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Making the diagnosis of cystic fibrosis
PEDIATRICS THE JOURNAL OF
April 1998
Volume 132
Number 4
EDITORIALS
M
Making the diagnosis of cystic fibrosis
The diagnosis of cystic fibrosis has never been simple. Initially, CF was recognized as a clinical syndrome, but the features were not clearly distinguished from those of other causes of malabsorption and failure to thrive, such as gluten-sensitive enteropathy, until the late 1930s.1 In the late 1950s, the development of the sweat test, performed by quantitative pilocarpine iontophoresis, resolved many diagnostic dilemmas.2 Today this test remains clinically reliable3; however, falsenegative and false-positive test results have always been recognized. The cloning of the gene for the CF transmembrane conductance regulator in 19894,5 ushered in a new era, one in which clinicians hoped that genetic testing for CF would be both sensitive and specific. It soon became apparent that the most common mutation, a deletion of a phenylalanine residue at position 508 of CFTR,6 was not the only mutation causing this disease. However, few predicted the large number of sequence alterations in CFTR that would eventually be described. More than 700 mutations of CFTR associated with clinical CF have been reported, as well as many other sequence alterations. This large number of mutations has made genetic
J Pediatr 1998;132:563-5 Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/18/88516
testing for CF more difficult to develop, although the rarity of most of the mutations has made it possible to screen by using a panel of 70 mutations with a sensitivity approaching 90% in the general population of the United States.7 The complexity of this problem has been increased by the recognition that there are clinical presentations of CF that were previously unrecognized; for example, many young men with bilateral absence of the vas deferens have been identified in infertility clinics, and some of them have two recognized CF mutations with few or no symptoms. Many have one copy of a CFTR mutation.8,9
See related articles, p. 589 and p. 596. To address the question “What is a diagnosis of CF?” the Cystic Fibrosis Foundation convened a consensus conference in 1996, which led to the statement prepared by Rosenstein and Cutting10 and published in this issue of The Journal. It was the consensus of the panel that laboratory criteria for the diagnosis of CF should be expanded to include identification of CFTR mutations and abnormal bioelectrical properties of nasal epithelium, in addition to the sweat test, in patients with typical clinical features, a family history of CF, or a positive result on newborn screening. It is be-
lieved that, in the future, most diagnoses of CF will still be confirmed by the sweat test but that the other methods of documenting abnormalities of CFTR should be used when the sweat test values are borderline or normal. The acceptance of a positive newborn screening result as a basis for supporting the diagnosis of CF, in the absence of a family history of CF or typical symptoms, is a new clinical criterion. This recommendation is based on the results of pilot studies that have shown that almost all infants identified in this way subsequently have classic symptoms of CF if they have a positive sweat test result or two CF mutations. The criteria by which a mutation of CFTR should be considered a disease-producing mutation are presented in the consensus statement,10 and such mutations are listed in the Cystic Fibrosis Mutation Database of the Cystic Fibrosis Genetic Analysis Consortium, which is available on the World Wide Web (http://www.genet. sickkids.on.ca/cftr/). CF Cystic fibrosis CFTR Cystic fibrosis transmembrane conductance regulator PD Potential difference
Study of genotype-phenotype relationships has led to the recognition that the full spectrum of clinical disease can be only partially predicted from the CF mutation. For example, in intron 8 of 563
EDITORIALS
CFTR, there is a polythymidine tract (long tract) in the messenger RNA splice acceptor site for exon 9 of CFTR, and three long-tract variants have been discovered: 5T, 7T, and 9T.11 The length of this tract affects the splicing efficiency of exon 9 and the amount of full-length functional CFTR produced. The mutation R117H on a 9T background does not meet the criteria for a CF mutation, but in conjunction with the 5T allele it often produces a clinical picture of CF with pancreatic sufficiency. In conjunction with a 7T allele, it is usually associated with an atypical presentation such as bilateral absence of the vas deferens.12 The panel recommended that in the majority of cases CF will be diagnosed from a sweat test but that, when the sweat test result is normal or borderline, diagnosis can be based on identification of two known CF mutations. However, the consensus panel determined that neither R117H alone, nor the presence of the 5T allele alone, is a CF mutation. The use of the nasal potential difference measurement to confirm the diagnosis of CF was considered acceptable by the consensus panel. This test is based on the recognition that CF respiratory epithelia conduct sodium (Na+) and chloride (Cl–) ions abnormally, with a resulting hyperpolarization of the membrane. Reduced chloride secretion through the cyclic adenosine monophosphate–regulated Cl– channel (CFTR) and increased Na+ resorption through the epithelial sodium channel13,14 are manifested by different patterns of PD responses to amiloride, chloride-free solutions, and isoproterenol that can be used for diagnostic testing.15 The consensus statement provides clinical guidelines for using PD measurements to validate a CF diagnosis; importantly, it also comments on the limitations of this technically challenging procedure. The most controversial recommendation to come out of the consensus conference relates to the question of which diagnosis should be given to a man who has only the genital manifestations of CFTR dysfunction (azoospermia) and who has no evidence of respiratory or pancreatic disease. It is recommended that if such a person has a positive sweat 564
THE JOURNAL OF PEDIATRICS APRIL 1998 test result, two CF mutations, or abnormal nasal PD measurements, he be given the diagnosis of CF. This question has been debated at national conferences, and clearly there are some CF physicians who are not comfortable calling this disorder “CF.” However, these men may be at risk of having later complications of CF, and their family members are at risk of having children with “classic CF.” The question of how to classify such individuals is likely to be revisited as new data become available. The possible value of nasal PD measurements when the diagnosis of CF is uncertain is addressed in the article by Wilson et al.16 In this study, 11 patients without an established diagnosis of CF, and with atypical clinical features and borderline or normal sweat chloride values, had nasal PD measurements, which were compared with the measurements of 39 healthy volunteers, 14 obligate heterozygotes for ∆F508, and 36 patients with typical CF. Nine of the eleven patients had nasal PD responses similar to those of healthy volunteers, but two of them had a “CF profile,” with mean baseline values of –47 mV and no response to the β-agonist isoproterenol in a solution free of Cl– (a test of the response to cyclic adenosine monophosphate). Subsequent genetic analysis showed that both of these patients had a CF mutation on one chromosome (∆F508/G551D), with the 5T allele on the other one, indicating that this genotype may lead to a mild CF phenotype. The results of this study suggest that nasal PD measurements, when performed according to a standard protocol that tests the different components of ion transport, will be useful for ascertaining the diagnosis of CF when the sweat test results are normal or borderline. These two articles help us to recognize a broader spectrum of CF and also to consider other approaches such as genetic analysis and nasal PD measurement when diagnosis proves difficult. The consensus statement should be regarded as a snapshot of current opinions concerning the diagnosis of CF that is likely to change as research on genotype-phenotype relationships and CFTR function continues. Such research will likely shed more light on diagnostic dilemmas such as those of the two
patients with abnormal nasal PD measurements, one CF mutation, and a 5T allele reported in the article by Wilson et al.16 Robert W. Wilmott, MD Director, Pulmonary Medicine, Allergy and Clinical Immunology Children’s Hospital Medical Center Cincinnati, OH 45229-3039
REFERENCES 1. Andersen DH. Cystic fibrosis of the pancreas and its relation to celiac diseases. Am J Dis Child 1938;56:344-99. 2. Gibson LE, Cooke RE. A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis. Pediatrics 1959;23:545-9. 3. LeGrys VA. Sweat testing for the diagnosis of cystic fibrosis: practical considerations. J Pediatr 1996;129:892-7. 4. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245: 1066-73. 5. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989;245:1059-65. 6. Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989;245: 1073-80. 7. Stern RC. Current concepts: the diagnosis of cystic fibrosis. N Engl J Med 1997;336:487-91. 8. Chillon M, Casals T, Mercier B, Bassas L, Lissens W, Silber S, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 1995;332:1475-80. 9. Colin AA, Sawyer SM, Mickle JE, Oates RD, Milunsky A, Amos JA. Pulmonary function and clinical observations in men with congenital bilateral absence of the vas deferens. Chest 1996; 110:440-5. 10. Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr 1998;132:589-95. 11. Chu CS, Trapnell BC, Curristin S, Cutting GR, Crystal RG. Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet 1993;3:151-6. 12. Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 1995;29:777-807. 13. Knowles MR, Stutts MJ, Spock A, Fischer N, Gatzy JT, Boucher RC. Abnormal ion permeation through cystic
THE JOURNAL OF PEDIATRICS VOLUME 132, NUMBER 4 fibrosis respiratory epithelium. Science 1983;221:1067-70. 14. Burch LH, Talbot CR, Knowles MK, Canessa CM, Rossier BC, Boucher RC. Relative expression of the human epithelial Na+ channel subunits in normal and
T
EDITORIALS
cystic fibrosis airways. Am J Physiol Cell Physiol 1995;38:C511-8. 15. Knowles MR, Paradiso AM, Boucher RC. In vivo nasal potential difference: techniques and protocols for assessing efficacy of gene transfer in cystic fibrosis.
Hum Gene Ther 1995;6:445-55. 16. Wilson DC, Ellis L, Zielenski J, Corey M, Ip WF, Tsui LC, et al. Uncertainty in the diagnosis of cystic fibrosis: Possible role of in vivo nasal potential difference measurements. J Pediatr 1998;132:596-9.
The hematopoietic garden: How does it grow? The extraordinarily rare congenital disorders of bone marrow failure that result in pancytopenia and single cytopenias have provoked an interest among pediatric hematologists inversely proportional to their frequency. This interest is based in large part on the belief that an understanding of these pathophysiologically diverse disorders will shed important light on the regulation of hematopoiesis and the important control mechanisms in developmental biology. Indeed, careful analysis of the inherited pediatric bone marrow failure syndromes already described (Table I) strongly suggests that the regulatory factors involved may serve multiple functions related to morphogenesis and hematopoiesis. This seems especially true because single gene defects are implicated.1 Thus these rare disorders provide a unique opportunity to study the consequences of a variety of defects, the understanding of which will further elucidate the mechanisms essential to the regulation of hematopoiesis in particular and cellular growth and differentiation in general. With regard to hematopoiesis, a complex array of extrinsic growth factors interact with hematopoietic progenitors under the influence of intrinsic transcriptional regulators, resulting in the differentiation of pluripotent stem cells and their multilineage and lineage committed progeny. These progenitors populate the bone
J Pediatr 1998;132:565-7 Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/18/86422
marrow with morphologically recognizable precursors that ultimately give rise to functional hematopoietic cells. This process takes place within hematopoietic niches in the bone marrow. These niches provide a lineage-specific scaffold on which stem cells and progenitors, accessory cells, and growth factors may interact at close range. Thus in addition to hormone, cytokine, and transcription factors, receptor-ligand interactions further contribute to this highly complex regulatory network.
See related article, p. 600. Methods in cellular and molecular biology developed over the past 2 decades have delineated many of the components of this complex system. Stem cell “seeds” are anchored by receptor-ligand “roots” nurtured in a stromal “soil” by specific and nonspecific growth factor “fertilizer” and nutrients to give rise to an impressive “hematopoietic garden.” But in some gardens autumn comes far too early in the form of hematopoietic failure (Table II), which could result from intrinsically faulty “seeds,” defective “soil,” or immunologic “weeds.” These examples of an early fall are best illustrated by the experiments of nature that constitute the childhood bone marrow failure syndromes. One of these, Diamond Blackfan anemia, a rare pure red cell aplasia of childhood, results in erythropoietic failure at a median age of
approximately 2 months.2 This erythroid failure is characterized by erythroid progenitors and precursors highly susceptible to apoptosis.3 It is interesting that the word apoptosis, the hematologic equivalent of autumn, is derived from the Greek word for the “falling off,” as of leaves from trees.4 Apoptosis or programmed cell death is a normal regulatory mechanism by which the processes of embryonic development, normal tissue homeostasis, and response to cellular injury, to name a few, are controlled. The investigation of another marrow failure syndrome, Fanconi anemia, has led to the discovery of what may be a family of new regulatory genes.1 Thus the description of any new syndrome has potential importance in understanding this complex hematopoietic horticulture. In this issue of The Journal, Aladjidi et al.5 describe six girls with early-onset severe aplastic anemia who presented to a single center over a 10-year period. All six girls had marked pancytopenia before 1 year of age. The detailed clinical and laboratory evaluation, age at presentation, and familial nature of the cases support the diagnosis of an inherited bone marrow failure in five of the six. A detailed review of the medical literature has accumulated and catalogued hundreds of cases of inherited bone marrow failure syndromes6; this includes patients categorized as having amegakaryocytic thrombocytopenia without any physical abnormalities who had pancytopenia before 1 year of age. The rapidity of the onset of marrow apla565
April 1998
Volume 132
Number 4
EDITORIALS
M
Making the diagnosis of cystic fibrosis
The diagnosis of cystic fibrosis has never been simple. Initially, CF was recognized as a clinical syndrome, but the features were not clearly distinguished from those of other causes of malabsorption and failure to thrive, such as gluten-sensitive enteropathy, until the late 1930s.1 In the late 1950s, the development of the sweat test, performed by quantitative pilocarpine iontophoresis, resolved many diagnostic dilemmas.2 Today this test remains clinically reliable3; however, falsenegative and false-positive test results have always been recognized. The cloning of the gene for the CF transmembrane conductance regulator in 19894,5 ushered in a new era, one in which clinicians hoped that genetic testing for CF would be both sensitive and specific. It soon became apparent that the most common mutation, a deletion of a phenylalanine residue at position 508 of CFTR,6 was not the only mutation causing this disease. However, few predicted the large number of sequence alterations in CFTR that would eventually be described. More than 700 mutations of CFTR associated with clinical CF have been reported, as well as many other sequence alterations. This large number of mutations has made genetic
J Pediatr 1998;132:563-5 Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/18/88516
testing for CF more difficult to develop, although the rarity of most of the mutations has made it possible to screen by using a panel of 70 mutations with a sensitivity approaching 90% in the general population of the United States.7 The complexity of this problem has been increased by the recognition that there are clinical presentations of CF that were previously unrecognized; for example, many young men with bilateral absence of the vas deferens have been identified in infertility clinics, and some of them have two recognized CF mutations with few or no symptoms. Many have one copy of a CFTR mutation.8,9
See related articles, p. 589 and p. 596. To address the question “What is a diagnosis of CF?” the Cystic Fibrosis Foundation convened a consensus conference in 1996, which led to the statement prepared by Rosenstein and Cutting10 and published in this issue of The Journal. It was the consensus of the panel that laboratory criteria for the diagnosis of CF should be expanded to include identification of CFTR mutations and abnormal bioelectrical properties of nasal epithelium, in addition to the sweat test, in patients with typical clinical features, a family history of CF, or a positive result on newborn screening. It is be-
lieved that, in the future, most diagnoses of CF will still be confirmed by the sweat test but that the other methods of documenting abnormalities of CFTR should be used when the sweat test values are borderline or normal. The acceptance of a positive newborn screening result as a basis for supporting the diagnosis of CF, in the absence of a family history of CF or typical symptoms, is a new clinical criterion. This recommendation is based on the results of pilot studies that have shown that almost all infants identified in this way subsequently have classic symptoms of CF if they have a positive sweat test result or two CF mutations. The criteria by which a mutation of CFTR should be considered a disease-producing mutation are presented in the consensus statement,10 and such mutations are listed in the Cystic Fibrosis Mutation Database of the Cystic Fibrosis Genetic Analysis Consortium, which is available on the World Wide Web (http://www.genet. sickkids.on.ca/cftr/). CF Cystic fibrosis CFTR Cystic fibrosis transmembrane conductance regulator PD Potential difference
Study of genotype-phenotype relationships has led to the recognition that the full spectrum of clinical disease can be only partially predicted from the CF mutation. For example, in intron 8 of 563
EDITORIALS
CFTR, there is a polythymidine tract (long tract) in the messenger RNA splice acceptor site for exon 9 of CFTR, and three long-tract variants have been discovered: 5T, 7T, and 9T.11 The length of this tract affects the splicing efficiency of exon 9 and the amount of full-length functional CFTR produced. The mutation R117H on a 9T background does not meet the criteria for a CF mutation, but in conjunction with the 5T allele it often produces a clinical picture of CF with pancreatic sufficiency. In conjunction with a 7T allele, it is usually associated with an atypical presentation such as bilateral absence of the vas deferens.12 The panel recommended that in the majority of cases CF will be diagnosed from a sweat test but that, when the sweat test result is normal or borderline, diagnosis can be based on identification of two known CF mutations. However, the consensus panel determined that neither R117H alone, nor the presence of the 5T allele alone, is a CF mutation. The use of the nasal potential difference measurement to confirm the diagnosis of CF was considered acceptable by the consensus panel. This test is based on the recognition that CF respiratory epithelia conduct sodium (Na+) and chloride (Cl–) ions abnormally, with a resulting hyperpolarization of the membrane. Reduced chloride secretion through the cyclic adenosine monophosphate–regulated Cl– channel (CFTR) and increased Na+ resorption through the epithelial sodium channel13,14 are manifested by different patterns of PD responses to amiloride, chloride-free solutions, and isoproterenol that can be used for diagnostic testing.15 The consensus statement provides clinical guidelines for using PD measurements to validate a CF diagnosis; importantly, it also comments on the limitations of this technically challenging procedure. The most controversial recommendation to come out of the consensus conference relates to the question of which diagnosis should be given to a man who has only the genital manifestations of CFTR dysfunction (azoospermia) and who has no evidence of respiratory or pancreatic disease. It is recommended that if such a person has a positive sweat 564
THE JOURNAL OF PEDIATRICS APRIL 1998 test result, two CF mutations, or abnormal nasal PD measurements, he be given the diagnosis of CF. This question has been debated at national conferences, and clearly there are some CF physicians who are not comfortable calling this disorder “CF.” However, these men may be at risk of having later complications of CF, and their family members are at risk of having children with “classic CF.” The question of how to classify such individuals is likely to be revisited as new data become available. The possible value of nasal PD measurements when the diagnosis of CF is uncertain is addressed in the article by Wilson et al.16 In this study, 11 patients without an established diagnosis of CF, and with atypical clinical features and borderline or normal sweat chloride values, had nasal PD measurements, which were compared with the measurements of 39 healthy volunteers, 14 obligate heterozygotes for ∆F508, and 36 patients with typical CF. Nine of the eleven patients had nasal PD responses similar to those of healthy volunteers, but two of them had a “CF profile,” with mean baseline values of –47 mV and no response to the β-agonist isoproterenol in a solution free of Cl– (a test of the response to cyclic adenosine monophosphate). Subsequent genetic analysis showed that both of these patients had a CF mutation on one chromosome (∆F508/G551D), with the 5T allele on the other one, indicating that this genotype may lead to a mild CF phenotype. The results of this study suggest that nasal PD measurements, when performed according to a standard protocol that tests the different components of ion transport, will be useful for ascertaining the diagnosis of CF when the sweat test results are normal or borderline. These two articles help us to recognize a broader spectrum of CF and also to consider other approaches such as genetic analysis and nasal PD measurement when diagnosis proves difficult. The consensus statement should be regarded as a snapshot of current opinions concerning the diagnosis of CF that is likely to change as research on genotype-phenotype relationships and CFTR function continues. Such research will likely shed more light on diagnostic dilemmas such as those of the two
patients with abnormal nasal PD measurements, one CF mutation, and a 5T allele reported in the article by Wilson et al.16 Robert W. Wilmott, MD Director, Pulmonary Medicine, Allergy and Clinical Immunology Children’s Hospital Medical Center Cincinnati, OH 45229-3039
REFERENCES 1. Andersen DH. Cystic fibrosis of the pancreas and its relation to celiac diseases. Am J Dis Child 1938;56:344-99. 2. Gibson LE, Cooke RE. A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis. Pediatrics 1959;23:545-9. 3. LeGrys VA. Sweat testing for the diagnosis of cystic fibrosis: practical considerations. J Pediatr 1996;129:892-7. 4. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245: 1066-73. 5. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989;245:1059-65. 6. Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989;245: 1073-80. 7. Stern RC. Current concepts: the diagnosis of cystic fibrosis. N Engl J Med 1997;336:487-91. 8. Chillon M, Casals T, Mercier B, Bassas L, Lissens W, Silber S, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 1995;332:1475-80. 9. Colin AA, Sawyer SM, Mickle JE, Oates RD, Milunsky A, Amos JA. Pulmonary function and clinical observations in men with congenital bilateral absence of the vas deferens. Chest 1996; 110:440-5. 10. Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr 1998;132:589-95. 11. Chu CS, Trapnell BC, Curristin S, Cutting GR, Crystal RG. Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet 1993;3:151-6. 12. Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet 1995;29:777-807. 13. Knowles MR, Stutts MJ, Spock A, Fischer N, Gatzy JT, Boucher RC. Abnormal ion permeation through cystic
THE JOURNAL OF PEDIATRICS VOLUME 132, NUMBER 4 fibrosis respiratory epithelium. Science 1983;221:1067-70. 14. Burch LH, Talbot CR, Knowles MK, Canessa CM, Rossier BC, Boucher RC. Relative expression of the human epithelial Na+ channel subunits in normal and
T
EDITORIALS
cystic fibrosis airways. Am J Physiol Cell Physiol 1995;38:C511-8. 15. Knowles MR, Paradiso AM, Boucher RC. In vivo nasal potential difference: techniques and protocols for assessing efficacy of gene transfer in cystic fibrosis.
Hum Gene Ther 1995;6:445-55. 16. Wilson DC, Ellis L, Zielenski J, Corey M, Ip WF, Tsui LC, et al. Uncertainty in the diagnosis of cystic fibrosis: Possible role of in vivo nasal potential difference measurements. J Pediatr 1998;132:596-9.
The hematopoietic garden: How does it grow? The extraordinarily rare congenital disorders of bone marrow failure that result in pancytopenia and single cytopenias have provoked an interest among pediatric hematologists inversely proportional to their frequency. This interest is based in large part on the belief that an understanding of these pathophysiologically diverse disorders will shed important light on the regulation of hematopoiesis and the important control mechanisms in developmental biology. Indeed, careful analysis of the inherited pediatric bone marrow failure syndromes already described (Table I) strongly suggests that the regulatory factors involved may serve multiple functions related to morphogenesis and hematopoiesis. This seems especially true because single gene defects are implicated.1 Thus these rare disorders provide a unique opportunity to study the consequences of a variety of defects, the understanding of which will further elucidate the mechanisms essential to the regulation of hematopoiesis in particular and cellular growth and differentiation in general. With regard to hematopoiesis, a complex array of extrinsic growth factors interact with hematopoietic progenitors under the influence of intrinsic transcriptional regulators, resulting in the differentiation of pluripotent stem cells and their multilineage and lineage committed progeny. These progenitors populate the bone
J Pediatr 1998;132:565-7 Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/18/86422
marrow with morphologically recognizable precursors that ultimately give rise to functional hematopoietic cells. This process takes place within hematopoietic niches in the bone marrow. These niches provide a lineage-specific scaffold on which stem cells and progenitors, accessory cells, and growth factors may interact at close range. Thus in addition to hormone, cytokine, and transcription factors, receptor-ligand interactions further contribute to this highly complex regulatory network.
See related article, p. 600. Methods in cellular and molecular biology developed over the past 2 decades have delineated many of the components of this complex system. Stem cell “seeds” are anchored by receptor-ligand “roots” nurtured in a stromal “soil” by specific and nonspecific growth factor “fertilizer” and nutrients to give rise to an impressive “hematopoietic garden.” But in some gardens autumn comes far too early in the form of hematopoietic failure (Table II), which could result from intrinsically faulty “seeds,” defective “soil,” or immunologic “weeds.” These examples of an early fall are best illustrated by the experiments of nature that constitute the childhood bone marrow failure syndromes. One of these, Diamond Blackfan anemia, a rare pure red cell aplasia of childhood, results in erythropoietic failure at a median age of
approximately 2 months.2 This erythroid failure is characterized by erythroid progenitors and precursors highly susceptible to apoptosis.3 It is interesting that the word apoptosis, the hematologic equivalent of autumn, is derived from the Greek word for the “falling off,” as of leaves from trees.4 Apoptosis or programmed cell death is a normal regulatory mechanism by which the processes of embryonic development, normal tissue homeostasis, and response to cellular injury, to name a few, are controlled. The investigation of another marrow failure syndrome, Fanconi anemia, has led to the discovery of what may be a family of new regulatory genes.1 Thus the description of any new syndrome has potential importance in understanding this complex hematopoietic horticulture. In this issue of The Journal, Aladjidi et al.5 describe six girls with early-onset severe aplastic anemia who presented to a single center over a 10-year period. All six girls had marked pancytopenia before 1 year of age. The detailed clinical and laboratory evaluation, age at presentation, and familial nature of the cases support the diagnosis of an inherited bone marrow failure in five of the six. A detailed review of the medical literature has accumulated and catalogued hundreds of cases of inherited bone marrow failure syndromes6; this includes patients categorized as having amegakaryocytic thrombocytopenia without any physical abnormalities who had pancytopenia before 1 year of age. The rapidity of the onset of marrow apla565