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Fanconi’s anaemia and unilateral thumb polydactyly – Don’t miss it
Journal of Plastic, Reconstructive & Aesthetic Surgery (2012) 65, 1083e1086
Fanconi’s anaemia and unilateral thumb polydactyly e Don’t miss it* D.J. Wilks, S.P.J. Kay, G. Bourke* Department of Plastic and Reconstructive Surgery, Leeds General Infirmary, Leeds LS1 3EX, United Kingdom Received 25 July 2011; accepted 4 February 2012
KEYWORDS Fanconi anaemia; Radial longitudinal deficiency; Thumb hypoplasia; Thumb duplication; Syndrome
Summary Fanconi’s anaemia (FA) is a rare, life threatening inherited syndrome. Patients usually present late in the first decade of life with aplastic anaemia or acute myeloid leukaemia. FA children are also at high risk of solid organ tumours, anogenital squamous cancers, and endocrinopathies. These patients can present with unilateral radial abnormalities including thumb duplication. Hand surgeons can help achieve early diagnosis and improved survival in this group by early referral for screening. In a retrospective study of 202 children with radial ray anomalies seen over a 20 year period seven children had FA. Of these seven with FA, four had bilateral thumb hypoplasia and three had unilateral thumb anomalies e two unilateral thumb hypoplasias and one thumb duplication. The three children with unilateral anomalies were diagnosed late, presenting with bone marrow failure. All three have subsequently died following late bone marrow transplants. This study highlights the link between unilateral radial anomalies, including thumb duplication and FA and the importance of early genetic referral for diagnosis and surveillance. ª 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction Fanconi’s anaemia (FA) is a rare heritable syndrome that is thought to affect approximately 3 per million live births in the US.1 FA is characterised by progressive bone marrow
* This work was presented at the 8th World Symposium on Congenital Malformations of the Hand and Upper Limb 2009 and BAPRAS summer meeting 2009. * Corresponding author. Tel.: þ44 (0)1133922876. E-mail address: [email protected] (G. Bourke).
failure and a marked predisposition to malignancy. Affected children have a median life expectancy of 30 years and 90% will develop bone marrow failure within the first decade of life. Early marrow transplantation can be life saving. Early diagnosis is important. A screening test is available but given the low yield and costs involved, routine screening of every child is not undertaken. It is known that upper limb radial anomalies are linked with FA. Children with these anomalies should be screened. We identified the incidence of FA amongst children presenting to a large, supraregional congenital hand service. Particular attention was paid to the age at which
1748-6815/$ - see front matter ª 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjps.2012.02.015
1084 FA was diagnosed, the type of radial anomaly and the existence of additional organ anomalies or endocrine imbalances.
Materials and methods A retrospective analysis was conducted of all children presenting with a radial anomaly (Radial longitudinal deficiency (RLD), thumb hypoplasia or thumb duplication) to the Children’s Hand Clinic in Leeds between January 1988 and September 2008. For each patient the type of radial anomaly was recorded and classified. Thumb duplications were grouped according to the Wassel classification.2 Those with radial deficiency were grouped according to the Bayne and Klug classification3 and children with hypoplastic thumbs further classified using the Blauth scale.4 Classifications were made with reference to recorded clinical findings, intraoperative findings and radiology. The age of presentation to the hand service was recorded along with the route of referral. Children included in the study were then cross-referenced with the regional genetic diagnostic service and the presence of known syndromes recorded.
Results A total of 202 patients with radial ray anomalies were identified. There was a slight male predominance (56%). The median age of presentation to the Children’s Hand Clinic was 10.0 months and 73% attended before the age of 2 years. Figure 1 illustrates the classification of radial ray anomalies observed along with the frequency of syndromes identified amongst each group. Forty-five (22%) children were identified as having a recognised syndrome (Table 1) and 33 children, without
D.J. Wilks et al. diagnosable syndromes, had evidence of at least one additional somatic anomaly; the most frequent of which being cardiac. At the time of presentation to the Children’s Hand Clinic, 118 (58%) children had been assessed by a paediatrician. A total of 45 (22%) children were seen by the regional genetics service either before or after the hand clinic visit.
Fanconi’s anaemia e timing of diagnosis and implications FA was diagnosed in seven patients in our study (3.5%). Four of these children had bilateral upper limb anomalies in keeping with what has been previously documented in the literature most recently by Webb et al.5 However, in our study, three of the seven children with FA had unilateral anomalies including one child with thumb duplication. Although two of the children with unilateral anomalies had additional pathology (unilateral renal agenesis, panhypopituitarism), the third child (with unilateral thumb hypoplasia) had no identifiable co-morbidities. The characteristics of all the children with FA are displayed in Table 2. The diagnosis of FA was made in the four children with bilateral hypoplastic thumbs within the first year life. However, the three children with less severe, unilateral anomalies were diagnosed late (aged 3.8, 4.4 and 10.0 years) following the onset of bone marrow failure. They were diagnosed either upon routine testing for elective operations or whilst treating infections. All three have since undergone urgent bone marrow transplants but none have survived more than 12 months post transplant. The advanced stage of their disease at the time of transplantation and the lack of opportunity to identify suitably
Figure 1 Hierarchical flow chart displaying the frequency of radial anomalies and syndromes associated with each diagnosis. Note: one patient within the unilateral hypoplasia group had a contralateral duplication (RLD, radial longitudinal dysplasia).
Fanconi’s anaemia and unilateral thumb polydactyly Table 1 Syndromes identified amongst children with radial ray anomalies. Syndrome
Frequency
VACTERL Holt oram Fanconi anaemia Okihiro Townes Other
14 10 7 2 2 10
Total
45
matched donors may have contributed to this poor outcome. In contrast, of the four children diagnosed before age 1, one child received a HLA matched sibling bone marrow transplant aged 4 and continues to do well 3.4 years post transplant. The other two children currently remain well with normal haematologic parameters. HLA matched siblings have been identified in both cases in preparation for transplantation at the time when marrow failure ensues. One child died during cardiac surgery.
Discussion Fanconi’s anaemia e the facts First described by the Swiss paediatrician Guido Fanconi in 1927, FA is a rare genetic disease, thought to affect approximately 1 in 300,000 live births.1 FA is a progressive bone marrow failure, cancer predisposing syndrome. Thirteen distinct genetic foci (termed complementation types) are associated with the disease, most of which are inherited in an autosomal recessive fashion.6 Bone marrow failure
Table 2
1085 typically occurs by ten years of age. Prompt bone marrow transplantation can be life saving. Data from 64 FA children who have undergone haematopoietic stem cell transplants (HSCT) show success rates associated with HLA matched sibling donors are consistently the highest, with 87% survival at 8 years.7 Success rates with transplantation from unmatched relatives and unrelated donors are significantly poorer, with 69% and 40% surviving to 8 years respectively.7 HSCT should ideally be carried out prior to the need for regular transfusions which may cause iron overload and HLA sensitisation, before the onset of myelodysplasia or AML and before neutropenia increases the risks of persistent infection. Univariate data suggests outcomes of transplantation are improved if carried out before the age of 10 years.7 Only 20% of FA patients have HLA matched siblings at the time of diagnosis. The possibility exists for the parents of the remaining 80% to give birth to a HLA matched but FA free sibling who may act as a stem cell donor. This may occur through normal conception but there is a risk of giving birth to another child affected by FA. Using preimplantation genetic diagnosis to select embryos with a HLA match but without FA e the so-called ‘Saviour Sibling,’ was first described in 2001.8 This process is long and complex, taking 4 years or more and requiring a mother of less than 35 years. This option is therefore, effectively eliminated in patients presenting late or with marrow failure. The association with haematological malignancy and FA is well documented.9,10 Individuals with FA have a 50-fold increased risk of all forms of cancers compared to the general population.9 Oesophageal cancer has a 2000-fold relative risk, head and neck squamous carcinomas 700fold relative risk and vulval cancer 4000-fold relative risk.9 Regular screening and management through a specialist multidisciplinary setting is therefore imperative and must commence at an early age.
Characteristics of children affected by Fanconi anaemia.
Sex
Age at diagnosis (Yrs)
Age at clinic (Yrs)
Anomaly (grade)
Co-existing anomalies
Outcome
M
Birth
0.2
Bilateral hypoplasia (2,4)
Tetralogy of fallot
F
Birth
0.2
Bilateral hypoplasia (2,4)
M
Birth
0.3
Bilateral hypoplasia (1,2)
M
0.7
1.9
Bilateral hypoplasia (4,3)
F
3.8
1.3
Unilateral hypoplasia (2)
Dysplastic hips Recurrent UTIs Pan pituitary deficiency Patent ductus arteriosus Micropenis Growth hormone deficiency Pelvic kidney Nil
M
4.4
2.3
Unilateral hypoplasia
Unilateral renal agenesis
F
10.0
1.5
Unilateral duplication (4)
Pan pituitary deficiency
Died following cardiac surgery Sibling BMT aged 4 Remains well Remains well Sibling HLA match Awaiting BMT Remains well Sibling HLA match Awaiting BMT Unrelated BMT aged 4. Died aged 4.5 Sibling BMT age 6 Died GVHD age 7 Haploid stem cell transplant age 11 Died GVHD age 11
1086
Diagnosis and costs Accurate and early diagnosis of FA is essential to improve survival. However, as the disease shows a marked clinical heterogeneity, lacking any pathognomic features, clinical diagnosis can be difficult. The most consistent clinical findings in affected children are skeletal abnormalities, present in 70%, taking the form of radial or vertebral anomalies or congenital dysplastic hips.11 Cafe ´ au lait spots, hypo- or hyperpigmentation are seen in 64%. A similar number are affected by growth delay. The most accurate test for FA is a chromosome breakage test using either Mitomycin or Diepoxybutane. This can be performed using a simple venous blood sample. Eleven centres perform chromosomal breakage analysis for FA in the UK, the cost of which varies from approximately £400 to £550 (I Kesterton, S Morris personal communication, July 21, 2010).
Unilateral anomalies including thumb duplication In this study, we describe a single case of FA in association with a Wassel 4 thumb duplication. In 1992, Alter demonstrated the link between thumb duplication and anaemias leading to bone marrow failure such as FA.12 In her study 7% of 700 cases of Fanconi Anaemia had evidence of thumb duplication. Despite this, children with thumb duplication and unilateral radial anomalies have not been routinely screened.13 In our study 3 of 7 cases of FA had unilateral anomalies with one case of thumb duplication. This contrasts with the 1 unilateral case in a total of 6 cases of FA in the recent paper by Webb et al.5 The small sample size in both studies makes data interpretation very difficult. It is not possible to draw robust, statistically significant conclusions from our data. However the results of our study combined with that of Alter would suggest that there is a definite link between radial anomalies (bilateral and unilateral, including duplication) and FA and strengthens the argument for screening all children with radial anomalies. The data, so far gathered, indicates the need for a prospective, multicentre trial to clarify the incidence of FA in children with the relatively common condition of thumb polydactyly.
How can we improve outcome? Children with multiple system involvement and bilateral upper limb anomalies will be diagnosed early with FA. However, it is those children with unilateral anomalies, who may not present to other clinicians that need to be referred to clinical genetics for cytogenetic assessment. The Leeds Children’s Hand Clinic assesses approximately 10 patients per year with radial anomalies. Of these, 1 in 4 will already have seen a geneticist. At a cost of £384 per test, screening all patients with radial anomalies using a DEB or MMC stress test will cost an additional £3000 per year. Based on the frequency of FA observed in this study, the cost of screening per case identified is approximately £11,081. This figure is likely to be an overestimate if
D.J. Wilks et al. children within this study remain undiagnosed. This additional cost is justified given the benefits that early intervention can afford these children.
Conclusion Defining the incidence and association of signs and symptoms with a syndrome that has such low frequency has inherent difficultly. The presence of bilateral RLD and thumb hypoplasia is well documented in patients with FA.5 However, the link between FA and unilateral anomalies including thumb duplication although previously published and presented12,13 has not translated into action in clinical practice. It is essential to recognise the variable presentation of FA and the need for genetic screening in all children with radial ray anomalies: unilateral, bilateral and duplications. Early diagnosis facilitates timely bone marrow transplantation and malignancy screening that may save lives.
Funding None.
Conflict of interest None.
References 1. Tischkowitz MD, Hodgson SV. Fanconi anaemia. J Med Genet 2003;40:1e10. 2. Wassel HD. The results of surgery for polydactyly of the thumb. Clin Orthop Relat Res. 1969;64:175e93. 3. Bayne LG, Klug MS. Long-term review of the surgical treatment of radial deficiencies. J Hand Surg 1987;12A:169e79. 4. Blauth W, Schneider-Sickert F. Numerical variations. In: Blauth W, Schneider-Sickert F, editors. Congenital deformities of the hand: an atlas of their surgical treatment. Berlin: Springer-Verlag; 1981. p. 120e1. 5. Webb ML, Rosen H, Taghinia A, et al. Incidence of Fanconi anemia in children with congenital thumb anomalies referred for diepoxybutane testing. J Hand Surg 2011;36(6):1052e7. 6. Alter BP. Diagnosis, genetics, and management of inherited bone marrow failure syndromes. Hematology 2007;12:29e39. 7. Wagner JE, Eapen M, Macmillan ML, et al. Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood 2007;109:2256e62. 8. Verlinsky Y, Rechitsky S, Schoolcraft W, Strom C, Kuliev A. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. JAMA 2001;285:3130e3. 9. Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood 2003;101:822e6. 10. Alter BP. Cancer in Fanconi anemia, 1927e2001. Cancer 2003; 97:425e40. 11. Dokal I. The genetics of Fanconi’s anaemia. Baillieres Best Pract Res Clin Haematol 2000;13:407e25. 12. Alter BP. Arm anomalies and bone marrow failure may go hand in hand. J Hand Surg 1992;17:566e71. 13. Wilks DJ, Bourke GB, Kay SPJ. Fanconi’s anaemia: A role for the children’s hand surgeon. The 8th world symposium on congenital malformations of the hand and upper limb, Hamburg, Germany; September 2009.
Fanconi’s anaemia and unilateral thumb polydactyly e Don’t miss it* D.J. Wilks, S.P.J. Kay, G. Bourke* Department of Plastic and Reconstructive Surgery, Leeds General Infirmary, Leeds LS1 3EX, United Kingdom Received 25 July 2011; accepted 4 February 2012
KEYWORDS Fanconi anaemia; Radial longitudinal deficiency; Thumb hypoplasia; Thumb duplication; Syndrome
Summary Fanconi’s anaemia (FA) is a rare, life threatening inherited syndrome. Patients usually present late in the first decade of life with aplastic anaemia or acute myeloid leukaemia. FA children are also at high risk of solid organ tumours, anogenital squamous cancers, and endocrinopathies. These patients can present with unilateral radial abnormalities including thumb duplication. Hand surgeons can help achieve early diagnosis and improved survival in this group by early referral for screening. In a retrospective study of 202 children with radial ray anomalies seen over a 20 year period seven children had FA. Of these seven with FA, four had bilateral thumb hypoplasia and three had unilateral thumb anomalies e two unilateral thumb hypoplasias and one thumb duplication. The three children with unilateral anomalies were diagnosed late, presenting with bone marrow failure. All three have subsequently died following late bone marrow transplants. This study highlights the link between unilateral radial anomalies, including thumb duplication and FA and the importance of early genetic referral for diagnosis and surveillance. ª 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction Fanconi’s anaemia (FA) is a rare heritable syndrome that is thought to affect approximately 3 per million live births in the US.1 FA is characterised by progressive bone marrow
* This work was presented at the 8th World Symposium on Congenital Malformations of the Hand and Upper Limb 2009 and BAPRAS summer meeting 2009. * Corresponding author. Tel.: þ44 (0)1133922876. E-mail address: [email protected] (G. Bourke).
failure and a marked predisposition to malignancy. Affected children have a median life expectancy of 30 years and 90% will develop bone marrow failure within the first decade of life. Early marrow transplantation can be life saving. Early diagnosis is important. A screening test is available but given the low yield and costs involved, routine screening of every child is not undertaken. It is known that upper limb radial anomalies are linked with FA. Children with these anomalies should be screened. We identified the incidence of FA amongst children presenting to a large, supraregional congenital hand service. Particular attention was paid to the age at which
1748-6815/$ - see front matter ª 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjps.2012.02.015
1084 FA was diagnosed, the type of radial anomaly and the existence of additional organ anomalies or endocrine imbalances.
Materials and methods A retrospective analysis was conducted of all children presenting with a radial anomaly (Radial longitudinal deficiency (RLD), thumb hypoplasia or thumb duplication) to the Children’s Hand Clinic in Leeds between January 1988 and September 2008. For each patient the type of radial anomaly was recorded and classified. Thumb duplications were grouped according to the Wassel classification.2 Those with radial deficiency were grouped according to the Bayne and Klug classification3 and children with hypoplastic thumbs further classified using the Blauth scale.4 Classifications were made with reference to recorded clinical findings, intraoperative findings and radiology. The age of presentation to the hand service was recorded along with the route of referral. Children included in the study were then cross-referenced with the regional genetic diagnostic service and the presence of known syndromes recorded.
Results A total of 202 patients with radial ray anomalies were identified. There was a slight male predominance (56%). The median age of presentation to the Children’s Hand Clinic was 10.0 months and 73% attended before the age of 2 years. Figure 1 illustrates the classification of radial ray anomalies observed along with the frequency of syndromes identified amongst each group. Forty-five (22%) children were identified as having a recognised syndrome (Table 1) and 33 children, without
D.J. Wilks et al. diagnosable syndromes, had evidence of at least one additional somatic anomaly; the most frequent of which being cardiac. At the time of presentation to the Children’s Hand Clinic, 118 (58%) children had been assessed by a paediatrician. A total of 45 (22%) children were seen by the regional genetics service either before or after the hand clinic visit.
Fanconi’s anaemia e timing of diagnosis and implications FA was diagnosed in seven patients in our study (3.5%). Four of these children had bilateral upper limb anomalies in keeping with what has been previously documented in the literature most recently by Webb et al.5 However, in our study, three of the seven children with FA had unilateral anomalies including one child with thumb duplication. Although two of the children with unilateral anomalies had additional pathology (unilateral renal agenesis, panhypopituitarism), the third child (with unilateral thumb hypoplasia) had no identifiable co-morbidities. The characteristics of all the children with FA are displayed in Table 2. The diagnosis of FA was made in the four children with bilateral hypoplastic thumbs within the first year life. However, the three children with less severe, unilateral anomalies were diagnosed late (aged 3.8, 4.4 and 10.0 years) following the onset of bone marrow failure. They were diagnosed either upon routine testing for elective operations or whilst treating infections. All three have since undergone urgent bone marrow transplants but none have survived more than 12 months post transplant. The advanced stage of their disease at the time of transplantation and the lack of opportunity to identify suitably
Figure 1 Hierarchical flow chart displaying the frequency of radial anomalies and syndromes associated with each diagnosis. Note: one patient within the unilateral hypoplasia group had a contralateral duplication (RLD, radial longitudinal dysplasia).
Fanconi’s anaemia and unilateral thumb polydactyly Table 1 Syndromes identified amongst children with radial ray anomalies. Syndrome
Frequency
VACTERL Holt oram Fanconi anaemia Okihiro Townes Other
14 10 7 2 2 10
Total
45
matched donors may have contributed to this poor outcome. In contrast, of the four children diagnosed before age 1, one child received a HLA matched sibling bone marrow transplant aged 4 and continues to do well 3.4 years post transplant. The other two children currently remain well with normal haematologic parameters. HLA matched siblings have been identified in both cases in preparation for transplantation at the time when marrow failure ensues. One child died during cardiac surgery.
Discussion Fanconi’s anaemia e the facts First described by the Swiss paediatrician Guido Fanconi in 1927, FA is a rare genetic disease, thought to affect approximately 1 in 300,000 live births.1 FA is a progressive bone marrow failure, cancer predisposing syndrome. Thirteen distinct genetic foci (termed complementation types) are associated with the disease, most of which are inherited in an autosomal recessive fashion.6 Bone marrow failure
Table 2
1085 typically occurs by ten years of age. Prompt bone marrow transplantation can be life saving. Data from 64 FA children who have undergone haematopoietic stem cell transplants (HSCT) show success rates associated with HLA matched sibling donors are consistently the highest, with 87% survival at 8 years.7 Success rates with transplantation from unmatched relatives and unrelated donors are significantly poorer, with 69% and 40% surviving to 8 years respectively.7 HSCT should ideally be carried out prior to the need for regular transfusions which may cause iron overload and HLA sensitisation, before the onset of myelodysplasia or AML and before neutropenia increases the risks of persistent infection. Univariate data suggests outcomes of transplantation are improved if carried out before the age of 10 years.7 Only 20% of FA patients have HLA matched siblings at the time of diagnosis. The possibility exists for the parents of the remaining 80% to give birth to a HLA matched but FA free sibling who may act as a stem cell donor. This may occur through normal conception but there is a risk of giving birth to another child affected by FA. Using preimplantation genetic diagnosis to select embryos with a HLA match but without FA e the so-called ‘Saviour Sibling,’ was first described in 2001.8 This process is long and complex, taking 4 years or more and requiring a mother of less than 35 years. This option is therefore, effectively eliminated in patients presenting late or with marrow failure. The association with haematological malignancy and FA is well documented.9,10 Individuals with FA have a 50-fold increased risk of all forms of cancers compared to the general population.9 Oesophageal cancer has a 2000-fold relative risk, head and neck squamous carcinomas 700fold relative risk and vulval cancer 4000-fold relative risk.9 Regular screening and management through a specialist multidisciplinary setting is therefore imperative and must commence at an early age.
Characteristics of children affected by Fanconi anaemia.
Sex
Age at diagnosis (Yrs)
Age at clinic (Yrs)
Anomaly (grade)
Co-existing anomalies
Outcome
M
Birth
0.2
Bilateral hypoplasia (2,4)
Tetralogy of fallot
F
Birth
0.2
Bilateral hypoplasia (2,4)
M
Birth
0.3
Bilateral hypoplasia (1,2)
M
0.7
1.9
Bilateral hypoplasia (4,3)
F
3.8
1.3
Unilateral hypoplasia (2)
Dysplastic hips Recurrent UTIs Pan pituitary deficiency Patent ductus arteriosus Micropenis Growth hormone deficiency Pelvic kidney Nil
M
4.4
2.3
Unilateral hypoplasia
Unilateral renal agenesis
F
10.0
1.5
Unilateral duplication (4)
Pan pituitary deficiency
Died following cardiac surgery Sibling BMT aged 4 Remains well Remains well Sibling HLA match Awaiting BMT Remains well Sibling HLA match Awaiting BMT Unrelated BMT aged 4. Died aged 4.5 Sibling BMT age 6 Died GVHD age 7 Haploid stem cell transplant age 11 Died GVHD age 11
1086
Diagnosis and costs Accurate and early diagnosis of FA is essential to improve survival. However, as the disease shows a marked clinical heterogeneity, lacking any pathognomic features, clinical diagnosis can be difficult. The most consistent clinical findings in affected children are skeletal abnormalities, present in 70%, taking the form of radial or vertebral anomalies or congenital dysplastic hips.11 Cafe ´ au lait spots, hypo- or hyperpigmentation are seen in 64%. A similar number are affected by growth delay. The most accurate test for FA is a chromosome breakage test using either Mitomycin or Diepoxybutane. This can be performed using a simple venous blood sample. Eleven centres perform chromosomal breakage analysis for FA in the UK, the cost of which varies from approximately £400 to £550 (I Kesterton, S Morris personal communication, July 21, 2010).
Unilateral anomalies including thumb duplication In this study, we describe a single case of FA in association with a Wassel 4 thumb duplication. In 1992, Alter demonstrated the link between thumb duplication and anaemias leading to bone marrow failure such as FA.12 In her study 7% of 700 cases of Fanconi Anaemia had evidence of thumb duplication. Despite this, children with thumb duplication and unilateral radial anomalies have not been routinely screened.13 In our study 3 of 7 cases of FA had unilateral anomalies with one case of thumb duplication. This contrasts with the 1 unilateral case in a total of 6 cases of FA in the recent paper by Webb et al.5 The small sample size in both studies makes data interpretation very difficult. It is not possible to draw robust, statistically significant conclusions from our data. However the results of our study combined with that of Alter would suggest that there is a definite link between radial anomalies (bilateral and unilateral, including duplication) and FA and strengthens the argument for screening all children with radial anomalies. The data, so far gathered, indicates the need for a prospective, multicentre trial to clarify the incidence of FA in children with the relatively common condition of thumb polydactyly.
How can we improve outcome? Children with multiple system involvement and bilateral upper limb anomalies will be diagnosed early with FA. However, it is those children with unilateral anomalies, who may not present to other clinicians that need to be referred to clinical genetics for cytogenetic assessment. The Leeds Children’s Hand Clinic assesses approximately 10 patients per year with radial anomalies. Of these, 1 in 4 will already have seen a geneticist. At a cost of £384 per test, screening all patients with radial anomalies using a DEB or MMC stress test will cost an additional £3000 per year. Based on the frequency of FA observed in this study, the cost of screening per case identified is approximately £11,081. This figure is likely to be an overestimate if
D.J. Wilks et al. children within this study remain undiagnosed. This additional cost is justified given the benefits that early intervention can afford these children.
Conclusion Defining the incidence and association of signs and symptoms with a syndrome that has such low frequency has inherent difficultly. The presence of bilateral RLD and thumb hypoplasia is well documented in patients with FA.5 However, the link between FA and unilateral anomalies including thumb duplication although previously published and presented12,13 has not translated into action in clinical practice. It is essential to recognise the variable presentation of FA and the need for genetic screening in all children with radial ray anomalies: unilateral, bilateral and duplications. Early diagnosis facilitates timely bone marrow transplantation and malignancy screening that may save lives.
Funding None.
Conflict of interest None.
References 1. Tischkowitz MD, Hodgson SV. Fanconi anaemia. J Med Genet 2003;40:1e10. 2. Wassel HD. The results of surgery for polydactyly of the thumb. Clin Orthop Relat Res. 1969;64:175e93. 3. Bayne LG, Klug MS. Long-term review of the surgical treatment of radial deficiencies. J Hand Surg 1987;12A:169e79. 4. Blauth W, Schneider-Sickert F. Numerical variations. In: Blauth W, Schneider-Sickert F, editors. Congenital deformities of the hand: an atlas of their surgical treatment. Berlin: Springer-Verlag; 1981. p. 120e1. 5. Webb ML, Rosen H, Taghinia A, et al. Incidence of Fanconi anemia in children with congenital thumb anomalies referred for diepoxybutane testing. J Hand Surg 2011;36(6):1052e7. 6. Alter BP. Diagnosis, genetics, and management of inherited bone marrow failure syndromes. Hematology 2007;12:29e39. 7. Wagner JE, Eapen M, Macmillan ML, et al. Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood 2007;109:2256e62. 8. Verlinsky Y, Rechitsky S, Schoolcraft W, Strom C, Kuliev A. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. JAMA 2001;285:3130e3. 9. Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood 2003;101:822e6. 10. Alter BP. Cancer in Fanconi anemia, 1927e2001. Cancer 2003; 97:425e40. 11. Dokal I. The genetics of Fanconi’s anaemia. Baillieres Best Pract Res Clin Haematol 2000;13:407e25. 12. Alter BP. Arm anomalies and bone marrow failure may go hand in hand. J Hand Surg 1992;17:566e71. 13. Wilks DJ, Bourke GB, Kay SPJ. Fanconi’s anaemia: A role for the children’s hand surgeon. The 8th world symposium on congenital malformations of the hand and upper limb, Hamburg, Germany; September 2009.