Bailey.Glen at 18:43, 3 November 2023

2023-11-03T18:43:53Z

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 ==Primary Author(s)*==
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 ==Notes==
 <nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

Bailey.Glen: Created page with "
==Primary Author(s)*== Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue,..."

2023-11-03T18:02:24Z

Created page with " ==Primary Author(s)*== Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue,..."

New page

==Primary Author(s)*==

Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.

__TOC__

==Cancer Category/Type==

Myelodysplastic Syndrome

==Cancer Sub-Classification / Subtype==

Refractory Cytopenia of Childhood

==Definition / Description of Disease==

Refractory Cytopenia of Childhood (RCC) is a low-grade MDS most common in childhood, which is characterized by <2% blood blasts and <5% bone marrow blasts and persistent cytopenia<ref>{{Cite journal|last=Hasle|first=H.|last2=Niemeyer|first2=C. M.|last3=Chessells|first3=J. M.|last4=Baumann|first4=I.|last5=Bennett|first5=J. M.|last6=Kerndrup|first6=G.|last7=Head|first7=D. R.|date=2003-02|title=A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases|url=https://pubmed.ncbi.nlm.nih.gov/12592323|journal=Leukemia|volume=17|issue=2|pages=277–282|doi=10.1038/sj.leu.2402765|issn=0887-6924|pmid=12592323}}</ref>. Since more than 80% RCC has a hypocellular bone marrow, it is important to distinguish RCC with aplastic anemia from other bone marrow failure disorders<ref>{{Cite journal|last=Niemeyer|first=Charlotte M.|last2=Baumann|first2=Irith|date=2011|title=Classification of childhood aplastic anemia and myelodysplastic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/22160017|journal=Hematology. American Society of Hematology. Education Program|volume=2011|pages=84–89|doi=10.1182/asheducation-2011.1.84|issn=1520-4383|pmid=22160017}}</ref>. Aplastic anemia is an autoimmune-mediated disorder, while RCC is caused by a clonal stem cell defect with the potential to progress to an advanced disease. The presence of micromegakaryocytes is a strong indicator of RCC. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment<ref name=":0">Arber DA, et al., (2016). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p106-109.</ref>.

==Synonyms / Terminology==

Refractory Cytopenia of Childhood (RCC)

==Epidemiology / Prevalence==

RCC accounts for 50% of all cases of MDS<ref name=":0" /> <ref>{{Cite journal|last=Passmore|first=S. Jane|last2=Chessells|first2=Judith M.|last3=Kempski|first3=Helena|last4=Hann|first4=Ian M.|last5=Brownbill|first5=Pat A.|last6=Stiller|first6=Charles A.|date=2003-06|title=Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival|url=https://pubmed.ncbi.nlm.nih.gov/12780790|journal=British Journal of Haematology|volume=121|issue=5|pages=758–767|doi=10.1046/j.1365-2141.2003.04361.x|issn=0007-1048|pmid=12780790}}</ref><ref>{{Cite journal|last=Germing|first=Ulrich|last2=Strupp|first2=Corinna|last3=Giagounidis|first3=Aristoteles|last4=Haas|first4=Rainer|last5=Gattermann|first5=Norbert|last6=Starke|first6=Carsten|last7=Aul|first7=Carlo|date=2012-06|title=Evaluation of dysplasia through detailed cytomorphology in 3156 patients from the Düsseldorf Registry on myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/22421409|journal=Leukemia Research|volume=36|issue=6|pages=727–734|doi=10.1016/j.leukres.2012.02.014|issn=1873-5835|pmid=22421409}}</ref>.

*Most common childhood MDS
*No significant sex predilection

==Clinical Features==

The clinical symptoms are usually related to cytopenia such as anemia, bleeding tendency, and infection. However, approximately 20% of patients have no clinical symptoms or signs<ref>{{Cite journal|last=Kardos|first=Gabriela|last2=Baumann|first2=Irith|last3=Passmore|first3=S. Jane|last4=Locatelli|first4=Franco|last5=Hasle|first5=Henrik|last6=Schultz|first6=Kirk R.|last7=Starý|first7=Jan|last8=Schmitt-Graeff|first8=Annette|last9=Fischer|first9=Alexandra|date=2003-09-15|title=Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7|url=https://pubmed.ncbi.nlm.nih.gov/12763938|journal=Blood|volume=102|issue=6|pages=1997–2003|doi=10.1182/blood-2002-11-3444|issn=0006-4971|pmid=12763938}}</ref>.

*Hemoglobin concentration: <10 g/dL AND
*Platelet count: <150 x109/L

==Sites of Involvement==

Peripheral blood and bone marrow

==Morphologic Features==

The main morphologic features of the peripheral blood smear and bone marrow are for the diagnosis of RCC<ref name=":0" />.
{| class="wikitable"
|+
!'''Categories'''
!'''Morphologic Features'''
|-
|Peripheral blood
|Anisopoikilocytosis and macrocytosis; neutropenia with pseudo-Pelger-Huet nulei, hypogranularity or agranularity,
|-
|Bone marrow aspirate/biopsy
|Erythropoiesis: immature erythroid precursors, nuclear budding, multinuclearity, internuclear bridging;

Graulopoiesis: pseudo-Pelger-Huet nulei, hypogranularity or agranularity, macrocytic bands;
Megakaryopoiesis: absent or very few, however, micromegakaryocyte is crucial for the diagnosis.
|}

==Immunophenotype==

CD61, CD41, von Willebrand factor are useful to help detect the micromegakaryocyte. No increase of CD34 staining should be observed, which indicates the progression of high grade MDS<ref name=":0" />.

==Chromosomal Rearrangements (Gene Fusions)==

No
==Characteristic Chromosomal Aberrations / Patterns==

Monosomy 7 (CCHMC), trisomy 8 and other abnormalities, including complex karyotypes.

Pictures are needed to be upload!! 

==Genomic Gain/Loss/LOH==

Monosomy 7 is the most frequent cytogenetic abnormality of RCC patients, followed by trisomy 8 and other abnormalities, including complex karyotypes<ref>{{Cite journal|last=Kardos|first=Gabriela|last2=Baumann|first2=Irith|last3=Passmore|first3=S. Jane|last4=Locatelli|first4=Franco|last5=Hasle|first5=Henrik|last6=Schultz|first6=Kirk R.|last7=Starý|first7=Jan|last8=Schmitt-Graeff|first8=Annette|last9=Fischer|first9=Alexandra|date=2003-09-15|title=Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7|url=https://pubmed.ncbi.nlm.nih.gov/12763938|journal=Blood|volume=102|issue=6|pages=1997–2003|doi=10.1182/blood-2002-11-3444|issn=0006-4971|pmid=12763938}}</ref><ref>{{Cite journal|last=Niemeyer|first=Charlotte M.|last2=Baumann|first2=Irith|date=2011|title=Classification of childhood aplastic anemia and myelodysplastic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/22160017|journal=Hematology. American Society of Hematology. Education Program|volume=2011|pages=84–89|doi=10.1182/asheducation-2011.1.84|issn=1520-4383|pmid=22160017}}</ref><ref>{{Cite journal|last=Gupta|first=Ruchi|last2=Harankhedkar|first2=Shivangi|last3=Rahman|first3=Khaliqur|last4=Singh|first4=Manish K.|last5=Chandra|first5=Dinesh|last6=Mittal|first6=Navkirti|last7=Gupta|first7=Anshul|last8=Nityanand|first8=Soniya|date=2018-10|title=Prevalence of Chromosome 7 Abnormalities in Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Single Center Study and Brief Literature Review|url=https://pubmed.ncbi.nlm.nih.gov/30369728|journal=Indian Journal of Hematology & Blood Transfusion: An Official Journal of Indian Society of Hematology and Blood Transfusion|volume=34|issue=4|pages=602–611|doi=10.1007/s12288-018-0941-1|issn=0971-4502|pmc=6186231|pmid=30369728}}</ref>.
==Gene Mutations (SNV/INDEL)==

*Mutations are less common than in adult MDS with a different profile
*Most frequent mutations: ''RAS/MAPK, SAMD9/SAMD9L, GATA2''<ref>{{Cite journal|last=Schwartz|first=Jason R.|last2=Ma|first2=Jing|last3=Lamprecht|first3=Tamara|last4=Walsh|first4=Michael|last5=Wang|first5=Shuoguo|last6=Bryant|first6=Victoria|last7=Song|first7=Guangchun|last8=Wu|first8=Gang|last9=Easton|first9=John|date=2017-11-16|title=The genomic landscape of pediatric myelodysplastic syndromes|url=https://pubmed.ncbi.nlm.nih.gov/29146900|journal=Nature Communications|volume=8|issue=1|pages=1557|doi=10.1038/s41467-017-01590-5|issn=2041-1723|pmc=5691144|pmid=29146900}}</ref><ref>{{Cite journal|last=Wlodarski|first=Marcin W.|last2=Hirabayashi|first2=Shinsuke|last3=Pastor|first3=Victor|last4=Starý|first4=Jan|last5=Hasle|first5=Henrik|last6=Masetti|first6=Riccardo|last7=Dworzak|first7=Michael|last8=Schmugge|first8=Markus|last9=van den Heuvel-Eibrink|first9=Marry|date=2016-03-17|title=Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents|url=https://pubmed.ncbi.nlm.nih.gov/26702063|journal=Blood|volume=127|issue=11|pages=1387–1397; quiz 1518|doi=10.1182/blood-2015-09-669937|issn=1528-0020|pmid=26702063}}</ref>.

===Other Mutations===
No

==Epigenomics (Methylation)==

No

==Genes and Main Pathways Involved==

*''RAS/MAPK'': involved in ''MAPK'' tyrosine Kinase pathway

*''SAMD9/SAMD9L'': involved in regulating the growth and proliferation and differentiation of cells
*''GATA2'': involved in regulating transcription of genes related with the development and proliferation of hematopoietic and endocrine cell lineages

==Diagnostic Testing Methods==

Bone marrow minimal histological criteria for refractory cytopenia of childhood<ref>Arber DA, et al., (2016). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p106-109.</ref><ref>{{Cite journal|last=Iwafuchi|first=Hideto|date=2018|title=The histopathology of bone marrow failure in children|url=https://pubmed.ncbi.nlm.nih.gov/29998978|journal=Journal of clinical and experimental hematopathology: JCEH|volume=58|issue=2|pages=68–86|doi=10.3960/jslrt.18018|issn=1880-9952|pmc=6413145|pmid=29998978}}</ref>. Refractory cytopenia of childhood is defined as persistent cytopenia with <5% blasts in bone marrow and <2% blasts in peripheral blood. The criteria of dysplasia must be fulfilled in ≥2 cell lineages or ≥10% of cells within one cell lineage on bone marrow aspirate smears. See table:
{| class="wikitable"
|+
!Cellularity
!Erythropoiesis
!Granulopoiesis
!Megakaryopoiesis
|-
|Variable
|A few clusters of ≥20 erythroid precursors.
Arrest in maturation, with increased number of proerythroblasts.

Increased number of mitoses.
|No minimal diagnostic criteria.
|Unequivocal micromegakaryocytes;
immunohistochemistry is obligatory (CD61, CD41, CD42b);

other dysplastic changes in variable numbers.
|}
In addition, RCC must be differentiated from aplastic anemia, bone marrow failure syndromes, infection, nutritional deficiencies, and metabolic diseases.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

*Diagnosis: <2% blood blasts and <5% bone marrow blasts and persistent cytopenia
*Prognosis: In RCC, patients with monosomy 7 have a higher probability of progression<ref>{{Cite journal|last=Passmore|first=S. Jane|last2=Chessells|first2=Judith M.|last3=Kempski|first3=Helena|last4=Hann|first4=Ian M.|last5=Brownbill|first5=Pat A.|last6=Stiller|first6=Charles A.|date=2003-06|title=Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival|url=https://pubmed.ncbi.nlm.nih.gov/12780790|journal=British Journal of Haematology|volume=121|issue=5|pages=758–767|doi=10.1046/j.1365-2141.2003.04361.x|issn=0007-1048|pmid=12780790}}</ref><ref>{{Cite journal|last=Pui|first=Ching-Hon|last2=Schrappe|first2=Martin|last3=Ribeiro|first3=Raul C.|last4=Niemeyer|first4=Charlotte M.|date=2004|title=Childhood and adolescent lymphoid and myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/15561680|journal=Hematology. American Society of Hematology. Education Program|pages=118–145|doi=10.1182/asheducation-2004.1.118|issn=1520-4391|pmid=15561680}}</ref><ref>{{Cite journal|last=Kardos|first=Gabriela|last2=Baumann|first2=Irith|last3=Passmore|first3=S. Jane|last4=Locatelli|first4=Franco|last5=Hasle|first5=Henrik|last6=Schultz|first6=Kirk R.|last7=Starý|first7=Jan|last8=Schmitt-Graeff|first8=Annette|last9=Fischer|first9=Alexandra|date=2003-09-15|title=Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7|url=https://pubmed.ncbi.nlm.nih.gov/12763938|journal=Blood|volume=102|issue=6|pages=1997–2003|doi=10.1182/blood-2002-11-3444|issn=0006-4971|pmid=12763938}}</ref>. Patients with trisomy 8 or a normal karyotype are unlikely to progress to advanced MDS.
*Therapeutic: Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for RCC patients. This treatment is suitable for patients with monosomy 7 or a complex karyotype in the early stage of the process. Some of the RCC patients benefit from immunosuppressive therapy, although it is unclear whether the immunosuppressive therapy has the risk of relapse long-term<ref>{{Cite journal|last=Hasegawa|first=Daisuke|last2=Manabe|first2=Atsushi|last3=Yagasaki|first3=Hiroshi|last4=Ohtsuka|first4=Yoshitoshi|last5=Inoue|first5=Masami|last6=Kikuchi|first6=Akira|last7=Ohara|first7=Akira|last8=Tsuchida|first8=Masahiro|last9=Kojima|first9=Seiji|date=2009-12|title=Treatment of children with refractory anemia: the Japanese Childhood MDS Study Group trial (MDS99)|url=https://pubmed.ncbi.nlm.nih.gov/19499580|journal=Pediatric Blood & Cancer|volume=53|issue=6|pages=1011–1015|doi=10.1002/pbc.22121|issn=1545-5017|pmid=19499580}}</ref><ref>{{Cite journal|last=Yoshimi|first=Ayami|last2=van den Heuvel-Eibrink|first2=Marry M.|last3=Baumann|first3=Irith|last4=Schwarz|first4=Stephan|last5=Simonitsch-Klupp|first5=Ingrid|last6=de Paepe|first6=Pascale|last7=Campr|first7=Vit|last8=Kerndrup|first8=Gitte Birk|last9=O'Sullivan|first9=Maureen|date=2014-04|title=Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood|url=https://pubmed.ncbi.nlm.nih.gov/24162791|journal=Haematologica|volume=99|issue=4|pages=656–663|doi=10.3324/haematol.2013.095786|issn=1592-8721|pmc=3971075|pmid=24162791}}</ref>.

==Familial Forms==

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==Other Information==

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==Links==

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==References==
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==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

HAEM4:Refractory Cytopenia of Childhood - Revision history

Bailey.Glen at 18:43, 3 November 2023

Bailey.Glen: Created page with " ==Primary Author(s)*== Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue,..."

Bailey.Glen: Created page with "
==Primary Author(s)*== Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue,..."