title: Clinical and genetic analysis of unclassifiable inherited bone marrow failure syndromes.
abstract: 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.
authors.affiliation: Marrow Failure and Myelodysplasia Program, Division of Haematology, Research Institute, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada.
authors.forename: Juliana T
authors.initials: JT
authors.lastname: Teo
authors.forename: Robert
authors.initials: R
authors.lastname: Klaassen
authors.forename: Conrad V
authors.initials: CV
authors.lastname: Fernandez
authors.forename: Rochelle
authors.initials: R
authors.lastname: Yanofsky
authors.forename: John
authors.initials: J
authors.lastname: Wu
authors.forename: Josette
authors.initials: J
authors.lastname: Champagne
authors.forename: Mariana
authors.initials: M
authors.lastname: Silva
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Lipton
authors.forename: Jossee
authors.initials: J
authors.lastname: Brossard
authors.forename: Yvan
authors.initials: Y
authors.lastname: Samson
authors.forename: Sharon
authors.initials: S
authors.lastname: Abish
authors.forename: Macgregor
authors.initials: M
authors.lastname: Steele
authors.forename: Kaiser
authors.initials: K
authors.lastname: Ali
authors.forename: Uma
authors.initials: U
authors.lastname: Athale
authors.forename: Lawrence
authors.initials: L
authors.lastname: Jardine
authors.forename: John P
authors.initials: JP
authors.lastname: Hand
authors.forename: Elena
authors.initials: E
authors.lastname: Tsangaris
authors.forename: Isaac
authors.initials: I
authors.lastname: Odame
authors.forename: Joseph
authors.initials: J
authors.lastname: Beyene
authors.forename: Yigal
authors.initials: Y
authors.lastname: Dror
mesh_terms: D000741:Anemia, Aplastic / Q000453:epidemiology; D001855:Bone Marrow Diseases / Q000145:classification / Q000453:epidemiology / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D020732:Cytogenetic Analysis; D005260:Female; D006402:Hematologic Diseases; D006801:Humans; D007223:Infant; D008297:Male; D009436:Neural Tube Defects / Q000453:epidemiology; D009503:Neutropenia / Q000453:epidemiology; D010198:Pancytopenia / Q000453:epidemiology; D010641:Phenotype; D012042:Registries; D013577:Syndrome; D013921:Thrombocytopenia / Q000453:epidemiology