UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Overview of variant sickle cell syndromes

Author
Elliott P Vichinsky, MD
Section Editor
Donald H Mahoney, Jr, MD
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

Variant sickle cell syndromes include any hemoglobinopathy in which the sickle mutation is inherited in combination with another globin gene mutation (eg, alpha globin, beta globin, gamma globin). These syndromes may have different clinical severity compared with homozygous sickle mutation (HbSS).

This topic presents an overview of the variant sickle cell syndromes and their clinical features.

Related subjects including the diagnosis of sickle syndromes, clinical manifestations, and management, as well as sickle cell trait (generally a benign carrier state) are discussed separately.

Prenatal testing – (See "Prenatal screening and testing for hemoglobinopathy".)

Diagnosis – (See "Diagnosis of sickle cell disorders".)

                

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Fri Mar 18 00:00:00 GMT 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997; 337:762.
  2. Kaul DK, Fabry ME, Costantini F, et al. In vivo demonstration of red cell-endothelial interaction, sickling and altered microvascular response to oxygen in the sickle transgenic mouse. J Clin Invest 1995; 96:2845.
  3. Motulsky AG. Frequency of sickling disorders in U.S. blacks. N Engl J Med 1973; 288:31.
  4. Bunn HF, Noguchi CT, Hofrichter J, et al. Molecular and cellular pathogenesis of hemoglobin SC disease. Proc Natl Acad Sci U S A 1982; 79:7527.
  5. Hirsch RE, Raventos-Suarez C, Olson JA, Nagel RL. Ligand state of intraerythrocytic circulating HbC crystals in homozygote CC patients. Blood 1985; 66:775.
  6. Fabry ME, Kaul DK, Raventos-Suarez C, et al. SC erythrocytes have an abnormally high intracellular hemoglobin concentration. Pathophysiological consequences. J Clin Invest 1982; 70:1315.
  7. Ballas SK, Lewis CN, Noone AM, et al. Clinical, hematological, and biochemical features of Hb SC disease. Am J Hematol 1982; 13:37.
  8. RIVER GL, ROBBINS AB, SCHWARTZ SO. S-C hemoglobin: a clinical study. Blood 1961; 18:385.
  9. West MS, Wethers D, Smith J, Steinberg M. Laboratory profile of sickle cell disease: a cross-sectional analysis. The Cooperative Study of Sickle Cell Disease. J Clin Epidemiol 1992; 45:893.
  10. McCurdy PR. 32-DFP and 51-Cr for measurement of red cell life span in abnormal hemoglobin syndromes. Blood 1969; 33:214.
  11. Lawrence C, Fabry ME, Nagel RL. The unique red cell heterogeneity of SC disease: crystal formation, dense reticulocytes, and unusual morphology. Blood 1991; 78:2104.
  12. Bunn HF. Subunit assembly of hemoglobin: an important determinant of hematologic phenotype. Blood 1987; 69:1.
  13. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991; 325:11.
  14. Moser FG, Miller ST, Bello JA, et al. The spectrum of brain MR abnormalities in sickle-cell disease: a report from the Cooperative Study of Sickle Cell Disease. AJNR Am J Neuroradiol 1996; 17:965.
  15. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998; 91:288.
  16. Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med 1991; 115:614.
  17. Zarkowsky HS, Gallagher D, Gill FM, et al. Bacteremia in sickle hemoglobinopathies. J Pediatr 1986; 109:579.
  18. Buchanan GR, Smith SJ, Holtkamp CA, Fuseler JP. Bacterial infection and splenic reticuloendothelial function in children with hemoglobin SC disease. Pediatrics 1983; 72:93.
  19. Koshy M, Entsuah R, Koranda A, et al. Leg ulcers in patients with sickle cell disease. Blood 1989; 74:1403.
  20. Milner PF, Kraus AP, Sebes JI, et al. Sickle cell disease as a cause of osteonecrosis of the femoral head. N Engl J Med 1991; 325:1476.
  21. Platt OS, Rosenstock W, Espeland MA. Influence of sickle hemoglobinopathies on growth and development. N Engl J Med 1984; 311:7.
  22. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994; 330:1639.
  23. Condon PI, Hayes RJ, Serjeant GR. Retinal and choroidal neovascularization in sickle cell disease. Trans Ophthalmol Soc U K 1980; 100:434.
  24. Oteng-Ntim E, Meeks D, Seed PT, et al. Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis. Blood 2015; 125:3316.
  25. Drawz P, Ayyappan S, Nouraie M, et al. Kidney Disease among Patients with Sickle Cell Disease, Hemoglobin SS and SC. Clin J Am Soc Nephrol 2016; 11:207.
  26. Colella MP, de Paula EV, Machado-Neto JA, et al. Elevated hypercoagulability markers in hemoglobin SC disease. Haematologica 2015; 100:466.
  27. Gualandro SF, Fonseca GH, Yokomizo IK, et al. Cohort study of adult patients with haemoglobin SC disease: clinical characteristics and predictors of mortality. Br J Haematol 2015; 171:631.
  28. Lane PA, O'Connell JL, Lear JL, et al. Functional asplenia in hemoglobin SC disease. Blood 1995; 85:2238.
  29. Orringer EP, Fowler VG Jr, Owens CM, et al. Case report: splenic infarction and acute splenic sequestration in adults with hemoglobin SC disease. Am J Med Sci 1991; 302:374.
  30. Michlitsch J, Azimi M, Hoppe C, et al. Newborn screening for hemoglobinopathies in California. Pediatr Blood Cancer 2009; 52:486.
  31. SINGER K, SINGER L, GOLDBERG SR. Studies on abnormal hemoglobins. XI. Sickle cell-thalassemia disease in the Negro; the significance of the S+A+F and S+A patterns obtained by hemoglobin analysis. Blood 1955; 10:405.
  32. SMITH EW, CONLEY CL. Clinical features of the genetic variants of sickle cell disease. Bull Johns Hopkins Hosp 1954; 94:289.
  33. Gonzalez-Redondo JM, Stoming TA, Lanclos KD, et al. Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. Blood 1988; 72:1007.
  34. Gonzalez-Redondo JM, Kutlar A, Kutlar F, et al. Molecular characterization of Hb S(C) beta-thalassemia in American blacks. Am J Hematol 1991; 38:9.
  35. Christakis J, Vavatsi N, Hassapopoulou H, et al. A comparison of sickle cell syndromes in northern Greece. Br J Haematol 1991; 77:386.
  36. Serjeant GR, Sommereux AM, Stevenson M, et al. Comparison of sickle cell-beta0 thalassaemia with homozygous sickle cell disease. Br J Haematol 1979; 41:83.
  37. Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood 1994; 84:643.
  38. Voskaridou E, Tsetsos G, Tsoutsias A, et al. Pulmonary hypertension in patients with sickle cell/beta thalassemia: incidence and correlation with serum N-terminal pro-brain natriuretic peptide concentrations. Haematologica 2007; 92:738.
  39. Rigano P, Pecoraro A, Calvaruso G, et al. Cerebrovascular events in sickle cell-beta thalassemia treated with hydroxyurea: a single center prospective survey in adult Italians. Am J Hematol 2013; 88:E261.
  40. Zafeiriou DI, Prengler M, Gombakis N, et al. Central nervous system abnormalities in asymptomatic young patients with Sbeta-thalassemia. Ann Neurol 2004; 55:835.
  41. Pearson HA, Gallagher D, Chilcote R, et al. Developmental pattern of splenic dysfunction in sickle cell disorders. Pediatrics 1985; 76:392.
  42. Serjeant GR, Serjeant BE. Comparison of sickle cell-bº thalassemia and sickle cell-b+ thalassemia in Black populations. In: Thalassemia: Advances in detection and treatment, Birth Defects Original Article Series, Cao A, Carcassi U, Rowley PT (Eds), Alan R Liss, New York 1982. p.233.
  43. Sweeting I, Serjeant BE, Thomas PW, Serjeant GR. Microchromatographic quantitation of hemoglobin A levels in phenotypes of sickle cell-beta(+) thalassemia. J Chromatogr B Biomed Sci Appl 1997; 700:269.
  44. Embury SH, Lebo RV, Dozy AM, Kan YW. Organization of the alpha-globin genes in the Chinese alpha-thalassemia syndromes. J Clin Invest 1979; 63:1307.
  45. Embury SH, Miller JA, Dozy AM, et al. Two different molecular organizations account for the single alpha-globin gene of the alpha-thalassemia-2 genotype. J Clin Invest 1980; 66:1319.
  46. Dozy AM, Kan YW, Embury SH, et al. alpha-Globin gene organisation in blacks precludes the severe form of alpha-thalassaemia. Nature 1979; 280:605.
  47. Embury SH, Dozy AM, Miller J, et al. Concurrent sickle-cell anemia and alpha-thalassemia: effect on severity of anemia. N Engl J Med 1982; 306:270.
  48. Higgs DR, Aldridge BE, Lamb J, et al. The interaction of alpha-thalassemia and homozygous sickle-cell disease. N Engl J Med 1982; 306:1441.
  49. Steinberg MH, Rosenstock W, Coleman MB, et al. Effects of thalassemia and microcytosis on the hematologic and vasoocclusive severity of sickle cell anemia. Blood 1984; 63:1353.
  50. de Ceulaer K, Higgs DR, Weatherall DJ, et al. alpha-Thalassemia reduces the hemolytic rate in homozygous sickle-cell disease. N Engl J Med 1983; 309:189.
  51. Stevens MC, Maude GH, Beckford M, et al. Alpha thalassemia and the hematology of homozygous sickle cell disease in childhood. Blood 1986; 67:411.
  52. Embury SH, Clark MR, Monroy G, Mohandas N. Concurrent sickle cell anemia and alpha-thalassemia. Effect on pathological properties of sickle erythrocytes. J Clin Invest 1984; 73:116.
  53. Dover GJ, Chang VT, Boyer SH, et al. The cellular basis for different fetal hemoglobin levels among sickle cell individuals with two, three, and four alpha-globin genes. Blood 1987; 69:341.
  54. Thomas PW, Higgs DR, Serjeant GR. Benign clinical course in homozygous sickle cell disease: a search for predictors. J Clin Epidemiol 1997; 50:121.
  55. Kéclard L, Romana M, Lavocat E, et al. Sickle cell disorder, beta-globin gene cluster haplotypes and alpha-thalassemia in neonates and adults from Guadeloupe. Am J Hematol 1997; 55:24.
  56. Milner PF, Kraus AP, Sebes JI, et al. Osteonecrosis of the humeral head in sickle cell disease. Clin Orthop Relat Res 1993; :136.
  57. Fox PD, Dunn DT, Morris JS, Serjeant GR. Risk factors for proliferative sickle retinopathy. Br J Ophthalmol 1990; 74:172.
  58. Marcus SJ, Kinney TR, Schultz WH, et al. Quantitative analysis of erythrocytes containing fetal hemoglobin (F cells) in children with sickle cell disease. Am J Hematol 1997; 54:40.
  59. Bradley TB, Brawner JN, Conley CL. Further observations on an inherited anomaly characterized by persisetnce of fetal hemoglobin. Bull Johns Hopk Hosp 1961; 108:242.
  60. CONLEY CL, WEATHERALL DJ, RICHARDSON SN, et al. Hereditary persistence of fetal hemoglobin: a study of 79 affected persons in 15 Negro families in Baltimore. Blood 1963; 21:261.
  61. Murray N, Serjeant BE, Serjeant GR. Sickle cell-hereditary persistence of fetal haemoglobin and its differentiation from other sickle cell syndromes. Br J Haematol 1988; 69:89.
  62. Ngo DA, Aygun B, Akinsheye I, et al. Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin. Br J Haematol 2012; 156:259.
  63. Kinney TR, Friedman S, Cifuentes E, et al. Variations in globin synthesis in delta-beta-thalassaemia. Br J Haematol 1978; 38:15.
  64. O'Reilly RA. A kindred with hemoglobin Lepore. JAMA 1976; 236:478.
  65. Seward DP, Ware RE, Kinney TR. Hemoglobin sickle-Lepore: report of two siblings and review of the literature. Am J Hematol 1993; 44:192.
  66. Stevens MC, Lehmann H, Mason KP, et al. Sickle cell-Hb Lepore Boston syndrome. Uncommon differential diagnosis to homozygous sickle cell disease. Am J Dis Child 1982; 136:19.
  67. Schnee J, Aulehla-Scholz C, Eigel A, Horst J. Hb D Los Angeles (D-Punjab) and Hb Presbyterian: analysis of the defect at the DNA level. Hum Genet 1990; 84:365.
  68. STURGEON P, ITANO HA, BERGREN WR. Clinical manifestations of inherited abnormal hemoglobins. I. The interaction of hemoglobin-S with hemoglobin-D. Blood 1955; 10:389.
  69. Adachi K, Kim J, Ballas S, et al. Facilitation of Hb S polymerization by the substitution of Glu for Gln at beta 121. J Biol Chem 1988; 263:5607.
  70. Cooke JV, Mack JK. Sickle-cell anemia in a white American family. J Pediatr 1934; 5:601.
  71. Kelleher JF Jr, Park JO, Kim HC, Schroeder WA. Life-threatening complications in a child with hemoglobin SD-Los Angeles disease. Hemoglobin 1984; 8:203.
  72. Schmugge M, Frischknecht H, Yonekawa Y, et al. Stroke in hemoglobin (SD) sickle cell disease with moyamoya: successful hydroxyurea treatment after cerebrovascular bypass surgery. Blood 2001; 97:2165.
  73. Ramot B, Fisher S, Remez D, et al. Haemoglobin O in An Arab Family. Br Med J 1960; 2:1262.
  74. Milner PF, Miller C, Grey R, et al. Hemoglobin O arab in four negro families and its interaction with hemoglobin S and hemoglobin C. N Engl J Med 1970; 283:1417.
  75. Zimmerman SA, O'Branski EE, Rosse WF, Ware RE. Hemoglobin S/O(Arab): thirteen new cases and review of the literature. Am J Hematol 1999; 60:279.
  76. CHERNOFF AI, MINNICH V, CHONGCHAREONSUK S. Hemoglobin E, a hereditary abnormality of human hemoglobin. Science 1954; 120:605.
  77. Orkin SH, Kazazian HH Jr, Antonarakis SE, et al. Abnormal RNA processing due to the exon mutation of beta E-globin gene. Nature 1982; 300:768.
  78. Rees DC, Styles L, Vichinsky EP, et al. The hemoglobin E syndromes. Ann N Y Acad Sci 1998; 850:334.
  79. Masiello D, Heeney MM, Adewoye AH, et al. Hemoglobin SE disease: a concise review. Am J Hematol 2007; 82:643.
  80. Schroeder WA, Powars D, Reynolds RD, Fisher JI. Hb-E in combination with Hb-S and Hb-C in a black family. Hemoglobin 1977; 1:287.
  81. Eichhorn RF, Buurke EJ, Blok P, et al. Sickle cell-like crisis and bone marrow necrosis associated with parvovirus B19 infection and heterozygosity for haemoglobins S and E. J Intern Med 1999; 245:103.
  82. Rosenberg MR. In vivo and in vitro interactions of human haemoglobins A,S and C with a variant haemoglobin E. Nature 1968; 219:1042.
  83. Monplaisir N, Merault G, Poyart C, et al. Hemoglobin S Antilles: a variant with lower solubility than hemoglobin S and producing sickle cell disease in heterozygotes. Proc Natl Acad Sci U S A 1986; 83:9363.