PEDIATRICS Vol. 122 No. 1 July 2008, pp. e139-e148 (doi:10.1542/peds.2007-3415)
ARTICLE |
Clinical and Genetic Analysis of Unclassifiable Inherited Bone Marrow Failure Syndromes
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
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
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.
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
Inherited bone marrow failure syndromes (IBMFSs) are a heterogeneous group of genetic disorders characterized by varying degrees of peripheral cytopenias, resulting from inadequate hematopoiesis.1,2 These disorders may involve multiple lineages (eg, Fanconi anemia) or predominantly single cytopenias (eg, Kostmann neutropenia, Diamond-Blackfan anemia) and, hence, have been traditionally classified according to the affected lineage(s). Disorders involving multiple lineages may present with single cytopenia before progressing to pancytopenia. The composition and severity of physical malformations varies widely within each syndrome, and the complete phenotypes of some IBMFSs remain unclear. There is also a substantial overlap in hematologic and physical manifestations between the disorders. Furthermore, because characteristic hematologic abnormalities or physical malformations can develop later in life and are not always congenital (eg, nail dystrophy in dyskeratosis congenita), the diagnostic criteria do not always exist at presentation. For these reasons, the diagnosis of a specific IBMFS in an individual patient is frequently difficult, which may lead to misdiagnosis and improper treatment.
Individual cases of IBMFSs that could not be categorized as having a known syndrome have been reported and were partially reviewed elsewhere.2 Such cases may lead to multiple invasive and costly investigations, delay in diagnosis, misdiagnosis, inappropriate treatment, or uncertainties with regard to the natural history. The prevalence and characteristics of unclassified IBMFSs (UC-IBMFSs) have never been prospectively studied, and the magnitude of the problem is unknown. The Canadian Inherited Marrow Failure Registry (CIMFR) was established in January 2001.3 It is a prospective, multicenter study that intends to register all patients with IBMFSs in Canada. The CIMFR aims to investigate the prevalence, clinical phenotype, and the natural history of IBMFSs. Herein, we analyzed 39 cases with UC-IBMFS at the time of enrollment on the CIMFR. We asked whether the cases can be grouped according to their hematologic and nonhematologic manifestations to identify patterns and propose guidelines for workup. The clinical, laboratory, and genetic workup were compared with cases of classified IBMFSs (C-IBMFSs), and the diagnostic challenges are described.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
Registry
The CIMFR study was approved by the institutional ethics board of all of the participating institutions, which include 15 of 17 pediatric tertiary care centers across all provinces in Canada. Patients who received a diagnosis of an IBMFS (criterion 2 in Table 1) were recruited by hematologists at each center. Published diagnostic criteria were used for the specific syndromes.1,2 Patients with the following groups of disorders were excluded: (1) leukemia with an inherited syndrome not associated with antecedent marrow failure; (2) acquired aplastic anemia (patients who have aplastic anemia and do not fulfill the criteria in Table 1); (3) de novo myelodysplastic syndrome; and (4) de novo leukemia. Written consent was obtained from recruited patients or guardians.
|
Information collected on standardized forms included demographics, diagnosis, symptoms, family history, physical malformations, laboratory tests and imaging studies, treatment, and outcomes. Outcomes recorded included severe cytopenia(s), aplastic anemia, myelodysplasia, marrow cytogenetic abnormalities, leukemia, solid tumors, marrow transplantation, and death. Follow-up information was collected on an annual basis. The data collected were managed by the central CIMFR office located at the Hospital for Sick Children (Toronto, Ontario, Canada).
Data Analysis
We analyzed the clinical phenotype and short-term outcome of patients with UC-IBMFSs on the registry as of March 2006, by using data from the CIMFR database. The criteria for the diagnosis of UC-IBMFSs are summarized in Table 1. We performed descriptive analysis. Student's t test was used to determine the statistical significance of differences between the UC-IBMFSs and the classifiable IBMFSs (C-IBMFSs) for continuous variables, and Fisher's exact test was used to compare categorical variables. P < .05 was considered statistically significant. Statistical analyses were conducted by using SAS 9.1 (SAS Institute, Inc Cary, NC). Probability of death according to age was estimated by using a Kaplan-Meier plot.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
General Characteristics of the Patients With UC-IBMFSs
Of the 162 patients enrolled on the CIMFR study as of March 2006, 39 (24%) were registered in the category of UC-IBMFSs at study entry. The patients were from 30 families, including 5 families of affected siblings and 7 families with affected members in at least 2 successive generations. Of the 37 patients who had UC-IBMFSs and for whom family history was available, 23 (63%) had a first-degree relative affected with a bone marrow failure.
There was no significant difference between the ratio of male to female patients with UC-IBMFSs (23:16) and with C-IBMFSs (56:64) (P = .18). For 3 of the 162 cases on the registry, the gender of the patients was unknown.
All patients had their diagnosis of an IBMFS made between 1995 and 2006. The patients with UC-IBMFSs presented with their disease and received a diagnosis at an older age than the patients with C-IBMFSs. The median age at presentation with hematologic or nonhematologic manifestations was 9 months (range: 0 to 10 years, 11 months) compared with 1 month (range: 0–14 years) in the C-IBMFS group (P = .04). The diagnosis of bone marrow failure was made at a median age of 4.2 years (range: 0.0–30.1 years), compared with 12 months (range: 0.0–16.8 years) in the C-IBMFS group (P = .01). The median age at study entry was 7.25 years (range: 0.19–34.00 years), and median age at last follow-up was 8.46 years (range: 0.25–35.00 years). The median follow-up of the patients with UC-IBMFS on the CIMFR was 16 months (range: 0–45 months).
General Clinical Manifestations of the UC-IBMFSs
Manifestations related to cytopenias were the most common mode of presentation (25 [64%] patients). Physical malformations led to a diagnosis of an IBMFS for 12 patients. In 2 cases, the diagnosis was made on family screening.
The most common hematologic abnormality was pancytopenia (20 patients). Other hematologic abnormalities included isolated anemia (3 patients), isolated neutropenia (4 patients), and isolated thrombocytopenia (12 patients). At a median age of 8.4 years and a median of 21 months after study entry, 7 patients developed severe aplastic anemia, 2 patients progressed to myelodysplasia, 1 patient progressed to acute lymphoblastic leukemia, 1 patient progressed to lymphoma, 1 patient progressed to multifocal hemangioendothelioma, and 8 patients died.
Identifiable IBMFSs are mainly classified according to the predominant cytopenia and the characteristic extrahematologic manifestations.2 On the basis of hematologic manifestations and the presence or absence of associated physical malformations, we divided the patients with UC-IBMFSs into 8 groups to characterize the conditions. In a limited number of multiplex families and in cases in which a specific diagnosis was ultimately established, this also enabled us to correlate such grouping with the specific condition:
- Group 1: Multilineage cytopenias with physical malformations.
- Group 2: Multilineage cytopenias without physical malformations.
- Group 3: Isolated anemia with physical malformations.
- Group 4: Isolated anemia without physical malformations.
- Group 5: Isolated neutropenia with physical malformations.
- Group 6: Isolated neutropenia without physical malformations.
- Group 7: Isolated thrombocytopenia with physical malformations.
- Group 8: Isolated thrombocytopenia without physical malformations.
Group 1: Multilineage Cytopenias With Physical Malformations
In this largest group of UC-IBMFSs, 15 patients had multilineage cytopenias and physical malformations (Table 2). Two thirds were female. The patients belonged to 13 families. Parental consanguinity was present in 3 patients, and 6 patients had affected siblings. Median age at presentation with either hematologic or nonhematologic manifestations was 5 months (range: 0.0–to 8.5 years).
|
Peripheral blood cytopenia was apparent by 12 months of age in 8 (53%) patients (Table 3). Similar to patients with C-IBMFS with pancytopenia, most patients had high fetal hemoglobin levels and red blood cell mean corpuscular volume for their age (Table 3). Bone marrow testing was done in all cases. The most common abnormality was hypocellularity either at diagnosis (9 patients) or at follow-up (1 patient). As also seen in C-IBMFSs, sometimes the bone marrow specimens were normocellular (1 patient) or hypercellular (1 patient) or only 1 cell line was found reduced (1 patient). Six patients developed severe aplastic anemia according to previously published criteria4 (Table 3). One patient developed trilineage dysplasia with excess blasts and complex clonal marrow cytogenetic abnormality consistent with 46, XY,–7/46, XY,–7q 1.5 years after presentation.
|
The patients in this group had a variety of extrahematologic manifestations; however, these malformations appeared in multiple combinations, and no clear patterns were identified (Table 4). Five patients died at follow-up either as a result of their disease (1 patient) or after bone marrow transplantation (4 patients).
|
Group 2: Multilineage Cytopenias Without Physical Malformations
Five patients had multilineage cytopenia without physical malformations; all of them were boys. Two patients were a father and a son. In another case, the mother and a sister were reported as being affected, but they were not enrolled on the study. There were no consanguineous parents in this group. This suggests an autosomal dominant inheritance pattern in at least 2 of the 4 families in this group (Table 2).
Median age at presentation was 2 months. Two patients who belonged to the same family had high mean corpuscular volume and fetal hemoglobin for age (Table 3). Bone marrow examination showed a hypocellular specimen in 4 of the 5 cases. One patient had erythroid hypoplasia despite peripheral blood pancytopenia, although his father had general reduction in bone marrow cellularity. Three patients died at follow-up: 1 of non-Hodgkin's lymphoma, 1 of sepsis, and 1 at home of unknown cause (Table 4).
Group 3: Isolated Anemia With Physical Malformations
One male patient in this group eventually received a diagnosis of Diamond-Blackfan anemia. The patient was incidentally noted to have macrocytic anemia with relative reticulocytopenia at 3 years of age, when he was evaluated for growth failure and subtle nonspecific physical malformations. The diagnosis of Diamond-Blackfan anemia could not be initially established because of the late presentation, the absence of family history, and lack of positive genetic testing; however, 3 years after study entry, red blood cell adenosine deaminase levels were found to be high, and a diagnosis of Diamond-Blackfan anemia was established. Mutation analysis of the RPS19 gene was negative (Tables 2–4).
Group 4: Isolated Anemia Without Physical Malformations
There were 2 female patients from 2 different families in this group. One patient presented at birth; the other had severe chronic anemia from early childhood.
In 1 case, the marrow erythroid precursor cells were dysplastic with vacuolated forms, and the patient had a transient prominent increase in the number of ring sideroblasts in the erythroid precursors in bone marrow between 10 years and 14 years of age. Metabolic workup and mitochondrial DNA deletion analysis was negative. It is noteworthy that the other patient in this group, who did not have prominence of marrow ringed sideroblasts, had increased erythropoiesis on the first bone marrow testing at the age of 2 months; however, 2 subsequent bone marrow tests revealed pure red blood cell aplasia, and a diagnosis of Diamond-Blackfan anemia was ultimately made. This might reflect an initial phase of erythroid hyperplasia as a compensatory mechanism, which is of limited capacity and duration (Tables 2–4).
Group 5: Isolated Neutropenia With Physical Malformations
There were 2 brothers in this group. They had an additional affected brother who did not have physical malformations and was assigned to group 6. The patients presented at age 5 years and 12.6 years, respectively, with moderate neutropenia. Both had previously received a diagnosis of autism, strabismus, and delayed speech development. The clinical manifestations were not typical of severe congenital neutropenia or Kostmann neutropenia or the reported cases caused by WASP or GLI1 mutations (Tables 2–4).
Group 6: Isolated Neutropenia Without Physical Malformations
There were 3 patients in this group. One female child had a brother with fulminant hepatic failure and severe aplastic anemia (group 1). The parents were healthy and nonconsanguineous. This patient had mild neutropenia with a hypocellular bone marrow at study entry and developed acute lymphoblastic leukemia 28 months later.
One patient had a significant family history of monosomy 7 and leukemia in successive generations without consanguinity, which suggested an autosomal dominant disease. The child was found to have neutropenia and monosomy 7 at routine checkup at the age of 9 years, 8 months. He had high mean corpuscular volume but normal fetal hemoglobin. The later features are not consistent with severe congenital neutropenia, and ELA2 gene sequencing was normal. The third patient had moderate neutropenia and has 2 brothers who have neutropenia, autism, and speech delay and were classified as having group 5 disease (Tables 2–4).
Group 7: Isolated Thrombocytopenia With Physical Malformations
There were 2 male patients in this group. In both cases, bone marrow aspirates did not show reduced megakaryopoiesis; however, antiplatelet antibodies were negative, and the patients responded to platelet transfusions but not to prednisone or intravenous 
globulins. One patient had multiple physical malformations, including facial dysmorphism, oligodontia, patent ductus arteriosus, atrial septal defect, obstructive hydrocephalus, and developmental delay. The hypocellular bone marrow, reduced in vitro colony growth of marrow progenitors, increased marrow megakaryocytes, normal platelet morphology, and low reticulated platelet count were consistent with bone marrow failure with ineffective platelet production. Cytogenetic analyses of the bone marrow and peripheral blood lymphocytes as well as subtelomeric fluorescent in situ hybridization analysis of chromosome 11 were normal, which did not support a diagnosis of Paris-Trousseau/Jacobsen syndrome.5 The second patient had severe thrombocytopenia and intermittent severe gastrointestinal bleeding from birth. This patient lacked a family history and the physical stigmata of the other patient in this group but developed multifocal hemagioendothelioma at 4 years of age (Tables 2–4).
Group 8: Isolated Thrombocytopenia Without Physical Malformations
Nine patients had isolated thrombocytopenia. All had positive family histories in their first-degree relatives in at least 2 successive generations, suggesting autosomal dominant inheritance. Of the families in which the information about consanguinity was available, 1 pair of parents was consanguineous. Of note was the absence of myelodysplastic syndrome or acute myeloblastic leukemia in the affected family members. As of the last CIMFR follow-up, the patients in this subgroup were still assigned to the UC-IBMFS group. The differential diagnosis in these families includes MASTL-related autosomal dominant thrombocytopenia and AML1-related familial thrombocytopenia with predilection to acute myeloblastic leukemia (Tables 2–4).
Follow-up Diagnoses
On follow-up, specific diagnoses were assigned to 8 of the 39 patients with UC-IBMFSs on the CIMFR. Two siblings from group 1 initially presented with pancytopenia but later developed pancreatic lipomatosis by computed tomography of the pancreas and metaphyseal dysplasia. At this stage, they were diagnosed with Shwachman-Diamond syndromes, although sequencing of all 5 exons of the SBDS gene was normal. Two other siblings from group 1 were found to have biallelic mutations in the SBDS gene, and combined with the hematologic abnormalities and short stature in 1 of them, the diagnosis of Shwachman-Diamond syndrome was made. Before the genetic testing, these siblings did not receive a diagnosis of pancreatic insufficiency by the treating center because of lack of clinical findings. One patient from group 1 had failure to thrive, retinal dystrophy, developmental delay, thoracic kyphosis, hypotonia, and microcephaly and was found to have biallelic COH1 mutations, and a diagnosis of Cohen syndrome was made. Another patient from group 1 developed oral leukoplakia, and a clinical diagnosis of probable dyskeratosis congenita was made; however the patient lacked any nail or skin abnormalities and tested negative for TERC, TERT, DKC1, and NOP10. Two other patients, 1 from group 3 and 1 from group 4, ultimately received a diagnosis of Diamond-Blackfan anemia on the basis of high red blood cell adenosine deaminase levels or clinical course.
Diagnostic Tests and Cost
All patients underwent extensive diagnostic testing at the discretion of the treating physicians. To assess the cost of the diagnostic workup of a UC-IBMFS case, we collected information from the various laboratories about the cost of genetic tests and tests done in special referral laboratories (eg, red blood cell adenosine deaminase), which had been done in our cohort to establish a diagnosis (Table 5). We excluded from the cost analysis (1) nonspecific laboratory tests (eg, pancreatic enzymes; platelet function or imaging of the heart, abdomen, and skeleton), (2) tests done in research laboratory without a cost (eg, TERT, NOP10), (3) tests done to make a diagnosis of marrow failure (eg, bone marrow testing, fetal hemoglobin), (4) tests done to determine whether the case is genetic (eg, parental complete blood counts), (5) tests done after a diagnosis was established (which we considered as nondiagnostic evaluation of the patients), and (6) tests that were done to study disease pathogenesis (eg, clonogenic assays of marrow progenitors).
|
Thirty-two (82%) of the 39 patients with UC-IBMFSs underwent specific tests as described previously (Table 5). The average number of tests per patient for these UC-IBMFSs cases was 3.8 at a total cost of US $3160 per case. In comparison, 92 (75%) patients with C-IBMFSs underwent testing to diagnose their IBMFS. The average number of testing for these patients was 1.2 at a total cost of US $694 per case. The actual cost is probably higher, because we did not include commonly done radiologic tests, such as skeletal survey, abdominal ultrasound, and computed tomography.
The group of patients who had the most extensive genetic testing was group 1, namely, patients with pancytopenia and physical malformation. On average, the diagnostic workup included 4.3 tests per patient at a cost of US $4102 (range: US $1500–$8183). The patients in group 1 who had an affected first-degree family member underwent fewer tests (mean: 3.8 vs 5.7 tests per patient). When all 39 UC-IBMFS cases were analyzed, the patients with an affected first-degree family member also underwent fewer tests (mean: 4.4 vs 2.1 tests per patient). Among the 123 patients with C-IBMFSs on the CIMFR, a molecular diagnosis in a family member facilitated the establishment of a molecular diagnosis in only 4 cases; therefore, the higher cost of genetic testing for the patient with UC-IBMFSs was not attributable only to fewer previous molecular diagnoses in other family members.
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
We found a high prevalence (24%) of UC-IBMFSs among the IBMFSs registered in the CIMFR. These patients were registered by the co-investigators as unclassified, because their clinical phenotypes were either inconsistent with described syndromes or unsupported by available diagnostic modalities. Eighty percent of the UC-IBMFSs (or 19% of the total number of patients on the registry) remained unclassifiable at their last follow-up. Either they might have known syndromes that have atypical presentation and could not be diagnosed on the basis of clinical or molecular data, or they might have a yet uncategorized syndrome. Importantly, 20% of the patients with UC-IBMFSs ultimately received a diagnosis on the basis of the development of new clinical findings or newly available genetic tests. This is a small percentage of the total number of patients with UC-IBMFSs; however, as new genes are discovered, it is likely that more and more patients will eventually receive a specific diagnosis. The latter point also emphasizes the problem of overlapping clinical phenotype among the IBMFSs; incomplete knowledge of the genetic basis of many IBMFSs; and the lack of rapid and cost-effective, widely available diagnostic tests.
Clinical classification has been traditionally used for categorizing related disorders and has been extremely useful in advancing our ability to direct appropriate management and treatment; however, we should review this practice and ask whether and how genetic information can be incorporated into the diagnostic criteria of a disease. Our study sheds some light on this problem from both the clinical and the genetic perspectives. We divided the UC-IBMFSs in the CIMFR into 8 traditional subgroups on the basis of the hematologic manifestation and associated physical malformations. Although the number of the UC-IBMFS cases in our study is not sufficient to make accurate evaluation of the utility of such a division for each of the groups, it is apparent that clinical grouping according to the type of cytopenia and the presence or absence of extrahematologic physical malformation is not always sufficient to discriminate between conditions. For example, members of 2 of the 6 families of UC-IBMFSs were assigned to different groups. This is consistent with previous reports of diverse phenotypic expression of the IBMFSs in the same families.6,7
Because the patients with UC-IBMFSs presented at an older age than the patients with C-IBMFSs and lacked diagnostic criteria for a specific syndrome, a major difficulty is to classify many of the cases as inherited syndromes. For example, 4 patients in our series who belonged to group 1 (3 patients) and group 2 (1 patient) received treatment with immunosuppressive therapy (antithymocyte globulin, cyclosporine, and prednisone) as for acquired aplastic anemia. One patient gradually developed findings consistent of an inherited disease, and another patient had a sibling who later developed bone marrow failure. Two patients had 1 additional extrahematologic manifestation; however, because they presented after infancy and because they lack diagnostic criteria for a specific syndrome, the marrow failure could not be confidently related to an inherited syndrome. All were tested for SBDS, and 3 were tested for DKC1, TERC, and MPL; the results were negative.
Because of the wide availability of chromosomal fragility testing and the pleomorphic nature of this disease,8,9 61% of the patients were tested for Fanconi anemia by the chromosomal fragility assay. The wide availability of the test does not necessarily indicate that all UC-IBMFSs should be tested, because the clinical presentation might be inconsistent with the known clinical spectrum of Fanconi anemia (eg, autosomal dominant inheritance, isolated chronic neutropenia). In 12 cases, the differential diagnosis included dyskeratosis congenita, and genetic testing was done in this direction; however, the cases did not fulfill the diagnostic criteria,10 and in only 1 case did more diagnostic criteria develop later to suggest this clinical diagnosis. These patients might still have dyskeratosis congenita, because even among those families with typical presentation of dyskeratosis congenita, <50% can be genotyped, and because most of the patients in our series who belonged to this group were not tested for TERT or NOP10. In 14 cases, the differential diagnosis included Shwachman-Diamond syndrome; however, the patients did not have signs of exocrine pancreatic dysfunction, which is a major clinical criterion for the diagnosis of this disorder.11 Establishment of a diagnosis of Shwachman-Diamond syndrome after SBDS gene mutation analysis in 2 cases from group 1 and identification of clinically affected family members by family screening by using genetic testing (unpublished data) clearly demonstrate that genotypically proven Shwachman-Diamond syndrome has a much broader phenotype than initially recognized clinically. Larger numbers of patients, longer follow-up, and complete molecular testing are necessary to evaluate accurately the frequency of known and new syndromes among cases of UC-IBMFSs.
Inability to classify a disease can have a major impact on the family and the treating medical facility. First, some of the patients may receive unnecessary treatment. Second, as evident from this study, a significant number of patients with IBMFSs undergo many diagnostic tests for months or even years, and still approximately one fifth cannot receive an accurate diagnosis. An accurate diagnosis is sometimes critical, because treatment of the patient is tailored according to the specific syndrome. For example, a failure to diagnose IBMFS in a patient before hematopoietic stem cell transplantation may be fatal12 or may lead to using an affected asymptomatic sibling for transplantation. Third, it is reasonable to assume that having a UC-IBMFS whose natural history is unclear but carries a potential risk for life-threatening complications and cancer has enormous psychological impact on the patient and the family. Furthermore, the patient and the family are left with uncertainty with respect to genetic transmission and without having tools to offer prenatal diagnosis. Because our study showed a high prevalence of UC-IBMFSs, future studies should examine the psychological burden of such a diagnosis on patients and families.
Genetic tests have become increasingly available for diagnosing IBMFSs.13 The inability to classify a patient with a specific syndrome results in multiple testing with very high cost, as demonstrated in this study. The results of our study suggest that refining the clinical classification of the syndromes may not solve the problem, and novel diagnostic tools that will easily distinguish between the various syndromes and provide rapid and accurate diagnosis are necessary.
Because genetic tests remain costly and are not readily available for diagnostic purposes, they are ideally performed in a staged manner, leaving the least likely diagnosis to be pursued last (Table 6). Because some tests take months to complete or there is urgency in confirming a diagnosis before transplantation, in many cases, multiple tests have been done simultaneously. Retrospectively, most of these tests did not contribute to establishment of a diagnosis. Because our study is based on analysis of data from a multicenter registry, the indications for and the extent of genetic testing differ between centers. Prospective studies with a uniform approach to the diagnostic workup of patients may enable determination of the cost-effectiveness of each of the diagnostic tools.
|
|
CONCLUSIONS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
Our study shows for the first time that UC-IBMFSs are relatively common among the IBMFSs and present a major diagnostic and therapeutic dilemma. By illustrating the difficulty in using phenotype to predict diagnosis and direct diagnostic testing in UC-IBMFSs, our study raises exciting opportunities for research to identify new genes that are mutated in bone marrow failure syndromes and determine the phenotypic expression of known genetic causes of IBMFSs.
|
ACKNOWLEDGMENTS |
|---|
This work was supported by grants from Fanconi Anemia Canada, C17 Canadian Research Network, the Neutropenia Support Association of Canada, Amgen Inc, Canada, and Shwachman-Diamond Syndrome Canada.
We gratefully acknowledge Amanda Ciccolini and Mohammad Azouz for help with collecting the data for this article.
|
FOOTNOTES |
|---|
Accepted Jan 14, 2008.
Address correspondence to Yigal Dror, MD, Hospital for Sick Children, Division of Haematology/Oncology and the Cell Biology Program, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: yigal.dror{at}sickkids.ca
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Thus far, only case reports of UC-IBMFSs have been published, and the clinical and economic challenges posed by patients with such disorders are unknown.
|
| What This Study Adds This is the first comprehensive analysis of a cohort of patients with UC-IBMFSs. We report the prevalence, clinical characteristics, and cost of genetic testing. The results provide useful information for general pediatricians and pediatric hematologists.
|
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
- Dror Y. Inherited bone marrow failure syndromes. In: Arececi RJ, Hann CEW, Smith I, eds. Pediatric Hematology. 3rd ed. Oxford, England: Blackwell Publishing;2006 :30 –36
- Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Look AT, Ginsburg D, eds. Nathan and Oski's Hematology of Infancy and Childhood. 6th ed. Philadelphia, PA: WB Saunders; 2003:280–365
- Steele JM, Sung L, Klaassen R, et al. Disease progression in recently diagnosed patients with inherited marrow failure syndromes: a Canadian Inherited Marrow Failure Registry (CIMFR) Report. Pediatr Blood Cancer.2006; 47 (7):918 –925[CrossRef][Web of Science][Medline]
- International Agranulocytosis and Aplastic Anemia Study. Incidence of aplastic anemia: the relevance of diagnostic criteria.
Blood.1987; 70
(6):1718
–1721
[Abstract/Free Full Text] - Grossfeld PD, Mattina T, Lai Z, et al. The 11q terminal deletion disorder: a prospective study of 110 cases. Am J Med Genet A.2004; 129 (1):51 –61
- Willig TN, Draptchinskaia N, Dianzani I, et al. Mutations in ribosomal protein S19 gene and Diamond Blackfan anemia: wide variations in phenotypic expression.
Blood.1999; 94
(12):4294
–4306
[Abstract/Free Full Text] - Bellanné-Chantelot C, Clauin S, Leblanc T, et al. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register.
Blood.2004; 103
(11):4119
–4125
[Abstract/Free Full Text] - Kutler DI, Singh B, Satagopan J, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR).
Blood.2003; 101
(4):1249
–1256
[Abstract/Free Full Text] - Esmer C, Sanchez S, Ramos S, et al. DEB test for Fanconi anemia detection in patients with atypical phenotypes. Am J Med Genet A.2004; 124 (1):35 –39
- Dokal I. Dyskeratosis congenita in all its forms. Br J Haematol.2000; 110 (4):768 –779[CrossRef][Web of Science][Medline]
- Dror Y, Freedman MH. Shwachman-Diamond syndrome. Br J Haematol.2002; 118 (3):701 –713[CrossRef][Web of Science][Medline]
- Gluckman E, Auerbach AD, Horowitz MM, et al. Bone marrow transplantation for Fanconi anemia.
Blood.1995; 86
(7):2856
–2862
[Abstract/Free Full Text] - Lieberman L, Dror Y. Advances in understanding the genetic basis for bone-marrow failure. Curr Opin Pediatr.2006; 18 (1):15 –21[CrossRef][Web of Science][Medline]
- Dallman PR. Blood and blood forming cells. In: Rudolph A, ed. Pediatrics. New York, NY: Appleton-Century Crofts; 1977:1109–1111
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
