YBCMD-01877; No. of pages: 5; 4C: Blood Cells, Molecules and Diseases xxx (2014) xxx–xxx
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Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia Candice Feben a,⁎, Jennifer Kromberg b, Rosalind Wainwright c, David Stones d, Janet Poole e, Tabitha Haw a, Amanda Krause a a
Division of Human Genetics, National Health Laboratory Service and School of Pathology, The University of the Witwatersrand, Johannesburg, South Africa Division of Human Genetics, The University of the Witwatersrand, Johannesburg, South Africa Department of Pediatrics, Chris Hani Baragwanath Hospital, The University of the Witwatersrand, Johannesburg, South Africa d Department of Pediatrics, Universitas Hospital, The University of the Free State, Johannesburg, South Africa e Department of Pediatrics, Charlotte Maxeke Johannesburg Academic Hospital, The University of the Witwatersrand, Johannesburg, South Africa b c
a r t i c l e
i n f o
Article history: Submitted 22 October 2014 Accepted 15 November 2014 Available online xxxx (Communicated by M. Narla, DSc, 13 November 2014) Keywords: Fanconi anemia Bone marrow aplasia Hematopoietic stem cell transplantation Black South African patients FANCG founder mutation
a b s t r a c t Fanconi anemia (FA) is a rare disorder of DNA repair, associated with various somatic abnormalities but characterized by hematological disease that manifests as bone marrow aplasia and malignancy. The mainstay of treatment, in developed nations, is hematopoietic stem cell transplantation (HSCT) with subsequent surveillance for solid organ and non-hematological malignancies. In South Africa, FA in the Black population is caused by a homozygous deletion mutation in the FANCG gene in more than 80% of cases. Many affected patients are not diagnosed until late in the disease course when severe cytopenia and bone marrow aplasia are already present. Most patients are not eligible for HSCT at this late stage of the disease, even when it is available in the state health care system. In this study, the hematological presentation and disease progression in 30 Black South African patients with FA, confirmed to have the FANCG founder mutation, were evaluated and compared to those described in other FA cohorts. Our results showed that patients, homozygous for the FANCG founder mutation, present with severe cytopenia but progress to bone marrow failure at similar ages to other individuals affected with FA of heterogeneous genotype. Further, the incidence of myelodysplastic syndrome is similar to that which has been previously described in other FA cohorts. Although severe cytopenia at presentation may be predicted by a higher number of somatic anomalies, the recognition of the physical FA phenotype in Black South African patients is challenging and may not be useful in expediting referral of suspected FA patients for tertiary level investigations and care. Given the late but severe hematological presentation of FA in Black South African patients, an investigative strategy is needed for earlier recognition of affected individuals to allow for possible HSCT and management of bone marrow disease. © 2014 Elsevier Inc. All rights reserved.
Introduction Fanconi anemia (FA) is a rare genetic condition of impaired DNA repair, inherited in either an autosomal- or X-linked recessive manner [1,2]. Affected individuals present variably with diverse physical abnormalities including significant growth restriction, unusual patchy pigmentary changes, somatic anomalies of the limbs and urogenital, cardiovascular, gastrointestinal and central nervous system malformations [2,3]. The hallmark of this condition, however, remains a progressive decline in hematological function, with pancytopenia and deterioration to bone marrow aplasia or malignancy, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Affected individuals are also at risk for the development of solid tumors, ⁎ Corresponding author at: National Health Laboratory Service, Cnr Hospital and De Korte Street, Braamfontein, Johannesburg 2000, South Africa. Fax: +27 114899226. E-mail address: [email protected] (C. Feben).
particularly squamous cell carcinomas of the head, neck, esophagus and genital tract [2,4,5]. The management of the hematological manifestations of FA centers on therapies that initially stimulate increased bone marrow production of blood cell precursors (androgen administration), therapies which replace circulating blood cells during times of crisis or for palliation (packed red cell and platelet transfusions) and, ideally, therapies to replace the diseased bone marrow, particularly hematopoietic stem cell transplantation (HSCT). While HSCT is currently the only available cure for the hematologic complications of FA, including MDS and AML, affected individuals remain at risk for the development of solid tumors even after successful transplantation [2,6]. In South Africa, HSCT is available to only a minority of patients and usually in the private health care sector. HSCT in Black children is particularly hampered by a lack of Black African donors on the bone marrow registry (Dr. R. Wainwright, 2014, personal communication). The timing of HSCT is a contentious issue, although many would advocate transplantation in the pre-anemic
http://dx.doi.org/10.1016/j.bcmd.2014.11.011 1079-9796/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: C. Feben, et al., Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia, Blood Cells Mol. Diseases (2014), http://dx.doi.org/10.1016/j.bcmd.2014.11.011
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C. Feben et al. / Blood Cells, Molecules and Diseases xxx (2014) xxx–xxx
phase of the illness to increase survival rates and reduce post transplantation complications [2,6]. Further, it is recommended that patients who are eligible for HSCT do not receive blood product transfusions [2]. The timing of the diagnosis of FA thus impacts critically on the available and appropriate care for the affected patient. Sixteen genetic subtypes (complementation groups) of FA have been described, each with numerous causative mutations in specific genes, which have been designated FANC A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P and Q. The gene products function in a complicated, multiprotein cellular response to DNA damage. Worldwide, mutations in FANCA, FANCC and FANCG together account for more than 85% of FA cases [2,7,8]. Given the severity of the hematological manifestations of the condition and the need to provide appropriate and timely therapeutic intervention, many previous studies have attempted to identify an association between hematological outcome, as regards progression to bone marrow aplasia or malignancy, with complementation group in FA [9–11]. These studies have suggested that individuals with FANCG mutations have severe cytopenia and a high incidence of AML and MDS and that those individuals with FANCC mutations have the highest incidence of bone marrow failure. Conversely, other studies suggest that FANCC mutations confer the best hematological outcome [9–11]. Neveling et al. [12] have reviewed these data and commented on the futility of attempting genotype–phenotype correlations using complementation groups rather than specific mutations. Of interest though, even Ashkenazi Jewish and Japanese individuals with the same FANCC splice site mutation (IVS4 + 4A N T) have been shown to have different hematological outcomes, suggesting that neither complementation group nor mutation type alone can be used to predict hematological outcome and that “genetic background” may be of importance [13]. The influence of modifier genes, environmental factors and stochastic events on the FA phenotype is yet to be well described [12]. In South Africa, individuals with FA are seen in all ethnic and racial groups. In particular, the Ashkenazi Jewish, South African Black and Afrikaans populations have been closely studied from a molecular perspective and causative genetic founder mutations have been characterized in these groups [14–16]. In the South African Black population, the incidence of FA is estimated at 1/40000 [16]. A homozygous seven basepair deletion mutation (c.637_643delTACCGCC) in the FANCG gene is found in 82% of these affected patients. This mutation is located on a single haplotype, suggesting an ancient origin, and produces a truncated FANCG protein [16]. The homozygosity of most Black individuals with FA in South Africa is a unique situation, and as such, these patients provide an ideal cohort for mutation specific genotype–phenotype correlation studies. The aim of the present study was to evaluate and describe the hematological presentation and progression of FA in a cohort of South African Black patients, homozygous for the FANCG founder mutation, and to compare this hematological phenotype with that described in other FA cohorts. The physical phenotype of Black patients with FA, homozygous for the FANCG founder mutation, has been reported previously [17].
detect founder mutations has significantly reduced the cost of testing with good detection rates in founder population groups. The FANCG deletion mutation has previously been shown to be pathogenic and the cause of FA in most Black South African patients [16]. Hematological data, including full blood count results at presentation, initial and subsequent bone marrow biopsy results, age of development of aplastic anemia, age of transfusion dependence (defined as requiring more than five transfusions of blood or blood products in 1 year), treatment received and age of progression to bone marrow malignancy or myelodysplasia, were documented from a retrospective review of each patient's medical file. The development of non-hematological malignancies, including squamous cell carcinomas of the head, neck and esophagus and hepatocellular carcinomas, was also noted. In addition, the age of presentation with symptoms suggestive of FA (corresponding to the age at which the child first presented to a health care facility and was referred to a Pediatric Hematology/Oncology Clinic) and the nature of the presenting complaint were recorded. The median age of presentation with symptoms suggestive of FA and the median age of bone marrow failure were calculated. The mean values (with standard deviation (SD) and 95% confidence intervals (95% CI)) for the presenting hematological indices (hemoglobin (Hb), white cell count (WCC), platelet count and mean corpuscular volume (MCV)) were also calculated. The average hematological indices were compared to hematological reference values using a one-sample t-test. As reference ranges change with the age and sex of the child, the reference values used were the lower limit values for all age groups for Hb, WCC and platelet count and the upper limit value for all age groups for MCV as published by Lo [18]. The number of transfusion-dependent (TFD) patients and the median age of transfusion dependence were determined. A modified International Fanconi Anaemia Registry (IFAR) score, using the physical criteria of growth retardation (height for age Z-score b − 2SD of the mean), birthmarks (N2 pigmentary anomalies, including café au lait macules, hyper- and hypopigmented streaks and macules), microphthalmia (palpebral fissure length b− 2 SD of the mean for age), thumb and radius abnormalities (hypoplastic/absent radius, thumb or first metacarpal) and kidney and urinary tract abnormalities was calculated for each patient, using data previously collected during a physical phenotype study in the same patient cohort [17]. The total was scored out of five. The mean score of the entire cohort was determined (with SD and 95% CI). The patients were then divided into sub-cohorts based on their TFD status (and the age of TFD), MDS status and their hematological severity status (Hb b8 g/dl and platelet count b 20 × 109, as defined by Faivre et al. [10]). Modified IFAR scores were compared in different patient sub-cohorts to determine whether the number of physical anomalies present could be positively correlated with the severity of the hematological progression in these patients. The study was approved by the Human Research Ethics Committee of the University of the Witwatersrand (certificate number: M0906891) and the Ethics Committee of the University of the Free State (certificate number: ETOVS NR 52/2010).
Patients and methods Results Thirty unrelated Black patients were recruited between July 2009 and July 2011 from tertiary level Pediatric Hematology/Oncology Clinics in the cities of Johannesburg and Bloemfontein, in two provinces of South Africa. Molecular genetic testing (polymerase chain reaction based) is used as the first line investigation for FA in populations with known FA causing founder mutations in South Africa. This testing confirmed that each patient was homozygous for the FANCG seven base-pair deletion mutation (c.637_643delTACCGCC) [16]. Although it is recognized that chromosome breakage analysis is the internationally recommended gold-standard investigation for FA [2], this test is not routinely available in the under-resourced state health care system in South Africa owing to cost implications and technical issues associated with the laboratory system. The availability of molecular techniques to
Hematological data from the files of 30 unrelated Black South African patients with FA were analyzed. At the time of data collection, the median current age of the patients with FA attending the hematology/oncology clinics was 9 years, 3 months (range: 3 years–17 years, 5 months). The median age at presentation with symptoms suggestive of the diagnosis of FA, was 7 years, 1 month of age (Range: 2 years, 11 months–11 years, 9 months). The presenting complaint was defined as the initial reason for presentation at either the referral hospital or primary health care clinic or at the tertiary hematology/oncology clinic. The presenting complaints and their frequencies are presented in Table 1. Two individuals had more than one initial complaint. Recurrent epistaxis was the most frequent
Please cite this article as: C. Feben, et al., Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia, Blood Cells Mol. Diseases (2014), http://dx.doi.org/10.1016/j.bcmd.2014.11.011
C. Feben et al. / Blood Cells, Molecules and Diseases xxx (2014) xxx–xxx Table 1 Presenting complaints in 30 Black patients⁎ with FA. Complaint
Number of individuals (%)
Recurrent epistaxis Weakness/fatigue Recurrent infections Hematemesis Pallor Pigment abnormalities
16 (53%) 6 (20%) 5 (17%) 2 (7%) 2 (7%) 1 (3%)
⁎ Two patients had more than one initial complaint: one with epistaxis and hematemesis; one with epistaxis and fatigue.
complaint. Of note, only a single patient was referred on the basis of a physical anomaly (pigmentary abnormalities). The hematological indices recorded at the time of initial presentation are summarized and compared to pediatric reference values in Table 2. In all instances, the mean hematological values recorded in the patients with FA deviated very significantly from those of the reference population (one-sample t-test; p b 0.0001), reflecting severe cytopenia at the time of diagnosis of FA. In 2000, Faivre et al. evaluated presenting hematological indices across different FA complementation groups in terms of their severity. They allocated a score of one point for each of three defined severe hematological parameters (Hb of less than or equal to 8 g/dl, an absolute neutrophil count of less than or equal to 0.5 × 109/l and platelet count of less than or equal to 20 × 109/l), giving each patient in their cohort a score out of three. Individuals with FANCG mutations were found to have a significantly higher scores out of three (mean score: 2.11) than individuals in complementation groups A and C, indicating severe cytopenia at presentation [10]. While the same score was not calculated for individuals in the present cohort as absolute neutrophil counts were not recorded, it was possible to evaluate the Hb and platelet values to determine severity based on the defined Faivre criteria [11]. Altogether, 14/30 (46.7%) patients were noted to have both Hb and platelet values below those used to define severe cytopenia at presentation. Of the 16 patients who did not meet both severity criteria, 14 patients (88%) had Hb values below 8 g/dl, while only one patient (6%) had a platelet count below 20 × 109/l. One patient (1/16; 6%) did not meet the criteria for either severe Hb or platelet count at presentation. Bone marrow aspirate and trephine reports were available for review in 27 of the 30 patients (90%). The median age of bone marrow aplasia was calculated as 7 years, 1 month (range: 2 years, 11 months– 12 years; N = 27), consistent with the age of presentation in most cases. Bone marrow aplasia was confirmed at the time of initial presentation to the hematology/oncology clinic in the majority of cases (24/27; 89%). In three of the 27 cases (11.1%), the age of initial presenting complaint and the age of bone marrow failure could be distinguished. Initial bone marrow biopsy reports in these patients showed no evidence of marrow aplasia. In the first patient, the disease course progressed over 6 months from the initial presentation of fatigue, to bone marrow aplasia diagnosed on a second bone marrow aspirate and trephine biopsy. The second patient progressed to bone marrow aplasia over 24 months
Table 2 Mean hematological indices at the time of diagnosis with FA. Hematological parameter
Mean value in FA patient
Range in FA cohort
Reference value
Hemoglobin (g/dl) White cell count (x 109/l) Platelet count (x 109/l) Mean corpuscular volume (fl) (N = 26)
4.77 (SD = 2.05) 2.61 (SD = 1.11) 23.50 (SD = 13.2) 106.46 (SD = 7.94)
1.6–9.9 1.3–5.1 6–43 86–113.5
11.5⁎ 4.0⁎ 150.0⁎ 95.0⁎⁎
⁎ Lower limit reference values for hematological indices in a normal pediatric population as found in Nelson Textbook of Pediatrics (19th ed., 2011) [18]. ⁎⁎ Upper limit reference value for mean corpuscular volume in a normal pediatric population as found in Nelson Textbook of Pediatrics (19th ed., 2011) [18].
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from the initial presentation with epistaxis. The third also presented with epistaxis and progressed over 6 months to bone marrow aplasia. None of the affected individuals in the present cohort were found to have changes in keeping with AML or acute lymphocytic leukemia (ALL) on their full blood count parameters or on their bone marrow aspirate and trephine reports. Two of the 27 patients (7.4%) for whom bone marrow biopsy reports were available for review were found to have features of MDS at the time of their FA diagnosis. In a study by Faivre et al. [10], the authors suggested a significantly higher AML/MDS frequency at 10 years of age (6/18; 33%) in FANCG individuals compared with individuals with FANCA and FANCC mutations [10]. Thirteen of the patients in the present research group were 10 years of age or older, and two of them (2/13; 15.4%) had features of MDS on their bone marrow biopsy reports. There was no significant difference in the incidence of AML/MDS in the present research group to that of the Faivre et al. (2000) cohort (p = 0.4395, Fisher's exact test). None of the patients were known or suspected to have developed any solid tumors or non-hematological malignancies at the time of data collection. All patients were started on androgen therapy at the time of diagnosis. Eleven of the 30 patients (36.7%) were TFD at the end of the data collection period. The median age of TFD was 7 years, 10 months of age (N = 11; range: 4 years, 8 months–13 years, 4 months). Average modified IFAR scores for the cohort were calculated and are shown in Table 3, along with the comparative analysis of the IFAR scores in the defined sub-cohorts. As only two patients developed MDS, it was not possible to draw any conclusions regarding the relationship of the hematological progression to their physical phenotype, even though interestingly both patients had high modified IFAR scores [4,5]. There were no statistically significant differences in the average scores between the group of patients with early onset transfusion dependence (before 8 years), and those who became transfusion dependent after 8 years of age or had not yet developed transfusion dependence (patients under the age of 8 years and not yet TFD were excluded from this analysis). However, a statistically significant difference was found between the modified IFAR scores in the group of hematologically severe patients and those with milder hematological indices at presentation (Table 3), the former group having higher modified IFAR scores than the latter. The average age of the patients in these sub-cohorts was not significantly different and could not explain this finding.
Discussion Despite the fact that well-documented and clinically identifiable physical anomalies occur in children with FA, aplastic anemia, usually manifesting in the first decade of life, remains the primary presenting feature for affected children globally [19]. In South African Black patients, this trend appears to be mirrored, with referrals to tertiary centers occurring late in the disease course, if at all. Unpublished data suggest that only one out of 15 affected individuals are referred for tertiary hematological care. In the present South African cohort, all patients were referred to Pediatric Hematology/Oncology Clinics already manifesting symptoms of significant bone marrow disease, with only a single patient referred on the basis of a physical anomaly—unusual skin pigmentation. Unfortunately, a previous evaluation of the physical phenotype of the present cohort did not highlight specific features, which could be easily identified by practitioners servicing primary health care facilities and which could alert them to the possible diagnosis of FA and the need for tertiary referral [17]. Although recommendations have been made to expedite referral of patients with growth deficiency and/or pigmentary anomalies (shown to be the most common physical features of FA in Black South African patients) for pediatric or medical geneticist evaluation, most Black patients with FA in South Africa will not be diagnosed prior to the onset of hematological symptoms which suggest severe cytopenia [17].
Please cite this article as: C. Feben, et al., Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia, Blood Cells Mol. Diseases (2014), http://dx.doi.org/10.1016/j.bcmd.2014.11.011
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C. Feben et al. / Blood Cells, Molecules and Diseases xxx (2014) xxx–xxx
Table 3 Comparison of average IFAR scores between patient sub-groups. Cohort
Number
Average modified IFAR score
p value (t-test)
Total cohort
30
2.6 (SD: 1.27)
–
Sub-cohorts TFD onset before 8 years of age TFD onset after 8 years of age + non-TFD and older than 8 years of age⁎ Severe hematological indices at presentation (Hb b 8 g/dl and platelet count b20 × 109/l) Non-severe hematological indices at presentation (Hb N 8 g/dl or platelet count N20 × 109/l)
6 12 14 16
2.5 (SD: 1.048) 2.7 (SD: 1.3) 3.21 (SD: 0.97) 2.07 (SD: 1.22)
0.7486 0.0098
⁎ Twelve patients were under the age of 8 years and non-TFD.
In the present cohort, the median age of presentation with symptoms of FA, usually concurrent with the diagnosis of bone marrow aplasia, was 7 years, 1 month of age, consistent with published data for other individuals with FA with the same and heterogeneous FA genotypes [16,20,21]. The most common presenting symptom was recurrent epistaxis, similar to the major presenting complaint documented by Macdougall et al. [20] in a Black South African FA cohort over 25 years ago. Although this hemorrhagic symptom relates directly to the pathophysiology of FA, with thrombocytopenia described as the first identifiable hematological disturbance, apart from macrocytosis [7], in the South African Black patients, a severely low Hb (b8 g/dl) was shown to be more common at presentation than a severely low platelet count (b20 × 109/l). The initial hematological indices appear to suggest that Black individuals with FA have severe cytopenia at first presentation with symptoms of FA. Although the research cohort cannot be directly compared with the Faivre et al. [10] cohort, the low presenting Hb and platelet count in the present cohort is an indicator that individuals with the FANCG founder mutation also present with more severe hematological indices than patients with FA of heterogeneous genotypes. However, the severe hematological indices do not appear to predict an earlier age of bone marrow aplasia. None of the patients were known or suspected to have developed any non-hematological malignancies. Anecdotally, one Black patient with FA, homozygous for the FANCG founder mutation, although not a participant in the present study is suspected to have developed a cervical squamous cell malignancy. This patient was also infected with the human immunodeficiency virus, making it difficult to attribute the malignancy to her FA. Apart from this single case, little is known about the progression of Black individuals with FA in terms of non-hematological malignancy and solid tumors as most patients are reported to demise before the age of 20 years. The poor availability of HSCT as a cure for bone marrow disease in South Africa most likely accounts for this low reported incidence of solid tumors detected in FA patients. It has previously been suggested that the severity of the physical phenotype or the presence of certain physical features of FA can be used to predict the hematological outcome in a patient. Rosenberg et al. [22] showed that the presence of radial aplasia was predictive of bone marrow failure in their cohort of individuals with FA of heterogeneous genotype. Investigation into the physical phenotype of Black individuals homozygous for the FANCG founder mutation showed that radial aplasia is a very uncommon finding [17], suggesting that this particular anomaly cannot be used as a predictor for hematological outcome in Black patients. When a modified IFAR score was calculated in the present patients, the mean score was significantly higher in individuals with severe cytopenia at presentation. Thus, it might be expected that a higher number of physical anomalies predicts a more severe hematological course. However, the patients with severe cytopenia did not have an earlier average age of bone marrow aplasia than those with milder hematological derangements at presentation. The incidence of MDS at 10 years of age and the conversion rates to AML and ALL in the research group were consistent with figures published by Faivre et al. [10]. This finding may suggest that individuals with the homozygous FANCG founder mutation are at higher risk of MDS than affected individuals with non-FANCG mutations. The two
patients who developed MDS had high modified IFAR scores. Owing to the small sample size of this cohort, it was not possible to draw specific conclusions, although the observation may suggest that further research is warranted into the physical phenotype of patients with MDS to assess for somatic anomalies of FA. While we did not observe any conversion to AML or ALL in the present cohort, our data were limited by the short time frame of the collection period. Further, it is documented that the cumulative risk of developing AML is around 13% by the age of 50 years, with most patients showing conversion between 15 and 35 years [2]. With a median current age of 9 years, 3 months at the time of the study, our patient cohort was too young to have shown significant AML conversion. Again, given the poor availability of HSCT, most patients would be expected to demise prior to AML conversion. In the South African context where hematology/oncology and medical genetics services are only available in tertiary centers that require referral from primary and secondary care facilities, a strategy for the earlier diagnosis of FA is required. While the present study highlights a positive relationship between severe cytopenia and a higher average modified IFAR score, it has already been shown that the physical anomalies in patients with FA are subtle and difficult to recognize and thus not easily detected in primary and secondary health care facilities [17]. As the history of recurrent epistaxis is present in a high percentage of patients, this symptom may be useful as an investigative handle for FA. Promoting awareness around recurrent epistaxis in children and a review of the current investigative strategies for children presenting with same may result in more expedient referral of affected children to tertiary centers. While the differential diagnosis for epistaxis is large and includes many acquired causes [23], recurrent epistaxis, particularly in a child with growth restriction or pigmentary anomalies (as are often seen in Black patients with FA), warrants further pediatric evaluation with further medical geneticist assessment as required. Conclusion Fanconi anemia in the Black South African population has a predicted prevalence of 1/40000, with more than 80% of affected individuals carrying the same FANCG founder mutation. Unfortunately, the majority of affected individuals will not be referred for tertiary care management of their condition, while those who are referred are already manifesting symptoms of severe cytopenia and bone marrow aplasia. The physical phenotype of affected patients has been shown to be not easily recognizable in primary and secondary health care facilities, further impeding the diagnosis of the condition and the timely referral of patients for tertiary care. New strategies are needed to improve recognition of this condition, particularly regarding the triad of epistaxis, growth restriction and pigmentary anomalies often found in affected children, such that patients are referred in the pre- or early anemic phase to allow the opportunity for appropriate treatment, including HSCT. Acknowledgments The authors wish to thank the Medical Research Council of South Africa for financial assistance as well as the medical, nursing and paramedical staff at the Chris Hani Baragwanath Hospital, The Charlotte
Please cite this article as: C. Feben, et al., Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia, Blood Cells Mol. Diseases (2014), http://dx.doi.org/10.1016/j.bcmd.2014.11.011
C. Feben et al. / Blood Cells, Molecules and Diseases xxx (2014) xxx–xxx
Maxeke Johannesburg Academic Hospital and the Universitas Hospital, for their assistance in patient recruitment and for their advice and input into care and management of the affected patients. The authors wish to acknowledge Ms. C. Van Wyk who provided genetic counseling to patients involved in the study. Further, the willingness of the patients and their families to participate in the study is much appreciated.
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Please cite this article as: C. Feben, et al., Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia, Blood Cells Mol. Diseases (2014), http://dx.doi.org/10.1016/j.bcmd.2014.11.011
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Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia Candice Feben a,⁎, Jennifer Kromberg b, Rosalind Wainwright c, David Stones d, Janet Poole e, Tabitha Haw a, Amanda Krause a a
Division of Human Genetics, National Health Laboratory Service and School of Pathology, The University of the Witwatersrand, Johannesburg, South Africa Division of Human Genetics, The University of the Witwatersrand, Johannesburg, South Africa Department of Pediatrics, Chris Hani Baragwanath Hospital, The University of the Witwatersrand, Johannesburg, South Africa d Department of Pediatrics, Universitas Hospital, The University of the Free State, Johannesburg, South Africa e Department of Pediatrics, Charlotte Maxeke Johannesburg Academic Hospital, The University of the Witwatersrand, Johannesburg, South Africa b c
a r t i c l e
i n f o
Article history: Submitted 22 October 2014 Accepted 15 November 2014 Available online xxxx (Communicated by M. Narla, DSc, 13 November 2014) Keywords: Fanconi anemia Bone marrow aplasia Hematopoietic stem cell transplantation Black South African patients FANCG founder mutation
a b s t r a c t Fanconi anemia (FA) is a rare disorder of DNA repair, associated with various somatic abnormalities but characterized by hematological disease that manifests as bone marrow aplasia and malignancy. The mainstay of treatment, in developed nations, is hematopoietic stem cell transplantation (HSCT) with subsequent surveillance for solid organ and non-hematological malignancies. In South Africa, FA in the Black population is caused by a homozygous deletion mutation in the FANCG gene in more than 80% of cases. Many affected patients are not diagnosed until late in the disease course when severe cytopenia and bone marrow aplasia are already present. Most patients are not eligible for HSCT at this late stage of the disease, even when it is available in the state health care system. In this study, the hematological presentation and disease progression in 30 Black South African patients with FA, confirmed to have the FANCG founder mutation, were evaluated and compared to those described in other FA cohorts. Our results showed that patients, homozygous for the FANCG founder mutation, present with severe cytopenia but progress to bone marrow failure at similar ages to other individuals affected with FA of heterogeneous genotype. Further, the incidence of myelodysplastic syndrome is similar to that which has been previously described in other FA cohorts. Although severe cytopenia at presentation may be predicted by a higher number of somatic anomalies, the recognition of the physical FA phenotype in Black South African patients is challenging and may not be useful in expediting referral of suspected FA patients for tertiary level investigations and care. Given the late but severe hematological presentation of FA in Black South African patients, an investigative strategy is needed for earlier recognition of affected individuals to allow for possible HSCT and management of bone marrow disease. © 2014 Elsevier Inc. All rights reserved.
Introduction Fanconi anemia (FA) is a rare genetic condition of impaired DNA repair, inherited in either an autosomal- or X-linked recessive manner [1,2]. Affected individuals present variably with diverse physical abnormalities including significant growth restriction, unusual patchy pigmentary changes, somatic anomalies of the limbs and urogenital, cardiovascular, gastrointestinal and central nervous system malformations [2,3]. The hallmark of this condition, however, remains a progressive decline in hematological function, with pancytopenia and deterioration to bone marrow aplasia or malignancy, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Affected individuals are also at risk for the development of solid tumors, ⁎ Corresponding author at: National Health Laboratory Service, Cnr Hospital and De Korte Street, Braamfontein, Johannesburg 2000, South Africa. Fax: +27 114899226. E-mail address: [email protected] (C. Feben).
particularly squamous cell carcinomas of the head, neck, esophagus and genital tract [2,4,5]. The management of the hematological manifestations of FA centers on therapies that initially stimulate increased bone marrow production of blood cell precursors (androgen administration), therapies which replace circulating blood cells during times of crisis or for palliation (packed red cell and platelet transfusions) and, ideally, therapies to replace the diseased bone marrow, particularly hematopoietic stem cell transplantation (HSCT). While HSCT is currently the only available cure for the hematologic complications of FA, including MDS and AML, affected individuals remain at risk for the development of solid tumors even after successful transplantation [2,6]. In South Africa, HSCT is available to only a minority of patients and usually in the private health care sector. HSCT in Black children is particularly hampered by a lack of Black African donors on the bone marrow registry (Dr. R. Wainwright, 2014, personal communication). The timing of HSCT is a contentious issue, although many would advocate transplantation in the pre-anemic
http://dx.doi.org/10.1016/j.bcmd.2014.11.011 1079-9796/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: C. Feben, et al., Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia, Blood Cells Mol. Diseases (2014), http://dx.doi.org/10.1016/j.bcmd.2014.11.011
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C. Feben et al. / Blood Cells, Molecules and Diseases xxx (2014) xxx–xxx
phase of the illness to increase survival rates and reduce post transplantation complications [2,6]. Further, it is recommended that patients who are eligible for HSCT do not receive blood product transfusions [2]. The timing of the diagnosis of FA thus impacts critically on the available and appropriate care for the affected patient. Sixteen genetic subtypes (complementation groups) of FA have been described, each with numerous causative mutations in specific genes, which have been designated FANC A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P and Q. The gene products function in a complicated, multiprotein cellular response to DNA damage. Worldwide, mutations in FANCA, FANCC and FANCG together account for more than 85% of FA cases [2,7,8]. Given the severity of the hematological manifestations of the condition and the need to provide appropriate and timely therapeutic intervention, many previous studies have attempted to identify an association between hematological outcome, as regards progression to bone marrow aplasia or malignancy, with complementation group in FA [9–11]. These studies have suggested that individuals with FANCG mutations have severe cytopenia and a high incidence of AML and MDS and that those individuals with FANCC mutations have the highest incidence of bone marrow failure. Conversely, other studies suggest that FANCC mutations confer the best hematological outcome [9–11]. Neveling et al. [12] have reviewed these data and commented on the futility of attempting genotype–phenotype correlations using complementation groups rather than specific mutations. Of interest though, even Ashkenazi Jewish and Japanese individuals with the same FANCC splice site mutation (IVS4 + 4A N T) have been shown to have different hematological outcomes, suggesting that neither complementation group nor mutation type alone can be used to predict hematological outcome and that “genetic background” may be of importance [13]. The influence of modifier genes, environmental factors and stochastic events on the FA phenotype is yet to be well described [12]. In South Africa, individuals with FA are seen in all ethnic and racial groups. In particular, the Ashkenazi Jewish, South African Black and Afrikaans populations have been closely studied from a molecular perspective and causative genetic founder mutations have been characterized in these groups [14–16]. In the South African Black population, the incidence of FA is estimated at 1/40000 [16]. A homozygous seven basepair deletion mutation (c.637_643delTACCGCC) in the FANCG gene is found in 82% of these affected patients. This mutation is located on a single haplotype, suggesting an ancient origin, and produces a truncated FANCG protein [16]. The homozygosity of most Black individuals with FA in South Africa is a unique situation, and as such, these patients provide an ideal cohort for mutation specific genotype–phenotype correlation studies. The aim of the present study was to evaluate and describe the hematological presentation and progression of FA in a cohort of South African Black patients, homozygous for the FANCG founder mutation, and to compare this hematological phenotype with that described in other FA cohorts. The physical phenotype of Black patients with FA, homozygous for the FANCG founder mutation, has been reported previously [17].
detect founder mutations has significantly reduced the cost of testing with good detection rates in founder population groups. The FANCG deletion mutation has previously been shown to be pathogenic and the cause of FA in most Black South African patients [16]. Hematological data, including full blood count results at presentation, initial and subsequent bone marrow biopsy results, age of development of aplastic anemia, age of transfusion dependence (defined as requiring more than five transfusions of blood or blood products in 1 year), treatment received and age of progression to bone marrow malignancy or myelodysplasia, were documented from a retrospective review of each patient's medical file. The development of non-hematological malignancies, including squamous cell carcinomas of the head, neck and esophagus and hepatocellular carcinomas, was also noted. In addition, the age of presentation with symptoms suggestive of FA (corresponding to the age at which the child first presented to a health care facility and was referred to a Pediatric Hematology/Oncology Clinic) and the nature of the presenting complaint were recorded. The median age of presentation with symptoms suggestive of FA and the median age of bone marrow failure were calculated. The mean values (with standard deviation (SD) and 95% confidence intervals (95% CI)) for the presenting hematological indices (hemoglobin (Hb), white cell count (WCC), platelet count and mean corpuscular volume (MCV)) were also calculated. The average hematological indices were compared to hematological reference values using a one-sample t-test. As reference ranges change with the age and sex of the child, the reference values used were the lower limit values for all age groups for Hb, WCC and platelet count and the upper limit value for all age groups for MCV as published by Lo [18]. The number of transfusion-dependent (TFD) patients and the median age of transfusion dependence were determined. A modified International Fanconi Anaemia Registry (IFAR) score, using the physical criteria of growth retardation (height for age Z-score b − 2SD of the mean), birthmarks (N2 pigmentary anomalies, including café au lait macules, hyper- and hypopigmented streaks and macules), microphthalmia (palpebral fissure length b− 2 SD of the mean for age), thumb and radius abnormalities (hypoplastic/absent radius, thumb or first metacarpal) and kidney and urinary tract abnormalities was calculated for each patient, using data previously collected during a physical phenotype study in the same patient cohort [17]. The total was scored out of five. The mean score of the entire cohort was determined (with SD and 95% CI). The patients were then divided into sub-cohorts based on their TFD status (and the age of TFD), MDS status and their hematological severity status (Hb b8 g/dl and platelet count b 20 × 109, as defined by Faivre et al. [10]). Modified IFAR scores were compared in different patient sub-cohorts to determine whether the number of physical anomalies present could be positively correlated with the severity of the hematological progression in these patients. The study was approved by the Human Research Ethics Committee of the University of the Witwatersrand (certificate number: M0906891) and the Ethics Committee of the University of the Free State (certificate number: ETOVS NR 52/2010).
Patients and methods Results Thirty unrelated Black patients were recruited between July 2009 and July 2011 from tertiary level Pediatric Hematology/Oncology Clinics in the cities of Johannesburg and Bloemfontein, in two provinces of South Africa. Molecular genetic testing (polymerase chain reaction based) is used as the first line investigation for FA in populations with known FA causing founder mutations in South Africa. This testing confirmed that each patient was homozygous for the FANCG seven base-pair deletion mutation (c.637_643delTACCGCC) [16]. Although it is recognized that chromosome breakage analysis is the internationally recommended gold-standard investigation for FA [2], this test is not routinely available in the under-resourced state health care system in South Africa owing to cost implications and technical issues associated with the laboratory system. The availability of molecular techniques to
Hematological data from the files of 30 unrelated Black South African patients with FA were analyzed. At the time of data collection, the median current age of the patients with FA attending the hematology/oncology clinics was 9 years, 3 months (range: 3 years–17 years, 5 months). The median age at presentation with symptoms suggestive of the diagnosis of FA, was 7 years, 1 month of age (Range: 2 years, 11 months–11 years, 9 months). The presenting complaint was defined as the initial reason for presentation at either the referral hospital or primary health care clinic or at the tertiary hematology/oncology clinic. The presenting complaints and their frequencies are presented in Table 1. Two individuals had more than one initial complaint. Recurrent epistaxis was the most frequent
Please cite this article as: C. Feben, et al., Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia, Blood Cells Mol. Diseases (2014), http://dx.doi.org/10.1016/j.bcmd.2014.11.011
C. Feben et al. / Blood Cells, Molecules and Diseases xxx (2014) xxx–xxx Table 1 Presenting complaints in 30 Black patients⁎ with FA. Complaint
Number of individuals (%)
Recurrent epistaxis Weakness/fatigue Recurrent infections Hematemesis Pallor Pigment abnormalities
16 (53%) 6 (20%) 5 (17%) 2 (7%) 2 (7%) 1 (3%)
⁎ Two patients had more than one initial complaint: one with epistaxis and hematemesis; one with epistaxis and fatigue.
complaint. Of note, only a single patient was referred on the basis of a physical anomaly (pigmentary abnormalities). The hematological indices recorded at the time of initial presentation are summarized and compared to pediatric reference values in Table 2. In all instances, the mean hematological values recorded in the patients with FA deviated very significantly from those of the reference population (one-sample t-test; p b 0.0001), reflecting severe cytopenia at the time of diagnosis of FA. In 2000, Faivre et al. evaluated presenting hematological indices across different FA complementation groups in terms of their severity. They allocated a score of one point for each of three defined severe hematological parameters (Hb of less than or equal to 8 g/dl, an absolute neutrophil count of less than or equal to 0.5 × 109/l and platelet count of less than or equal to 20 × 109/l), giving each patient in their cohort a score out of three. Individuals with FANCG mutations were found to have a significantly higher scores out of three (mean score: 2.11) than individuals in complementation groups A and C, indicating severe cytopenia at presentation [10]. While the same score was not calculated for individuals in the present cohort as absolute neutrophil counts were not recorded, it was possible to evaluate the Hb and platelet values to determine severity based on the defined Faivre criteria [11]. Altogether, 14/30 (46.7%) patients were noted to have both Hb and platelet values below those used to define severe cytopenia at presentation. Of the 16 patients who did not meet both severity criteria, 14 patients (88%) had Hb values below 8 g/dl, while only one patient (6%) had a platelet count below 20 × 109/l. One patient (1/16; 6%) did not meet the criteria for either severe Hb or platelet count at presentation. Bone marrow aspirate and trephine reports were available for review in 27 of the 30 patients (90%). The median age of bone marrow aplasia was calculated as 7 years, 1 month (range: 2 years, 11 months– 12 years; N = 27), consistent with the age of presentation in most cases. Bone marrow aplasia was confirmed at the time of initial presentation to the hematology/oncology clinic in the majority of cases (24/27; 89%). In three of the 27 cases (11.1%), the age of initial presenting complaint and the age of bone marrow failure could be distinguished. Initial bone marrow biopsy reports in these patients showed no evidence of marrow aplasia. In the first patient, the disease course progressed over 6 months from the initial presentation of fatigue, to bone marrow aplasia diagnosed on a second bone marrow aspirate and trephine biopsy. The second patient progressed to bone marrow aplasia over 24 months
Table 2 Mean hematological indices at the time of diagnosis with FA. Hematological parameter
Mean value in FA patient
Range in FA cohort
Reference value
Hemoglobin (g/dl) White cell count (x 109/l) Platelet count (x 109/l) Mean corpuscular volume (fl) (N = 26)
4.77 (SD = 2.05) 2.61 (SD = 1.11) 23.50 (SD = 13.2) 106.46 (SD = 7.94)
1.6–9.9 1.3–5.1 6–43 86–113.5
11.5⁎ 4.0⁎ 150.0⁎ 95.0⁎⁎
⁎ Lower limit reference values for hematological indices in a normal pediatric population as found in Nelson Textbook of Pediatrics (19th ed., 2011) [18]. ⁎⁎ Upper limit reference value for mean corpuscular volume in a normal pediatric population as found in Nelson Textbook of Pediatrics (19th ed., 2011) [18].
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from the initial presentation with epistaxis. The third also presented with epistaxis and progressed over 6 months to bone marrow aplasia. None of the affected individuals in the present cohort were found to have changes in keeping with AML or acute lymphocytic leukemia (ALL) on their full blood count parameters or on their bone marrow aspirate and trephine reports. Two of the 27 patients (7.4%) for whom bone marrow biopsy reports were available for review were found to have features of MDS at the time of their FA diagnosis. In a study by Faivre et al. [10], the authors suggested a significantly higher AML/MDS frequency at 10 years of age (6/18; 33%) in FANCG individuals compared with individuals with FANCA and FANCC mutations [10]. Thirteen of the patients in the present research group were 10 years of age or older, and two of them (2/13; 15.4%) had features of MDS on their bone marrow biopsy reports. There was no significant difference in the incidence of AML/MDS in the present research group to that of the Faivre et al. (2000) cohort (p = 0.4395, Fisher's exact test). None of the patients were known or suspected to have developed any solid tumors or non-hematological malignancies at the time of data collection. All patients were started on androgen therapy at the time of diagnosis. Eleven of the 30 patients (36.7%) were TFD at the end of the data collection period. The median age of TFD was 7 years, 10 months of age (N = 11; range: 4 years, 8 months–13 years, 4 months). Average modified IFAR scores for the cohort were calculated and are shown in Table 3, along with the comparative analysis of the IFAR scores in the defined sub-cohorts. As only two patients developed MDS, it was not possible to draw any conclusions regarding the relationship of the hematological progression to their physical phenotype, even though interestingly both patients had high modified IFAR scores [4,5]. There were no statistically significant differences in the average scores between the group of patients with early onset transfusion dependence (before 8 years), and those who became transfusion dependent after 8 years of age or had not yet developed transfusion dependence (patients under the age of 8 years and not yet TFD were excluded from this analysis). However, a statistically significant difference was found between the modified IFAR scores in the group of hematologically severe patients and those with milder hematological indices at presentation (Table 3), the former group having higher modified IFAR scores than the latter. The average age of the patients in these sub-cohorts was not significantly different and could not explain this finding.
Discussion Despite the fact that well-documented and clinically identifiable physical anomalies occur in children with FA, aplastic anemia, usually manifesting in the first decade of life, remains the primary presenting feature for affected children globally [19]. In South African Black patients, this trend appears to be mirrored, with referrals to tertiary centers occurring late in the disease course, if at all. Unpublished data suggest that only one out of 15 affected individuals are referred for tertiary hematological care. In the present South African cohort, all patients were referred to Pediatric Hematology/Oncology Clinics already manifesting symptoms of significant bone marrow disease, with only a single patient referred on the basis of a physical anomaly—unusual skin pigmentation. Unfortunately, a previous evaluation of the physical phenotype of the present cohort did not highlight specific features, which could be easily identified by practitioners servicing primary health care facilities and which could alert them to the possible diagnosis of FA and the need for tertiary referral [17]. Although recommendations have been made to expedite referral of patients with growth deficiency and/or pigmentary anomalies (shown to be the most common physical features of FA in Black South African patients) for pediatric or medical geneticist evaluation, most Black patients with FA in South Africa will not be diagnosed prior to the onset of hematological symptoms which suggest severe cytopenia [17].
Please cite this article as: C. Feben, et al., Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia, Blood Cells Mol. Diseases (2014), http://dx.doi.org/10.1016/j.bcmd.2014.11.011
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C. Feben et al. / Blood Cells, Molecules and Diseases xxx (2014) xxx–xxx
Table 3 Comparison of average IFAR scores between patient sub-groups. Cohort
Number
Average modified IFAR score
p value (t-test)
Total cohort
30
2.6 (SD: 1.27)
–
Sub-cohorts TFD onset before 8 years of age TFD onset after 8 years of age + non-TFD and older than 8 years of age⁎ Severe hematological indices at presentation (Hb b 8 g/dl and platelet count b20 × 109/l) Non-severe hematological indices at presentation (Hb N 8 g/dl or platelet count N20 × 109/l)
6 12 14 16
2.5 (SD: 1.048) 2.7 (SD: 1.3) 3.21 (SD: 0.97) 2.07 (SD: 1.22)
0.7486 0.0098
⁎ Twelve patients were under the age of 8 years and non-TFD.
In the present cohort, the median age of presentation with symptoms of FA, usually concurrent with the diagnosis of bone marrow aplasia, was 7 years, 1 month of age, consistent with published data for other individuals with FA with the same and heterogeneous FA genotypes [16,20,21]. The most common presenting symptom was recurrent epistaxis, similar to the major presenting complaint documented by Macdougall et al. [20] in a Black South African FA cohort over 25 years ago. Although this hemorrhagic symptom relates directly to the pathophysiology of FA, with thrombocytopenia described as the first identifiable hematological disturbance, apart from macrocytosis [7], in the South African Black patients, a severely low Hb (b8 g/dl) was shown to be more common at presentation than a severely low platelet count (b20 × 109/l). The initial hematological indices appear to suggest that Black individuals with FA have severe cytopenia at first presentation with symptoms of FA. Although the research cohort cannot be directly compared with the Faivre et al. [10] cohort, the low presenting Hb and platelet count in the present cohort is an indicator that individuals with the FANCG founder mutation also present with more severe hematological indices than patients with FA of heterogeneous genotypes. However, the severe hematological indices do not appear to predict an earlier age of bone marrow aplasia. None of the patients were known or suspected to have developed any non-hematological malignancies. Anecdotally, one Black patient with FA, homozygous for the FANCG founder mutation, although not a participant in the present study is suspected to have developed a cervical squamous cell malignancy. This patient was also infected with the human immunodeficiency virus, making it difficult to attribute the malignancy to her FA. Apart from this single case, little is known about the progression of Black individuals with FA in terms of non-hematological malignancy and solid tumors as most patients are reported to demise before the age of 20 years. The poor availability of HSCT as a cure for bone marrow disease in South Africa most likely accounts for this low reported incidence of solid tumors detected in FA patients. It has previously been suggested that the severity of the physical phenotype or the presence of certain physical features of FA can be used to predict the hematological outcome in a patient. Rosenberg et al. [22] showed that the presence of radial aplasia was predictive of bone marrow failure in their cohort of individuals with FA of heterogeneous genotype. Investigation into the physical phenotype of Black individuals homozygous for the FANCG founder mutation showed that radial aplasia is a very uncommon finding [17], suggesting that this particular anomaly cannot be used as a predictor for hematological outcome in Black patients. When a modified IFAR score was calculated in the present patients, the mean score was significantly higher in individuals with severe cytopenia at presentation. Thus, it might be expected that a higher number of physical anomalies predicts a more severe hematological course. However, the patients with severe cytopenia did not have an earlier average age of bone marrow aplasia than those with milder hematological derangements at presentation. The incidence of MDS at 10 years of age and the conversion rates to AML and ALL in the research group were consistent with figures published by Faivre et al. [10]. This finding may suggest that individuals with the homozygous FANCG founder mutation are at higher risk of MDS than affected individuals with non-FANCG mutations. The two
patients who developed MDS had high modified IFAR scores. Owing to the small sample size of this cohort, it was not possible to draw specific conclusions, although the observation may suggest that further research is warranted into the physical phenotype of patients with MDS to assess for somatic anomalies of FA. While we did not observe any conversion to AML or ALL in the present cohort, our data were limited by the short time frame of the collection period. Further, it is documented that the cumulative risk of developing AML is around 13% by the age of 50 years, with most patients showing conversion between 15 and 35 years [2]. With a median current age of 9 years, 3 months at the time of the study, our patient cohort was too young to have shown significant AML conversion. Again, given the poor availability of HSCT, most patients would be expected to demise prior to AML conversion. In the South African context where hematology/oncology and medical genetics services are only available in tertiary centers that require referral from primary and secondary care facilities, a strategy for the earlier diagnosis of FA is required. While the present study highlights a positive relationship between severe cytopenia and a higher average modified IFAR score, it has already been shown that the physical anomalies in patients with FA are subtle and difficult to recognize and thus not easily detected in primary and secondary health care facilities [17]. As the history of recurrent epistaxis is present in a high percentage of patients, this symptom may be useful as an investigative handle for FA. Promoting awareness around recurrent epistaxis in children and a review of the current investigative strategies for children presenting with same may result in more expedient referral of affected children to tertiary centers. While the differential diagnosis for epistaxis is large and includes many acquired causes [23], recurrent epistaxis, particularly in a child with growth restriction or pigmentary anomalies (as are often seen in Black patients with FA), warrants further pediatric evaluation with further medical geneticist assessment as required. Conclusion Fanconi anemia in the Black South African population has a predicted prevalence of 1/40000, with more than 80% of affected individuals carrying the same FANCG founder mutation. Unfortunately, the majority of affected individuals will not be referred for tertiary care management of their condition, while those who are referred are already manifesting symptoms of severe cytopenia and bone marrow aplasia. The physical phenotype of affected patients has been shown to be not easily recognizable in primary and secondary health care facilities, further impeding the diagnosis of the condition and the timely referral of patients for tertiary care. New strategies are needed to improve recognition of this condition, particularly regarding the triad of epistaxis, growth restriction and pigmentary anomalies often found in affected children, such that patients are referred in the pre- or early anemic phase to allow the opportunity for appropriate treatment, including HSCT. Acknowledgments The authors wish to thank the Medical Research Council of South Africa for financial assistance as well as the medical, nursing and paramedical staff at the Chris Hani Baragwanath Hospital, The Charlotte
Please cite this article as: C. Feben, et al., Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia, Blood Cells Mol. Diseases (2014), http://dx.doi.org/10.1016/j.bcmd.2014.11.011
C. Feben et al. / Blood Cells, Molecules and Diseases xxx (2014) xxx–xxx
Maxeke Johannesburg Academic Hospital and the Universitas Hospital, for their assistance in patient recruitment and for their advice and input into care and management of the affected patients. The authors wish to acknowledge Ms. C. Van Wyk who provided genetic counseling to patients involved in the study. Further, the willingness of the patients and their families to participate in the study is much appreciated.
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Please cite this article as: C. Feben, et al., Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia, Blood Cells Mol. Diseases (2014), http://dx.doi.org/10.1016/j.bcmd.2014.11.011
