Published online July 1, 2008
PEDIATRICS Vol. 122 No. 1 July 2008, pp. e139-e148 (doi:10.1542/peds.2007-3415)

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ARTICLE

Clinical and Genetic Analysis of Unclassifiable Inherited Bone Marrow Failure Syndromes

Juliana T. Teo, MBBS, FRACP, FRCPA^a, Robert Klaassen, MD, FRCPC^b, Conrad V. Fernandez, Hon BSc, MD, FRCPC^c, Rochelle Yanofsky, MD, FRCPC^d, John Wu, MD, FRCPC^e, Josette Champagne, MD, FRCPC^f, Mariana Silva, MD, FRCPC^g, Jeffrey H. Lipton, MD, PhD, FRCPC^h, Jossee Brossard, MD, FRCPCⁱ, Yvan Samson, MD, FRCPC^j, Sharon Abish, MD, FRCPC^k, MacGregor Steele, MD, FRCPC^l, Kaiser Ali^m, Uma Athale, MD, FRCPCⁿ, Lawrence Jardine, BmS, MD, FRCPC^o, John P. Hand, MD, FRCPC^p, Elena Tsangaris, MSc, Sc^a, Isaac Odame, MB, ChB, MRCP, FRCPCH, FRCPath, FRCPC^a, Joseph Beyene, PhD, MSc, BSc^q and Yigal Dror, MD, FRCPC^a

^a Marrow Failure and Myelodysplasia Program, Division of Haematology/Oncology and Cell Biology Program, Research Institute, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario
^b Division of Haematology/Oncology, Children's Hospital of Eastern Ontario, Ottawa, Ontario
^c Division of Haematology/Oncology, Isaak Walton Killam Hospital for Children, Halifax, Nova Scotia
^d Division of Haematology/Oncology, CancerCare Manitoba, Winnipeg, Manitoba
^e Division of Haematology/Oncology, British Columbia Children's Hospital, Vancouver, British Columbia
^f Division of Haematology/Oncology, Hôpital Ste. Justine, Montréal, Québec
^g Department of Medicine, Queen's University, Kingston, Ontario
^h Department of Haematology, Princess Margaret Hospital, Toronto, Ontario
ⁱ Division of Haematology/Oncology, Centre U Sante de l'Estrie-Fleur, Sherbrooke, Quebec
^j Division of Haematology/Oncology, Centre Hospital University Quebec-Pav CHUL, Sainte-Foy, Quebec
^k Division of Haematology/Oncology, Montreal Children's Hospital, Montreal, Québec
^l Department of Medicine, Alberta Children's Hospital, Calgary, Alberta
^m Division of Haematology/Oncology, University of Saskatchewan, Saskatoon, Saskatchewan
ⁿ Division of Haematology/Oncology McMaster Children's Hospital/McMaster University Health Sciences Centre, Hamilton, Ontario
^o Children's Hospital of Western Ontario, London, Ontario
^p Division of Haematology/Oncology Janeway Child Health Centre, St. John's, Newfoundland
^q Population Health Sciences, Research Institute, The Hospital For Sick Children, Toronto, Ontario

OBJECTIVE. Unclassified inherited bone marrow failure syndromes are a heterogeneous group of genetic disorders that represent either new syndromes or atypical clinical courses of known inherited bone marrow failure syndromes. The relative prevalence of the unclassified inherited bone marrow failure syndromes and their characteristics and the clinical and economic challenges that they create have never been studied.

METHODS. We analyzed cases of inherited bone marrow failure syndrome in the Canadian Inherited Marrow Failure Registry that were deemed unclassifiable at study entry.

RESULTS. From October 2001 to March 2006, 39 of the 162 patients enrolled in the Canadian Inherited Marrow Failure Registry were registered as having unclassified inherited bone marrow failure syndromes. These patients presented at a significantly older age (median: 9 months) than the patients with classified inherited bone marrow failure syndrome (median: 1 month) and had substantial variation in the clinical presentations. The hematologic phenotype, however, was similar to the classified inherited bone marrow failure syndromes and included single- or multiple-lineage cytopenia, severe aplastic anemia, myelodysplasia, and malignancy. Grouping patients according to the affected blood cell lineage(s) and to the presence of associated physical malformations was not always sufficient to characterize a condition, because affected members from several families fit into different phenotypic groups. Compared with the classified inherited bone marrow failure syndromes, the patients with unclassified inherited bone marrow failure syndromes had 3.2 more specific diagnostic tests at 4.5 times higher cost per evaluated patient to attempt to categorize their syndrome. At last follow-up, only 20% of the unclassified inherited bone marrow failure syndromes were ultimately diagnosed with a specific syndrome on the basis of the development of new clinical findings or positive genetic tests.

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

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Key Words: unclassifiable inherited marrow failure • myelodysplastic syndrome • aplastic anemia

Abbreviations: IBMFS—inherited bone marrow failure syndrome • UC-IBMFS—unclassifiable inherited bone marrow failure syndrome • CIMFR—Canadian Inherited Marrow Failure Registry • C-IBMFS—classifiable inherited bone marrow failure syndrome

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Accepted Jan 14, 2008.

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