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Hereditary Spherocytosis Differential Diagnoses

  • Author: Gus Gonzalez, MD; Chief Editor: Emmanuel C Besa, MD  more...
Updated: Oct 13, 2015

Diagnostic Considerations

Hereditary spherocytosis (HS) can be caused by any of several genetic anomalies, which have different patterns of inheritance and produce disease with a range of severity. Thus, the clinical and laboratory features of HS can vary widely.

Moderate HS is the most common form, accounting for 60-75% of all HS cases. It is associated with mild-to-moderate anemia, modest splenomegaly, and intermittent jaundice. In most cases, the pattern of transmission is autosomal dominant, although recessive inheritance also is observed.

Mild HS occurs in 20-30% of cases of autosomal dominant HS. Anemia generally is not present because the bone marrow is able to fully compensate for the persistent destruction of red cells. Little or no splenomegaly occurs. These patients usually are asymptomatic. They often are not diagnosed until later in life, when they experience hemolytic or aplastic episodes triggered by infection or other stresses. The condition may be identified only through family surveys.

Severe HS occurs in approximately 5% of all patients with HS. Severe hemolytic anemia that requires red cell transfusions and an incomplete response to splenectomy characterize severe HS. The pattern of inheritance is recessive. The parents of affected patients have no signs of HS or have only a mild increase in the reticulocyte count, a few spherocytes on peripheral blood smear, a minimally abnormal incubated osmotic fragility test result, or an abnormal spectrin content detected when sensitive techniques are used.

Gilbert syndrome

HS may occasionally be mistaken for Gilbert syndrome, a hereditary disorder in which reduced conjugation of bilirubin in the liver results in jaundice. Although patients with Gilbert syndrome may be asymptomatic, most have nonspecific symptoms such as abdominal cramps, fatigue, and malaise. Laboratory studies may reveal unconjugated hyperbilirubinemia. In contrast to HS, patients with Gilbert syndrome have normal results on reticulocyte count and blood smear.

Differential Diagnoses

Contributor Information and Disclosures

Gus Gonzalez, MD Medical Oncologist, The Center for Cancer and Blood Disorders

Gus Gonzalez, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MB, BCh, FRCPC, DTM&H Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada, American Clinical and Climatological Association, International Society of Blood Transfusion

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: GSK Pharmaceuticals,Alexion,Johnson & Johnson Talecris,,Grifols<br/>Received honoraria from all the above companies for speaking and teaching.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.


E Randy Eichner, MD Professor, Department of Internal Medicine, University of Oklahoma Health Sciences Center

E Randy Eichner, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Sports Medicine, American Medical Society for Sports Medicine, and American Society of Hematology

Disclosure: Nothing to disclose.

  1. Bianchi P, Fermo E, Vercellati C, Marcello AP, Porretti L, Cortelezzi A, et al. Diagnostic power of laboratory tests for hereditary spherocytosis: a comparison study on 150 patients grouped according to the molecular and clinical characteristics. Haematologica. 2011 Nov 4. [Medline].

  2. [Guideline] Bolton-Maggs PH, Langer JC, Iolascon A, Tittensor P, King MJ. Guidelines for the diagnosis and management of hereditary spherocytosis - 2011 update. Br J Haematol. 2012 Jan. 156(1):37-49. [Medline].

  3. Abdullah F, Zhang Y, Camp M, Rossberg MI, Bathurst MA, Colombani PM, et al. Splenectomy in hereditary spherocytosis: Review of 1,657 patients and application of the pediatric quality indicators. Pediatr Blood Cancer. 2009 Jul. 52(7):834-7. [Medline].

  4. Perrotta S, Della Ragione F, Rossi F, et al. {beta}-spectrinBari: a truncated {beta}-chain responsible for dominant hereditary spherocytosis. Haematologica. 2009 Jul 16. epub ahead of print. [Medline]. [Full Text].

  5. Maciag M, Plochocka D, Adamowicz-Salach A, Burzynska B. Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA. Br J Haematol. 2009 Aug. 146(3):326-32. [Medline].

  6. Zaninoni A, Vercellati C, Imperiali FG, Marcello AP, Fattizzo B, Fermo E, et al. Detection of red blood cell antibodies in mitogen-stimulated cultures from patients with hereditary spherocytosis. Transfusion. 2015 Aug 10. [Medline].

  7. Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet. 2008 Oct 18. 372(9647):1411-26. [Medline].

  8. Wang C, Cui Y, Li Y, Liu X, Han J. A systematic review of hereditary spherocytosis reported in Chinese biomedical journals from 1978 to 2013 and estimation of the prevalence of the disease using a disease model. Intractable Rare Dis Res. 2015 May. 4 (2):76-81. [Medline]. [Full Text].

  9. Teunissen M, Hijmans CT, Cnossen MH, Bronner MB, Grootenhuis MA, Peters M. Quality of life and behavioral functioning in Dutch pediatric patients with hereditary spherocytosis. Eur J Pediatr. 2014 Apr 16. [Medline].

  10. Christensen RD, Yaish HM, Gallagher PG. A pediatrician's practical guide to diagnosing and treating hereditary spherocytosis in neonates. Pediatrics. 2015 Jun. 135 (6):1107-14. [Medline].

  11. Casale M, Perrotta S. Splenectomy for hereditary spherocytosis: complete, partial or not at all?. Expert Rev Hematol. 2011 Dec. 4(6):627-35. [Medline].

  12. Morinis J, Dutta S, Blanchette V, Butchart S, Langer JC. Laparoscopic partial vs total splenectomy in children with hereditary spherocytosis. J Pediatr Surg. 2008 Sep. 43(9):1649-52. [Medline].

  13. Grace RF, Mednick RE, Neufeld EJ. Compliance with immunizations in splenectomized individuals with hereditary spherocytosis. Pediatr Blood Cancer. 2009 Jul. 52(7):865-7. [Medline].

  14. Rice HE, Englum BR, Rothman J, Leonard S, Reiter A, et al. Clinical outcomes of splenectomy in children: report of the splenectomy in congenital hemolytic anemia registry. Am J Hematol. 2015 Mar. 90 (3):187-92. [Medline].

  15. Agre P, Asimos A, Casella JF, McMillan C. Inheritance pattern and clinical response to splenectomy as a reflection of erythrocyte spectrin deficiency in hereditary spherocytosis. N Engl J Med. 1986 Dec 18. 315(25):1579-83. [Medline].

  16. Costa FF, Agre P, Watkins PC, et al. Linkage of dominant hereditary spherocytosis to the gene for the erythrocyte membrane-skeleton protein ankyrin. N Engl J Med. 1990 Oct 11. 323(15):1046-50. [Medline].

  17. Gallagher PG. Hematologically important mutations: ankyrin variants in hereditary spherocytosis. Blood Cells Mol Dis. 2005 Nov-Dec. 35(3):345-7.

  18. Glader BE, Naumovski L. Hereditary red blood cell disorders. In: Emery AE, Rimoin, DL, eds. Principles and Practice of Medical Genetics. New York, NY:. Churchill Livingstone. 1996.

  19. Hassoun H, Palek J. Hereditary spherocytosis: a review of the clinical and molecular aspects of the disease. Blood Rev. 1996 Sep. 10(3):129-47. [Medline].

  20. Hassoun H, Vassiliadis JN, Murray J, et al. Hereditary spherocytosis with spectrin deficiency due to an unstable truncated beta spectrin. Blood. 1996 Mar 15. 87(6):2538-45. [Medline].

  21. Korones D, Pearson HA. Normal erythrocyte osmotic fragility in hereditary spherocytosis. J Pediatr. 1989 Feb. 114(2):264-6. [Medline].

  22. Lee RD, Glader JN, Lukens JN. In: Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM, eds. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md: Lippincott Williams & Wilkins; 1999:. 1132-42.

  23. Nakashima K, Beutler E. Erythrocyte cellular and membrane deformability in hereditary spherocytosis. Blood. 1979 Mar. 53(3):481-5. [Medline].

  24. Peters LL, Lux SE. Ankyrins: structure and function in normal cells and hereditary spherocytes. Semin Hematol. 1993 Apr. 30(2):85-118. [Medline].

  25. Rice HE, Oldham KT, Hillery CA, et al. Clinical and hematologic benefits of partial splenectomy for congenital hemolytic anemias in children. Ann Surg. 2003 Feb. 237(2):281-8.

  26. Sackey K. Hemolytic anemia: Part 1. Pediatr Rev. 1999 May. 20(5):152-8; quiz 159. [Medline].

  27. Sackey K. Hemolytic anemia: Part 2. Pediatr Rev. 1999 Jun. 20(6):204-8. [Medline].

  28. Savvides P, Shalev O, John KM, Lux SE. Combined spectrin and ankyrin deficiency is common in autosomal dominant hereditary spherocytosis. Blood. 1993 Nov 15. 82(10):2953-60. [Medline].

  29. Stoehr GA, Stauffer UG, Eber SW. Near-total splenectomy: a new technique for the management of hereditary spherocytosis. Ann Surg. 2005 Jan. 241(1):40-7.

  30. Hsiao M, Sathya C, Nathens AB, de Mestral C, Hill AD, Langer JC. Is activity restriction appropriate for patients with hereditary spherocytosis? A population-based analysis. Ann Hematol. 2013 Apr. 92(4):523-5. [Medline].

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