Clinical and Genetic Analysis of Unclassifiable Inherited Bone Marrow Failure Syndromes

Teo, Juliana; Klaassen, Robert J.; Fernandez, Conrad V.; Yanofsky, Rochelle; Wu, John; Champagne, Josette; Silva, Mariana; Lipton, Jeffrey H.; Brossard, Jossee; Samson, Yvan; Abish, Sharon; Steele, MacGregor; Ali, K.; Athale, Uma H.; Jardine, Lawrence; Hand, John P; Tsangaris, Elena; Odame, Isaac; Beyene, Joseph; Dror, Yigal

doi:10.1542/peds.2007-3415

Cited by 40 publications

(46 citation statements)

References 10 publications

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“…It can result from either inherited or acquired causes. Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan syndrome, and amegakaryocytic thrombocytopenia are the four major inherited causes of AA [8]. Acquired AA is now increasingly being recognized as an immune-mediated disorder.…”

Section: Discussionmentioning

confidence: 99%

Severe Aplastic Anemia Manifesting After Complete Remission of Acute Promyelocytic Leukemia: Is it a Fortuitous Association?

Handigund

Malur

Dhumale³

et al. 2012

Indian J Hematol Blood Transfus

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Acute leukemia, secondary myelodysplasia and paroxysmal nocturnal hemoglobinuria evolving from severe aplastic anemia (AA) following immunosuppressive therapy are well recognized. However, severe AA occurring after complete remission of acute promyelocytic leukemia (APL) has been documented only once in 2009. We report a case of 30-year-old male diagnosed with APL who achieved complete cytogenetic remission with all-trans retinoic acid based induction regimen and developed severe AA few months later during maintenance therapy.

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Section: Discussionmentioning

confidence: 99%

Severe Aplastic Anemia Manifesting After Complete Remission of Acute Promyelocytic Leukemia: Is it a Fortuitous Association?

Handigund

Malur

Dhumale³

et al. 2012

Indian J Hematol Blood Transfus

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“…It is often difficult to predict how children will tolerate this therapy, especially if they have other congenital anomalies, pre-existing organ dysfunction or decreased ability to tolerate toxic therapy, as seen in children with Fanconi anemia and dyskeratosis congenita. Those children with inherited bone marrow failure syndromes and even those with unclassifiable bone marrow failure syndromes may have a predisposition for other malignancies, the risk of which is not eliminated by HSCT [2].…”

Section: Discussionmentioning

confidence: 99%

“…This could be considered as an unclassifiable inherited bone marrow failure syndrome, which is associated with multilineage cytopenias with physical malformations [2]. It is difficult to know whether there is an underlying genetic abnormality that may be responsible for the progression to MDS or merely a coincidence as has been suggested by Sharathkumar [9].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, Passmore [4] described a small number of patients with MDS with an undiagnosed genetic syndrome with associated abnormalities including: short stature, microcephaly, developmental delay, xanthomata, and xanthogranulomata. There is growing evidence that there are patients with as of yet unclassified inherited bone marrow failure syndromes, which predispose them to MDS/AML or other malignancies [2].…”

Section: Discussionmentioning

confidence: 99%

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A Case of a Young Girl with Myelodysplastic Syndrome (MDS), Dysmorphic Features, Short Stature, and Developmental Delay – Is there a Link?

Parker¹,

Bassal²

2012

J Clin Case Rep

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Myelodysplastic Syndrome (MDS) is a problem of ineffective hematopoesis, due to a clonal disorder of the hematopoetic stem cells. MDS is rare in children and considered premalignant as it often progresses to leukemia over time. There are known inherited predisposing conditions to MDS that have been reported in the literature. We describe the case of a 12-year-old girl with multiple dysmorphic features, short stature, and developmental delay with a new diagnosis of MDS (RAEB) with no confirmed genetic diagnosis linking all these features together. We propose that her underlying syndromic diagnosis may have predisposed her to MDS.

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“…7 Patients were considered to have unclassified IBMFS if they did not fit the clinical, laboratory and genetic diagnostic criteria of known IBMFS. 7 The majority of these patients underwent extensive genetic testing, which was negative. Genetic testing was performed at the discretion of the referring physician.…”

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confidence: 99%

Response to comments from Drs. Alter and Rosenberg

Dror

Cada

2015

Haematologica

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We thank Drs. Alter and Rosenberg for their comments 1 on our paper 2 . In adults, and more so in children, the classifications of myelodysplastic syndrome (MDS) are still debated, and modifications are periodically proposed. Controversy prevails with regard to whether some MDS groups need to be combined together or further split, and whether some cases should be classified as MDS or acute myeloid leukemia (AML). The inclusion criteria of pediatric MDS vary in different published studies and sometimes are not precisely stated. In particular, there are no "standard definitions" of MDS in inherited bone marrow failure syndromes (IBMFS ). The advantage of the CCC classification is that it was designed to include all categories of MDS (de novo, therapy-related and syndrome-associated). In contrast to the WHO classification, the CCC classification includes the category of refractory cytopenia with ringed sideroblasts since despite its rarity, this cytopathology exists in children as evidenced by this series and other reports in the literature.6 Had we used the pediatric WHO MDS classification we could not have categorized either of our cases of refractory cytopenia with ringed sideroblasts. In addition, the significance of refractory cytopenia with dysplasia has not been systematically and thoroughly studied in IBMFS; therefore, this category was included in our classification while in the WHO classification it was omitted.The first component of the CCC classification refers to the etiology of MDS, which we termed "category". In our classification, the category can be general (e.g. syndromic MDS) or more specific (e.g. Fanconi anemia-associated MDS). We analyzed the differential risk of disease progression and survival among patients with various syndromic diagnoses.We used the diagnostic criteria for MDS published by Hasle and colleagues.4 This also applied to cases with refractory cytopenia. The only exception was a patient with constitutional trisomy 8, who led us to propose expansion of the published criteria. As explained in the Discussion, this patient clearly had MDS, since he had an MDS/AML predisposition syndrome (constitutional trisomy 8), progressive cytopenia and a hypercellular marrow. He had no prominent dysplasia, no ringed sideroblasts, no excess blasts, no cytogenetic abnormalities and no indication of any other dietary, metabolic or infectious etiologies that could account for the blood dyscrasia.With regard to the cases of unclassified IBMFS, we stated in the Online Supplementary Data that patients who fulfilled specific diagnostic criteria for an IBMFS were recruited by hematologists at each center submitting data to the registry.7 Patients were considered to have unclassified IBMFS if they did not fit the clinical, laboratory and genetic diagnostic criteria of known IBMFS.7 The majority of these patients underwent extensive genetic testing, which was negative. Genetic testing was performed at the discretion of the referring physician.As stated in the Methods of our paper, when we compared the ris...

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Clinical and Genetic Analysis of Unclassifiable Inherited Bone Marrow Failure Syndromes

Abstract: Unclassified inherited bone marrow failure syndromes are relatively common among the inherited bone marrow failure syndromes and present a major diagnostic and therapeutic dilemma.

Cited by 40 publications

References 10 publications

Severe Aplastic Anemia Manifesting After Complete Remission of Acute Promyelocytic Leukemia: Is it a Fortuitous Association?

Severe Aplastic Anemia Manifesting After Complete Remission of Acute Promyelocytic Leukemia: Is it a Fortuitous Association?

A Case of a Young Girl with Myelodysplastic Syndrome (MDS), Dysmorphic Features, Short Stature, and Developmental Delay – Is there a Link?

Response to comments from Drs. Alter and Rosenberg

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