syndrome 23 and Infantile Osteopetrosis. 24 In regards to disease severity, to date a consensus risk-stratification system for patients with JMML is lacking. High-risk features that have been reported in some cohorts include older age, 1,2,11,13,18 mutations in PTPN11, 11,13 presence of monosomy 7 or other cytogenetic abnormalities, 2,11,13 low platelet counts, 18,19 elevated HgbF, 1,18 increased blasts or an AML-like gene-expression profile, 1,13 DNA hypermethylation, 20,25,26 and the presence of more than one somatic mutation in genes such as SETBP1, SH2B3, ASXL1, JAK3, and others.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study

Dvorak

Satwani

Stieglitz

et al. 2018

Pediatric Blood & Cancer

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study

Dvorak

Satwani

Stieglitz

et al. 2018

Pediatric Blood & Cancer

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“…Auch hat die Befundkonstellation Hepatosplenomegalie, Leukozytose, Anämie und Thrombozytopenie, wie sie für die infantile Osteopetrose typisch ist, die Differenzialdiagnose einer Leukämie, z.B. der Juvenilen Myelo-Monozytären Leukämie (JMML) (36). Macrocephalus, Kraniosynostose und Hydrocephalus führten gelegentlich zu neurochirurgischen Interventionen, auch bevor die Diagnose Osteopetrose gestellt werden konnte.…”

Section: Diagnostik Und Genotyp-phänotyp-korrelationunclassified

Osteopetrose

Kornak¹,

Schulz²

2018

Osteologie

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ZusammenfassungUnter der Diagnose Osteopetrose wird eine heterogene Gruppe von seltenen monogenetischen Knochenerkrankungen zusammengefasst, die sich durch eine reduzierte Osteoklasten-Aktivität, eine gesteigerte Knochenmasse und eine gesteigerte Knochenbrüchigkeit auszeichnet. Die Osteopetrosen werden verursacht durch Mutationen in verschiedenen Genen, die in der Osteoklastogenese oder Osteoklasten-Funktion involviert sind. Durch den Verlust der Knochenresorption werden Knochenumbau und -neubildung beeinträchtigt, wodurch sich die Qualität und Architektur des Knochengewebes verschlechtert. Häufige klinische Zeichen sind Osteosklerose, Knochendeformitäten, hämatologische Insuffizienzen durch Verengung der Knochenmarkräume, Sehstörungen durch Verengung der Foramina nervi optici und andere neurologische Störungen. Bis auf eine X-chromosomale Form sind alle infantilen schweren Osteopetrosen autosomal rezessiv vererbt. Die rezessiven Formen verlaufen gewöhnlich ohne Behandlung tödlich im Säuglings- oder Kindesalter, wobei allerdings selten mildere klinische Verläufe als sog. Intermediäre Osteopetrose vorkommen. Die dominante Form ist assoziiert mit Mutationen im CLCN7-Gen und verläuft in der Regel milder. Die meisten schweren Osteopetrosen können durch eine allogene hämatopoetische Stammzelltransplantation (HSZT) behandelt werden, sofern sie Osteoklasten-autonome Ursachen haben und nicht mit einer primären neurologischen Komponente verbunden sind.

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“…And various types of immunodeficiency-Wiskott-Aldrich syndrome, leukocyte adhesion defect, and osteopetrosis-may mimic JMML. 33 The international consensus on current diagnostic criteria for JMML includes molecular genetics as a mandatory part of the workup (Table 2). …”

Section: Differential Diagnosesmentioning

confidence: 99%

Myelodysplastic and myeloproliferative disorders of childhood

Hasle

2016

Hematology

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Myelodysplastic syndrome (MDS) and myeloproliferative disorders are rare in children; they are divided into low-grade MDS (refractory cytopenia of childhood [RCC]), advanced MDS (refractory anemia with excess blasts in transformation), and juvenile myelomonocytic leukemia (JMML), each with different characteristics and management strategies. Underlying genetic predisposition is recognized in an increasing number of patients. Germ line GATA2 mutation is found in 70% of adolescents with MDS and monosomy 7. It is challenging to distinguish RCC from aplastic anemia, inherited bone marrow failure, and reactive conditions. RCC is often hypoplastic and may respond to immunosuppressive therapy. In case of immunosuppressive therapy failure, hypercellular RCC, or RCC with monosomy 7, hematopoietic stem cell transplantation (HSCT) using reduced-intensity conditioning regimens is indicated. Almost all patients with refractory anemia with excess blasts are candidates for HSCT; children age 12 years or older have a higher risk of treatmentrelated death, and the conditioning regimens should be adjusted accordingly. Unraveling the genetics of JMML has demonstrated that JMML in patients with germ line PTPN11 and CBL mutations often regresses spontaneously, and therapy is seldom indicated. Conversely, patients with JMML and neurofibromatosis type 1, somatic PTPN11, KRAS, and most of those with NRAS mutations have a rapidly progressive disease, and early HSCT is indicated. The risk of relapse after HSCT is high, and prophylaxis for graft-versus-host disease and monitoring should be adapted to this risk. Learning Objectives• To recognize the challenges in making a diagnosis of MDS in children • To know the different therapeutic strategies in low-grade and advanced MDS • To understand the genetics of JMML and how it may be used for treatment stratification Myelodysplastic and myeloproliferative disorders are rare in children and have different morphologic features, cytogenetic findings, prognostic factors, and therapeutic aims than in adults. Therefore, there is a need for a pediatric approach to the classification of these disorders 1 as integrated in the 2008 version of the World Health Organization classification 2 that recognizes the specific features of diseases in children vs those in adults (Table 1).The diseases are divided into low-grade myelodysplastic syndrome (MDS), advanced MDS, and juvenile myelomonocytic leukemia (JMML). The myeloid leukemia of Down syndrome represents a specific entity that should not be included in series of MDSs and will not be discussed in this review. There is an increasing recognition that more children have an underlying genetic predisposition for the development of MDS or JMML. For a more thorough overview, the reader is referred to several reviews published recently. 3-7Low-grade MDS MDS with less than 2% blasts in peripheral blood (PB) or less than 5% blasts in the bone marrow (BM) are classified as refractory cytopenia of childhood (RCC) or low-grade MDS.1,2 The majority of the children wit...

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Unmistakable Morphology? Infantile Malignant Osteopetrosis Resembling Juvenile Myelomonocytic Leukemia in Infants

Cited by 18 publications

References 13 publications

Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study

Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study

Osteopetrose

Myelodysplastic and myeloproliferative disorders of childhood

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