REVIEW ARTICLE
Diamond-Blackfan anemia and nutritional deficiency-induced anemia in children David Gelbart, MMS, PA-C
ABSTRACT Diamond-Blackfan anemia is a rare, inherited disease that characteristically presents as a chronic, normochromic macrocytosis due to red cell lineage bone marrow failure. Although studies are elaborating on the genetic basis for its associated comorbidities, little has been published comparing this anemia to other chronic anemias that have similar laboratory results in children. This article offers a global perspective of the disease and compares it with anemia due to vitamin B12 and folate deficiency in children. Keywords: Diamond-Blackfan anemia, bone marrow failure, autosomal dominant, macrocytosis, reticulopenia, inherited erythroblastopenia FIGURE 1. Characteristics of Diamond-Blackfan anemia
D
iamond-Blackfan anemia is a rare worldwide (5 to 7 cases per 1,000,000 population), autosomaldominant disease caused by a failure of erythrocyte progenitor cells in the bone marrow.1,2 Although the apparently numerous factors leading to this malfunction are not completely understood, the result is a clinical anemia characterized by normochromic macrocytosis with reticulocytopenia that usually presents within the first year of life.2 About 90% of patients present in early childhood, with the remainder presenting “nonclassically” (after age 1 year) and typically less severely.3 Research is attempting to better implicate the known gene mutations of the disease with several associated congenital defects. The combination of the disease’s variable symptomatology and distinct hematologic characteristics is particularly worrisome: Diamond-Blackfan anemia can be misdiagnosed due to its similarities with other chronic childhood anemias, including those caused by nutritional deficiencies. This article describes the evidence-based research on David Gelbart is a physician assistant at Advanced Care Emergency Services at Western Arizona Regional Medical Center in Bullhead City, Ariz. The author has disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000442702.95598.fc Copyright © 2014 American Academy of Physician Assistants
36
www.JAAPA.com
include decreased reticulocytes and normal to decreased white cells and platelets.
Diamond-Blackfan anemia and provides a guide for including Diamond-Blackfan anemia in the differential diagnosis of normochromic, macrocytic anemia in pediatric patients. BACKGROUND Interest in the pathogenesis of Diamond-Blackfan anemia has led to the consideration of this disease as the prototype of ribosome-based disorders.2 More than half of patients are found to have one or more mutations on RPS and/or RPL genes, most notably, RPS19.2,3 These genes encode ribosomal proteins that normally contribute to the differentiation and proliferation of red blood cell progenitor cells; however, in Diamond-Blackfan anemia, this pathway appears absent or altered.2,4 A current thought based on recent research is that altered ribosomal proteins increase erythroblastic apoptosis.4 Single point, missense, and deletion mutations of the RPS genes have been statistically implicated in the associated congenital anomalies as well, but these mechanisms are not understood.3 Fifty-five percent of patients do not possess a mutation in the known RPS genes, suggesting a multifactor pathogenesis of the disease.2 In addition, the heterogeneous manifestations appear to correlate with patterns of gene mutation. For Volume 27 • Number 4 • April 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Diamond-Blackfan anemia and nutritional deficiency-induced anemia in children
Key points Diamond-Blackfan anemia characteristically presents as a chronic normochromic macrocytosis. However, it can be confused with anemias caused by nutritional deficiencies. About 90% of patients with this rare, inherited disease present in early childhood. Patients with Diamond-Blackfan anemia are at increased risk for complications associated with chronic bone marrow disorder, including hematologic malignancies. Hematopoietic stem-cell transplantation is the definitive treatment for Diamond-Blackfan anemia.
example, alterations of the RPL5 gene may yield multiple malformations including those of the thumbs, heart, and craniofacial region; RPS11 is linked to deformity of the thumbs alone.3 Regardless of the mechanisms responsible for erythroid cell failure, patients with Diamond-Blackfan anemia are at increased risk for complications associated with chronic bone marrow disorder. These include hematologic malignancies such as acute myeloid leukemia, acute lymphoblastic leukemia, myelodysblastic syndrome, and Hodgkin and non-Hodgkin lymphoma.2,4 Other nonhematologic cancers also have been reported. VITAMIN B12 AND FOLATE DEFICIENCY ANEMIAS Nutritional deficits such as vitamin B deficiency anemias can manifest as normochromic, macrocytic anemia with low reticulocyte counts. Other apparent clinical signs, such as lethargy, failure to thrive, and psychological changes, also parallel the symptomology of Diamond-Blackfan anemia in children. Insufficient dietary intake of vitamin B12 and folate in infants and children is rare, even with the increased demand for these vitamins during growth and development.4 Causes of nutritional deficiencies include malabsorption diseases, congenital deficits of vitaminprotein carriers, HIV, and infants or nursing mothers adhering to vegan diets.2,5 Because Diamond-Blackfan anemia is rare, providers must consider Diamond-Blackfan anemia and nutritional deficiencies as the underlying pathology in this clinical picture. PSYCHONEUROLOGICAL ISSUES Vitamin B deficiencies may cause central nervous system demyelination and lead to psychological and neurologic impairments, so improved psychosocial function is a treatment goal for children with nutritional deficiencyinduced anemia.6 Interestingly, a recent study reported that Diamond-Blackfan anemia may contribute to signs of obsessive compulsive disorder (OCD), which is often misdiagnosed for other causes of learning disability.7 Consider investigating for Diamond-Blackfan anemia in a child with normochromic macrocytosis and reticulocy-
topenia who has psychological or behavior disturbances affecting school performance and social integration. Symptoms may include irritability; compulsive behaviors such as pica in the absence of iron deficiency; or behaviors consistent within the spectrum of autism and Asperger disease or attention-deficit hyperactivity disorder. Although evidence linking OCD to Diamond-Blackfan anemia is limited, the basis for the concern, especially in the differential diagnosis of other chronic anemias affecting psychoneurologic function, is the apparent association of cerebral hemosiderosis in OCD.7 Psychological manifestations secondary to hemosiderosis may occur in patients with Diamond-Blackfan anemia even in the absence of the above comorbidities. Hemosiderosis occurs iatrogenically because blood transfusions— mainstay in the treatment of Diamond-Blackfan anemia— can lead to iron accumulation in the brain. Because of the possible association of OCD with Diamond-Blackfan anemia and the iatrogenic hemosiderosis of blood transfusions, more regular MRIs may be warranted in children with normochromic, macrocytic anemia. MRI is useful in detecting iron overload in the brain, and could serve as a diagnostic tool in the differential diagnosis of Diamond-Blackfan anemia and nutritional deficiency anemias. For example, iron accumulation in DiamondBlackfan anemia in the absence of blood transfusions may further clinically link OCD to Diamond-Blackfan anemia and aid in ruling out vitamin B deficiencies. Conversely, children who are newly diagnosed with nutritional deficiency anemia may benefit from a routine head MRI for the more rapid diagnosis of Diamond-Blackfan anemia, which might otherwise be missed. One last implication of the psychological comorbidities with Diamond-Blackfan anemia relates to the medical treatment of these symptoms. Because hemosiderosis may result either from OCD or through blood transfusion, and because iron overload destroys dopaminergenic neurons, dopaminergic agonists may be ineffective in treating psychological manifestations in patients with Diamond-Blackfan anemia. However, SSRIs have been shown effective in treating OCD in patients who also have Diamond-Blackfan anemia.7 CONGENITAL ANOMALIES Characteristic features of Diamond-Blackfan anemia include several reported congenital anomalies. Up to 47% of patients with Diamond-Blackfan anemia will present with these associated findings.8 Identifying these anomalies has been helpful in the diagnosis of Diamond-Blackfan anemia; however, clinicians should be aware that most of these signs have not been genotypically linked to DiamondBlackfan anemia or may be accounted for by exogenous intervention. Therefore, nutritional deficiency-induced anemias may not be ruled out solely on the basis of these findings.
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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37
Diamond-Blackfan anemia and nutritional deficiency-induced anemia in children
Thumb deformities Perhaps the most specific congenital anomaly to Diamond-Blackfan anemia is thumb deformity. Multiple studies have shown a direct correlation between these malformations and mutations of the RPS and RPL genes. The CDC reports that about 20% of patients with Diamond-Blackfan anemia will present with altered thumb structure or function.9 A triphalangeal thumb occurs when the digit has an additional joint, resembling the other fingers on the hand. Bifid thumbs are divided longitudinally in the middle, resembling two separate thumbs with a common origin. Hypoplastic thumbs may be short, underdeveloped, or ectopically located. Flat or absent thenar musculature may decrease or disallow function. Many patients with these comorbidities will benefit greatly from routine surgery that can be done on an outpatient basis or require only an overnight stay.9 Short stature Much research acknowledges short stature as a statistically significant finding among patients with Diamond-Blackfan anemia. Although ribosomal protein gene mutations may contribute to this finding, several factors exclude short stature as a reported congenital anomaly in Diamond-Blackfan anemia. In children who are at least two standard deviations below average height, causes include other chronic illnesses, maternal intrauterine infection, constitutional delay, endocrinopathies, inheritance, and spinal deformity. Short stature is common among patients with Diamond-Blackfan anemia and chronic nutritional deficiency that may manifest as anemia. Use of corticosteroids to treat Diamond-Blackfan anemia also may contribute to short stature. Because corticosteroid use in children can retard growth, differentiating the disease from the treatment as a cause of short stature is difficult. Also, chronic corticosteroid use suppresses the immune system, increasing the patient’s chance for chronic infection. Although the author did not perform a statistical analysis of chronic infection associated with corticosteroid treatment in Diamond-Blackfan anemia, chronic infection may be a factor in short stature not directly caused by the pathogenesis of Diamond-Blackfan anemia. Cardiac anomalies About 15% of patients with Diamond-Blackfan anemia present with a heart defect at birth.9 The most common defects are atrial septal defects, ventricular septal defects, and coarctation of the aorta.9 Although cardiac anomalies are not specific to DiamondBlackfan anemia, they are important comorbidities of the disease. Maxillofacial anomalies Between 3% and 10% of patients with Diamond-Blackfan anemia also have cleft lip and palate.10 However, no correlation is apparent between cleft lip or palate and the RPS genes, suggesting multiple genotypic contributions to Diamond-Blackfan anemia.11 Additionally, some patients have reported relatives who had cleft palates in the absence of Diamond-Blackfan anemia,
suggesting that some of these cases may not be associated with Diamond-Blackfan anemia.10 Further, because cleft palates cause feeding difficulty in children, the anomaly itself is a mechanism for nutritional deficiency.12 This suggests a potential scenario for normochromic macrocytosis with cleft palate in the absence of Diamond-Blackfan anemia. Similarly, studies have linked maternal vitamin B deficiencies to these malformations and to vitamin B deficiency in nursing infants.5,13 Although cleft lip and palate is important in the multidisciplinary care of patients with Diamond-Blackfan anemia, this feature may not be useful in definitively excluding anemias relating to nutritional deficiency. Other congenital anomalies Diamond-Blackfan anemia is known for its wide array of clinical presentations. Other congenital anomalies in patients with Diamond-Blackfan include ocular manifestations such as glaucoma, cataracts, and strabismus, and congenital defects of the kidneys and penis (hypospadias).7 A Cathie facies, the characteristic facial presentation in patients with Diamond-Blackfan anemia, is characterized by hypertelorism and a snub nose.14 INTERPRETING LABORATORY VALUES Although not definitively diagnostic, a complete blood cell (CBC) count provides much information concerning the cause of anemia. Diamond-Blackfan anemia presents as a normochromic, macrocytic anemia, as do vitamin B12 and folate deficiency anemias. The lowered reticulocyte count seen in Diamond-Blackfan anemia directly relates to the malfunction of bone marrow erythroid cells; nutritional deficiencies also may affect other cell lines in the bone marrow. These causes cannot be differentiated on the basis of a low reticulocyte count alone. Diamond-Blackfan anemia is associated with higher serum levels of vitamin B12 and folate, which would provide an efficient method for ruling out these deficiencies in the investigation of chronic anemia. Unfortunately, no data are available about the statistical significance of this measurement in DiamondBlackfan anemia. Additionally, the most recent international consensus on Diamond-Blackfan anemia did not list these laboratory findings as even minor supporting criteria for the diagnosis of Diamond-Blackfan anemia.14 Nevertheless, acquiring these serum levels may help to suggest DiamondBlackfan anemia over nutritional deficiency. Erythrocyte adenosine deaminase (eADA) levels, if tested for before blood transfusion, may be more diagnostic than vitamin serum levels. Although the reasons for increased eADA activity are poorly understood, the enzyme is known for its involvement in purine metabolism.15 Up to 85% of patients with Diamond-Blackfan anemia have elevated levels of this isoenzyme.8,15 Patients who have received a blood transfusion within the previous 8 to 12 weeks can have falsely normal eADA levels, so this test should be ordered before transfusion if possible.14,15 If transfusion has taken place before testing,
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
www.JAAPA.com
43
REVIEW ARTICLE
specialized laboratories can test for reticulocyte ADA.15 The eADA level will remain elevated after the patient achieves clinical remission by any means, including corticosteroid therapy.15 Aside from genomic screening, the only way to definitely diagnose Diamond-Blackfan anemia is by bone marrow biopsy.14,15 Bone marrow analyses that are unremarkable except for a paucity of erythroid precursor cells are consistent with the diagnosis of Diamond-Blackfan anemia.15 TREATMENT Guidelines for the diagnosis of Diamond-Blackfan anemia and the standard of care were established by international consensus in 2008.16 Red blood cell transfusion is the initial approach to correcting severe anemia; however, corticosteroid treatment is considered first-line medical therapy upon cessation of transfusions.16 Although regimens will vary among patients, prednisone at 2 mg/kg/day typically improves hemoglobin levels within 2 to 4 weeks.16 Up to 80% of patients with Diamond-Blackfan anemia will respond to this treatment, and 20% of responders will maintain a clinical remission by age 25 years.16 Because of the numerous adverse reactions associated with corticosteroids, the consensus is to withhold treatment, if possible, until patients are 1 year old, to facilitate acquired immunity through vaccination and to prevent growth suppression.16 For patients refractory to corticosteroids, chronic blood transfusions remain the primary treatment. Monitor for iron overload in patients receiving repeated transfusions. Vlachos and colleagues predict an increase in infant ironblood levels from 3 to 7 mg/g dry weight to greater than 15 mg/g dry weight within 1 year of chronic therapy.14 Iron chelators, such as deferoxamine or per-oral deferasirox, should be integrated into treatment plans. The definitive treatment of Diamond-Blackfan anemia is hematopoietic stem-cell transplantation, which should be considered in patients under age 10 years who are unresponsive to repeated blood transfusions.14 Because Diamond-Blackfan anemia is a single-line bone marrow malfunction, transplants should come from a human leukocyte antigen-matched relative if the patient does not have myelodysplasia or acute myeloid leukemia.14 SUMMARY Diamond-Blackfan anemia is an inherited disorder characterized by erythroid precursor failure in the bone marrow. The disease appears to result from mutation of the ribosomal protein encoding genes, ultimately manifesting in normochromic macrocytic anemia and various physical anomalies. Low reticulocyte count accompanies laboratory findings and is suggestive of bone marrow failure. Red cell paucity with otherwise unremarkable findings and a leukocyte count within normal limits confirms the singleline red cell malfunction. Although Diamond-Blackfan anemia has been compared with other pediatric hemato44
www.JAAPA.com
logic diseases, little research has identified the similarities of this disease to chronic anemias caused by nutritional deficiencies. Until better understanding of DiamondBlackfan anemia is achieved, blood transfusion and corticosteroid therapy remain the mainstay treatments. A significant proportion of patients with Diamond-Blackfan anemia will respond to therapy and can expect to live into adulthood. However, because of the increased risk of congenital anomalies and propensity for neoplastic development, providers must possess a clinical suspicion of this syndrome in order to more rapidly deliver appropriate therapy. JAAPA REFERENCES 1. Genetics Home Reference. Diamond-Blackfan anemia. http:// ghr.nlm.nih.gov/condition/diamond-blackfan-anemia. Accessed November 19, 2013. 2. Chiabrando D., Tolosano, E. Diamond Blackfan anemia at the crossroad between ribosome biogenesis and heme metabolism. Adv Hematol. 2010;2010:790632. 3. Gazda HT, Sheen MR, Vlachos A, et al. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008;83(6):769-780. 4. Harper J. Pediatric megaloblastic anemia. http://emedicine. medscape.com/article/959918-overview. Accessed November 19, 2013. 5. Honzik T, Adamovicova M, Smolka V, et al. Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional vitamin B12 deficiency—what have we learned? Eur J Paediatr Neurol. 2010;14(6):488-495. 6. Singh N. Vitamin B12 associated neurological diseases. http:// emedicine.medscape.com/article/1152670-overview#a0104. Accessed November 19, 2013. 7. Pallanti S, Masetti S, Bernardi S, et al. Obsessive compulsive disorder comorbidity in DBA. Clin Pract Epidemiol Ment Health. 2008;4:6. 8. Lipton JM, Ellis SR. Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis. Hematol Oncol Clin North Am. 2009;23(2):261-282. 9. National Center on Birth Defects and Developmental Disabilities. Congenital Anomalies in Blackfan Diamond Anemia. http://www.cdc.gov/ncbddd/dba/documents/factsheet_Cogenital Anomalies.pdf. Accessed November 19, 2013. 10. Ozden FO, Gunduz K, Ozden B, et al. Oral and dental manifestations of Diamond-Blackfan anemia: case reports. Eur J Dent. 2011;5(3):344-348. 11. Lipton JM, Atsidaftos E, Zyskind I, Vlachos A. Improving clinical care and elucidating the pathophysiology of Diamond Blackfan anemia: an update from the Diamond Blackfan anemia registry. Pediatr Blood Cancer. 2006;46(5):558-564. 12. Ize-Iyamu IN, Saheeb BD. Feeding intervention in cleft lip and palate babies: a practical approach to feeding efficiency and weight gain. Int J Oral Maxillofac Surg. 2011;40(9):916-919. 13. Schubert J, Schmidt R, Syska E. B group vitamins and cleft lip and cleft palate. Int J Oral Maxillofac Surg. 2002;31(4):410-413. 14. Vlachos A, Ball S, Dahl N, et al. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haemotol. 2008;142(6):859-876. 15. Vlachos A, Muir E. How I treat Diamond-Blackfan anemia. Blood. 2010;116(19):3715-3723. 16. Narla A, Vlachos A, Nathan DG. Diamond Blackfan anemia treatment: past, present, and future. Semin Hematol. 2011;48(2):117-123. Volume 27 • Number 4 • April 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Diamond-Blackfan anemia and nutritional deficiency-induced anemia in children David Gelbart, MMS, PA-C
ABSTRACT Diamond-Blackfan anemia is a rare, inherited disease that characteristically presents as a chronic, normochromic macrocytosis due to red cell lineage bone marrow failure. Although studies are elaborating on the genetic basis for its associated comorbidities, little has been published comparing this anemia to other chronic anemias that have similar laboratory results in children. This article offers a global perspective of the disease and compares it with anemia due to vitamin B12 and folate deficiency in children. Keywords: Diamond-Blackfan anemia, bone marrow failure, autosomal dominant, macrocytosis, reticulopenia, inherited erythroblastopenia FIGURE 1. Characteristics of Diamond-Blackfan anemia
D
iamond-Blackfan anemia is a rare worldwide (5 to 7 cases per 1,000,000 population), autosomaldominant disease caused by a failure of erythrocyte progenitor cells in the bone marrow.1,2 Although the apparently numerous factors leading to this malfunction are not completely understood, the result is a clinical anemia characterized by normochromic macrocytosis with reticulocytopenia that usually presents within the first year of life.2 About 90% of patients present in early childhood, with the remainder presenting “nonclassically” (after age 1 year) and typically less severely.3 Research is attempting to better implicate the known gene mutations of the disease with several associated congenital defects. The combination of the disease’s variable symptomatology and distinct hematologic characteristics is particularly worrisome: Diamond-Blackfan anemia can be misdiagnosed due to its similarities with other chronic childhood anemias, including those caused by nutritional deficiencies. This article describes the evidence-based research on David Gelbart is a physician assistant at Advanced Care Emergency Services at Western Arizona Regional Medical Center in Bullhead City, Ariz. The author has disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000442702.95598.fc Copyright © 2014 American Academy of Physician Assistants
36
www.JAAPA.com
include decreased reticulocytes and normal to decreased white cells and platelets.
Diamond-Blackfan anemia and provides a guide for including Diamond-Blackfan anemia in the differential diagnosis of normochromic, macrocytic anemia in pediatric patients. BACKGROUND Interest in the pathogenesis of Diamond-Blackfan anemia has led to the consideration of this disease as the prototype of ribosome-based disorders.2 More than half of patients are found to have one or more mutations on RPS and/or RPL genes, most notably, RPS19.2,3 These genes encode ribosomal proteins that normally contribute to the differentiation and proliferation of red blood cell progenitor cells; however, in Diamond-Blackfan anemia, this pathway appears absent or altered.2,4 A current thought based on recent research is that altered ribosomal proteins increase erythroblastic apoptosis.4 Single point, missense, and deletion mutations of the RPS genes have been statistically implicated in the associated congenital anomalies as well, but these mechanisms are not understood.3 Fifty-five percent of patients do not possess a mutation in the known RPS genes, suggesting a multifactor pathogenesis of the disease.2 In addition, the heterogeneous manifestations appear to correlate with patterns of gene mutation. For Volume 27 • Number 4 • April 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Diamond-Blackfan anemia and nutritional deficiency-induced anemia in children
Key points Diamond-Blackfan anemia characteristically presents as a chronic normochromic macrocytosis. However, it can be confused with anemias caused by nutritional deficiencies. About 90% of patients with this rare, inherited disease present in early childhood. Patients with Diamond-Blackfan anemia are at increased risk for complications associated with chronic bone marrow disorder, including hematologic malignancies. Hematopoietic stem-cell transplantation is the definitive treatment for Diamond-Blackfan anemia.
example, alterations of the RPL5 gene may yield multiple malformations including those of the thumbs, heart, and craniofacial region; RPS11 is linked to deformity of the thumbs alone.3 Regardless of the mechanisms responsible for erythroid cell failure, patients with Diamond-Blackfan anemia are at increased risk for complications associated with chronic bone marrow disorder. These include hematologic malignancies such as acute myeloid leukemia, acute lymphoblastic leukemia, myelodysblastic syndrome, and Hodgkin and non-Hodgkin lymphoma.2,4 Other nonhematologic cancers also have been reported. VITAMIN B12 AND FOLATE DEFICIENCY ANEMIAS Nutritional deficits such as vitamin B deficiency anemias can manifest as normochromic, macrocytic anemia with low reticulocyte counts. Other apparent clinical signs, such as lethargy, failure to thrive, and psychological changes, also parallel the symptomology of Diamond-Blackfan anemia in children. Insufficient dietary intake of vitamin B12 and folate in infants and children is rare, even with the increased demand for these vitamins during growth and development.4 Causes of nutritional deficiencies include malabsorption diseases, congenital deficits of vitaminprotein carriers, HIV, and infants or nursing mothers adhering to vegan diets.2,5 Because Diamond-Blackfan anemia is rare, providers must consider Diamond-Blackfan anemia and nutritional deficiencies as the underlying pathology in this clinical picture. PSYCHONEUROLOGICAL ISSUES Vitamin B deficiencies may cause central nervous system demyelination and lead to psychological and neurologic impairments, so improved psychosocial function is a treatment goal for children with nutritional deficiencyinduced anemia.6 Interestingly, a recent study reported that Diamond-Blackfan anemia may contribute to signs of obsessive compulsive disorder (OCD), which is often misdiagnosed for other causes of learning disability.7 Consider investigating for Diamond-Blackfan anemia in a child with normochromic macrocytosis and reticulocy-
topenia who has psychological or behavior disturbances affecting school performance and social integration. Symptoms may include irritability; compulsive behaviors such as pica in the absence of iron deficiency; or behaviors consistent within the spectrum of autism and Asperger disease or attention-deficit hyperactivity disorder. Although evidence linking OCD to Diamond-Blackfan anemia is limited, the basis for the concern, especially in the differential diagnosis of other chronic anemias affecting psychoneurologic function, is the apparent association of cerebral hemosiderosis in OCD.7 Psychological manifestations secondary to hemosiderosis may occur in patients with Diamond-Blackfan anemia even in the absence of the above comorbidities. Hemosiderosis occurs iatrogenically because blood transfusions— mainstay in the treatment of Diamond-Blackfan anemia— can lead to iron accumulation in the brain. Because of the possible association of OCD with Diamond-Blackfan anemia and the iatrogenic hemosiderosis of blood transfusions, more regular MRIs may be warranted in children with normochromic, macrocytic anemia. MRI is useful in detecting iron overload in the brain, and could serve as a diagnostic tool in the differential diagnosis of Diamond-Blackfan anemia and nutritional deficiency anemias. For example, iron accumulation in DiamondBlackfan anemia in the absence of blood transfusions may further clinically link OCD to Diamond-Blackfan anemia and aid in ruling out vitamin B deficiencies. Conversely, children who are newly diagnosed with nutritional deficiency anemia may benefit from a routine head MRI for the more rapid diagnosis of Diamond-Blackfan anemia, which might otherwise be missed. One last implication of the psychological comorbidities with Diamond-Blackfan anemia relates to the medical treatment of these symptoms. Because hemosiderosis may result either from OCD or through blood transfusion, and because iron overload destroys dopaminergenic neurons, dopaminergic agonists may be ineffective in treating psychological manifestations in patients with Diamond-Blackfan anemia. However, SSRIs have been shown effective in treating OCD in patients who also have Diamond-Blackfan anemia.7 CONGENITAL ANOMALIES Characteristic features of Diamond-Blackfan anemia include several reported congenital anomalies. Up to 47% of patients with Diamond-Blackfan anemia will present with these associated findings.8 Identifying these anomalies has been helpful in the diagnosis of Diamond-Blackfan anemia; however, clinicians should be aware that most of these signs have not been genotypically linked to DiamondBlackfan anemia or may be accounted for by exogenous intervention. Therefore, nutritional deficiency-induced anemias may not be ruled out solely on the basis of these findings.
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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37
Diamond-Blackfan anemia and nutritional deficiency-induced anemia in children
Thumb deformities Perhaps the most specific congenital anomaly to Diamond-Blackfan anemia is thumb deformity. Multiple studies have shown a direct correlation between these malformations and mutations of the RPS and RPL genes. The CDC reports that about 20% of patients with Diamond-Blackfan anemia will present with altered thumb structure or function.9 A triphalangeal thumb occurs when the digit has an additional joint, resembling the other fingers on the hand. Bifid thumbs are divided longitudinally in the middle, resembling two separate thumbs with a common origin. Hypoplastic thumbs may be short, underdeveloped, or ectopically located. Flat or absent thenar musculature may decrease or disallow function. Many patients with these comorbidities will benefit greatly from routine surgery that can be done on an outpatient basis or require only an overnight stay.9 Short stature Much research acknowledges short stature as a statistically significant finding among patients with Diamond-Blackfan anemia. Although ribosomal protein gene mutations may contribute to this finding, several factors exclude short stature as a reported congenital anomaly in Diamond-Blackfan anemia. In children who are at least two standard deviations below average height, causes include other chronic illnesses, maternal intrauterine infection, constitutional delay, endocrinopathies, inheritance, and spinal deformity. Short stature is common among patients with Diamond-Blackfan anemia and chronic nutritional deficiency that may manifest as anemia. Use of corticosteroids to treat Diamond-Blackfan anemia also may contribute to short stature. Because corticosteroid use in children can retard growth, differentiating the disease from the treatment as a cause of short stature is difficult. Also, chronic corticosteroid use suppresses the immune system, increasing the patient’s chance for chronic infection. Although the author did not perform a statistical analysis of chronic infection associated with corticosteroid treatment in Diamond-Blackfan anemia, chronic infection may be a factor in short stature not directly caused by the pathogenesis of Diamond-Blackfan anemia. Cardiac anomalies About 15% of patients with Diamond-Blackfan anemia present with a heart defect at birth.9 The most common defects are atrial septal defects, ventricular septal defects, and coarctation of the aorta.9 Although cardiac anomalies are not specific to DiamondBlackfan anemia, they are important comorbidities of the disease. Maxillofacial anomalies Between 3% and 10% of patients with Diamond-Blackfan anemia also have cleft lip and palate.10 However, no correlation is apparent between cleft lip or palate and the RPS genes, suggesting multiple genotypic contributions to Diamond-Blackfan anemia.11 Additionally, some patients have reported relatives who had cleft palates in the absence of Diamond-Blackfan anemia,
suggesting that some of these cases may not be associated with Diamond-Blackfan anemia.10 Further, because cleft palates cause feeding difficulty in children, the anomaly itself is a mechanism for nutritional deficiency.12 This suggests a potential scenario for normochromic macrocytosis with cleft palate in the absence of Diamond-Blackfan anemia. Similarly, studies have linked maternal vitamin B deficiencies to these malformations and to vitamin B deficiency in nursing infants.5,13 Although cleft lip and palate is important in the multidisciplinary care of patients with Diamond-Blackfan anemia, this feature may not be useful in definitively excluding anemias relating to nutritional deficiency. Other congenital anomalies Diamond-Blackfan anemia is known for its wide array of clinical presentations. Other congenital anomalies in patients with Diamond-Blackfan include ocular manifestations such as glaucoma, cataracts, and strabismus, and congenital defects of the kidneys and penis (hypospadias).7 A Cathie facies, the characteristic facial presentation in patients with Diamond-Blackfan anemia, is characterized by hypertelorism and a snub nose.14 INTERPRETING LABORATORY VALUES Although not definitively diagnostic, a complete blood cell (CBC) count provides much information concerning the cause of anemia. Diamond-Blackfan anemia presents as a normochromic, macrocytic anemia, as do vitamin B12 and folate deficiency anemias. The lowered reticulocyte count seen in Diamond-Blackfan anemia directly relates to the malfunction of bone marrow erythroid cells; nutritional deficiencies also may affect other cell lines in the bone marrow. These causes cannot be differentiated on the basis of a low reticulocyte count alone. Diamond-Blackfan anemia is associated with higher serum levels of vitamin B12 and folate, which would provide an efficient method for ruling out these deficiencies in the investigation of chronic anemia. Unfortunately, no data are available about the statistical significance of this measurement in DiamondBlackfan anemia. Additionally, the most recent international consensus on Diamond-Blackfan anemia did not list these laboratory findings as even minor supporting criteria for the diagnosis of Diamond-Blackfan anemia.14 Nevertheless, acquiring these serum levels may help to suggest DiamondBlackfan anemia over nutritional deficiency. Erythrocyte adenosine deaminase (eADA) levels, if tested for before blood transfusion, may be more diagnostic than vitamin serum levels. Although the reasons for increased eADA activity are poorly understood, the enzyme is known for its involvement in purine metabolism.15 Up to 85% of patients with Diamond-Blackfan anemia have elevated levels of this isoenzyme.8,15 Patients who have received a blood transfusion within the previous 8 to 12 weeks can have falsely normal eADA levels, so this test should be ordered before transfusion if possible.14,15 If transfusion has taken place before testing,
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
www.JAAPA.com
43
REVIEW ARTICLE
specialized laboratories can test for reticulocyte ADA.15 The eADA level will remain elevated after the patient achieves clinical remission by any means, including corticosteroid therapy.15 Aside from genomic screening, the only way to definitely diagnose Diamond-Blackfan anemia is by bone marrow biopsy.14,15 Bone marrow analyses that are unremarkable except for a paucity of erythroid precursor cells are consistent with the diagnosis of Diamond-Blackfan anemia.15 TREATMENT Guidelines for the diagnosis of Diamond-Blackfan anemia and the standard of care were established by international consensus in 2008.16 Red blood cell transfusion is the initial approach to correcting severe anemia; however, corticosteroid treatment is considered first-line medical therapy upon cessation of transfusions.16 Although regimens will vary among patients, prednisone at 2 mg/kg/day typically improves hemoglobin levels within 2 to 4 weeks.16 Up to 80% of patients with Diamond-Blackfan anemia will respond to this treatment, and 20% of responders will maintain a clinical remission by age 25 years.16 Because of the numerous adverse reactions associated with corticosteroids, the consensus is to withhold treatment, if possible, until patients are 1 year old, to facilitate acquired immunity through vaccination and to prevent growth suppression.16 For patients refractory to corticosteroids, chronic blood transfusions remain the primary treatment. Monitor for iron overload in patients receiving repeated transfusions. Vlachos and colleagues predict an increase in infant ironblood levels from 3 to 7 mg/g dry weight to greater than 15 mg/g dry weight within 1 year of chronic therapy.14 Iron chelators, such as deferoxamine or per-oral deferasirox, should be integrated into treatment plans. The definitive treatment of Diamond-Blackfan anemia is hematopoietic stem-cell transplantation, which should be considered in patients under age 10 years who are unresponsive to repeated blood transfusions.14 Because Diamond-Blackfan anemia is a single-line bone marrow malfunction, transplants should come from a human leukocyte antigen-matched relative if the patient does not have myelodysplasia or acute myeloid leukemia.14 SUMMARY Diamond-Blackfan anemia is an inherited disorder characterized by erythroid precursor failure in the bone marrow. The disease appears to result from mutation of the ribosomal protein encoding genes, ultimately manifesting in normochromic macrocytic anemia and various physical anomalies. Low reticulocyte count accompanies laboratory findings and is suggestive of bone marrow failure. Red cell paucity with otherwise unremarkable findings and a leukocyte count within normal limits confirms the singleline red cell malfunction. Although Diamond-Blackfan anemia has been compared with other pediatric hemato44
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logic diseases, little research has identified the similarities of this disease to chronic anemias caused by nutritional deficiencies. Until better understanding of DiamondBlackfan anemia is achieved, blood transfusion and corticosteroid therapy remain the mainstay treatments. A significant proportion of patients with Diamond-Blackfan anemia will respond to therapy and can expect to live into adulthood. However, because of the increased risk of congenital anomalies and propensity for neoplastic development, providers must possess a clinical suspicion of this syndrome in order to more rapidly deliver appropriate therapy. JAAPA REFERENCES 1. Genetics Home Reference. Diamond-Blackfan anemia. http:// ghr.nlm.nih.gov/condition/diamond-blackfan-anemia. Accessed November 19, 2013. 2. Chiabrando D., Tolosano, E. Diamond Blackfan anemia at the crossroad between ribosome biogenesis and heme metabolism. Adv Hematol. 2010;2010:790632. 3. Gazda HT, Sheen MR, Vlachos A, et al. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008;83(6):769-780. 4. Harper J. Pediatric megaloblastic anemia. http://emedicine. medscape.com/article/959918-overview. Accessed November 19, 2013. 5. Honzik T, Adamovicova M, Smolka V, et al. Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional vitamin B12 deficiency—what have we learned? Eur J Paediatr Neurol. 2010;14(6):488-495. 6. Singh N. Vitamin B12 associated neurological diseases. http:// emedicine.medscape.com/article/1152670-overview#a0104. Accessed November 19, 2013. 7. Pallanti S, Masetti S, Bernardi S, et al. Obsessive compulsive disorder comorbidity in DBA. Clin Pract Epidemiol Ment Health. 2008;4:6. 8. Lipton JM, Ellis SR. Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis. Hematol Oncol Clin North Am. 2009;23(2):261-282. 9. National Center on Birth Defects and Developmental Disabilities. Congenital Anomalies in Blackfan Diamond Anemia. http://www.cdc.gov/ncbddd/dba/documents/factsheet_Cogenital Anomalies.pdf. Accessed November 19, 2013. 10. Ozden FO, Gunduz K, Ozden B, et al. Oral and dental manifestations of Diamond-Blackfan anemia: case reports. Eur J Dent. 2011;5(3):344-348. 11. Lipton JM, Atsidaftos E, Zyskind I, Vlachos A. Improving clinical care and elucidating the pathophysiology of Diamond Blackfan anemia: an update from the Diamond Blackfan anemia registry. Pediatr Blood Cancer. 2006;46(5):558-564. 12. Ize-Iyamu IN, Saheeb BD. Feeding intervention in cleft lip and palate babies: a practical approach to feeding efficiency and weight gain. Int J Oral Maxillofac Surg. 2011;40(9):916-919. 13. Schubert J, Schmidt R, Syska E. B group vitamins and cleft lip and cleft palate. Int J Oral Maxillofac Surg. 2002;31(4):410-413. 14. Vlachos A, Ball S, Dahl N, et al. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haemotol. 2008;142(6):859-876. 15. Vlachos A, Muir E. How I treat Diamond-Blackfan anemia. Blood. 2010;116(19):3715-3723. 16. Narla A, Vlachos A, Nathan DG. Diamond Blackfan anemia treatment: past, present, and future. Semin Hematol. 2011;48(2):117-123. Volume 27 • Number 4 • April 2014
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