Hereditary spherocytosis

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Hereditary spherocytosis
ICD-10 D58.0
ICD-9 282.0
MedlinePlus 000530

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Zahir Ali Shaikh, MD[2]

Overview

Hereditary spherocytosis is a genetically-transmitted form of spherocytosis, an auto-hemolytic anemia characterized by the production of red blood cells that are sphere-shaped rather than donut-shaped, and therefore more prone to hemolysis.

Historical Perspective

  • Hereditary spherocytosis was first described in 1871.[1]
  • It is the commonest cause of inherited chronic hemolysis in the northern europe and north america.[2]

Classification

  • Hereditary Spherocytosis classified on basis of underlying defect in protein and also on the basis of severity of hemolysis.
  • Classification of hereditary spherocytosis on the basis of clinical severity.[3]"GeneReviews® - NCBI Bookshelf". 
Locus Gene Protein Inheritance Severity Comment
SPH1 ANK1 Ankyrin-1 AD/AR mild-moderate/moderately severe-severe often transfusion dependant
SPH2 SPTB Spectrin beta chain,erythrocytic AD/AR mild-moderate/severe 1 fatal infantile case described
SPH3 SPTA1 Spectrin alpha chain,erythrocytic1 AR severe transfusion dependant
SPH4 SLC4A1 Band3(anion transport protein) AD mild-moderate certain SLC4A1 variants cause disease only when biallelic
SPH5 EPB42 Protein 4.2 AR mild-moderate 1 moderately severe case described
Classification Mild Moderate Severe
Hemoglobin (g/dl) 110-150 80-120 60-80
Reticulocyte count (%) 3-6 >6 >10
Bilirubin (ug/l) 17-34 >34 >51
Splenectomy usually not required indicated during school age, usually before puberty necessary - delay until 6 years of age if possible

Pathophysiology

  • The defects in hereditary spherocytosis lie in the cell membrane.[3]
  • The proteins essential for integrity of membrane structure lie immediately under the lipid bilayer, horizental aplha & beta spectrin molecules form heterodimers with linkage to vertical elements- ankyrin, proteins 4.1 & 4.2 and band 3 (a transmembrane protein).
  • Different genes code for each of these proteins, therefore hereditary spherocytosis is a hetrogenous disorder which can result from a defect in any one of these proteins.
  • The destabilization of membrane leads to both abnormal morphology and reduced red cell life span.
  • The shorter the life span of red blood cells, the worse the clinical effects.
  • Genetic defect and clinical severity tend to be fairly constant within a given family,but between family varies from mild asymptomatic hemolysis to severe continuous anemia with jaundice.

Causes

  • Hereditary spherocytosis is caused by a variety of genetic mutations.[4][5]
  • There are 05 genes associated with hereditary spherocytosis including, alpha spectrin (SPTA1), beta spectrin (SPTB), ankyrin (ANK1), band3 (SLC4A1) and protein 4.2 (EPB42).
  • Mutations in one or more of hereditary spherocytosis related genes can cause membrane protein deficiency leading to hereditary spherocytosis.
Molecular and Genetic Characteristics of 5 Erythrocyte Membrane Protein Genes
Gene Chromosome Location Membrane Protein Prevalent Mutations Heredity Associated Disease
ANK1 8p11.2 Ankyrin-1 frameshift, nonsense, splicing, novel mutations autosomal dominant, autosomal recessive hereditary spherocytosis
SLC4A1 17q21 Band3 missense,frameshift,polymorphism autosomal dominant hereditary spherocytosis,distal renal tubular acisosis
SPTA1 1q22-q23 alpha spectrin SpaLEPRA allele, splicing, frameshift autosomal recessive hereditary spherocytosis, hereditary eliptocytosis, hereditary pyropoikilocytosis
SPTB 14q23-q24.1 beta spectrin splicing, frameshift, nonsense, novel mutations autosomal dominant hereditary spherocytosis, hereditary eliptocytosis, hereditary pyropoikilocytosis
EBP42 15q15-q21 protein 4.2 missense, nonsense autosomal recessive hereditary spherocytosis

Differentiating Hereditary Spherocytosis from Other Diseases

  • Hereditary spherocytosis presents with hemolysis, therefore should be differentiated from following diseases.[6][5]
    • Autoimmune hemolysis
    • Thermal injury
    • Clostridial septicemia
    • Wilson disease
    • Hemoglobinopathies
    • Hereditary stomatocytosis
    • Congenital dyserythrpoietic anemia type II

Epidemiology and Demographics

  • Hereditary spherocytosis is reported worldwide in all racial and ethnic groups.[7]
  • It is the most common inherited anemia in the northern European ancestry and north america.[8]
  • The reported incidence of hereditary spherocytosis is 1 in 2000 births.[9]
  • It is less commonly seen in african american and southeast asian people.[5]

Risk Factors

  • A positive family history is an important risk factor for hereditary spherocytosis, as it is an inherited condition.[10]
  • There are no other risk factors have been clearly identified for this condition.

Screening

  • It is also important to test newborns of affected parents for HS, as affected newborns may have severe hyperbilirubinemia and anemia. This may be done by a clinician with expertise in hemolytic anemias or by a genetic counselor. It is possible for an individual with no hemolysis, no spherocytes on the blood smear, and a normal reticulocyte count to be a carrier of HS, which may be relevant in certain families.

Natural History, Complications, and Prognosis

Natural History

  • Disease severity and age of presentationHS can present at any age and with any severity, with case reports describing a range of presentations, from hydrops fetalis in utero through diagnosis in the ninth decade of life.

Complications

Common complications of hemolysis include neonatal jaundice, splenomegaly, and pigment gallstones.

  • Neonatal jaundiceHS may present in the neonatal period with jaundice and hyperbilirubinemia, and the serum bilirubin level may not peak until several days after birth. Some experts have proposed that HS is underdiagnosed as a cause of neonatal jaundice. A requirement for phototherapy and/or exchange transfusion during this period is common.
  • SplenomegalySplenomegaly is rare in neonates, but can often be seen in older children and adults with HS. Early reports of family studies found palpable spleens in over three-fourths of affected members, but this may reflect a skewed population with the most severe disease. In these studies, the relationship between disease severity and splenic size was not linear.
  • Pigment gallstones — Pigment (bilirubin) gallstones are common in individuals with HS and may be the presenting finding in adults. Gallstones are unlikely before the age of 10 years but are seen in as many as half of adults, especially those with more severe hemolysis. Gallstones appear to be more common in individuals with Gilbert syndrome.

Prognosis

  • Overall, the long-term outlook for people with hereditary spherocytosis (HS) is usually good with treatment. However, it may depend on the severity of the condition in each person.
  • People with very mild HS may not have any signs or symptoms unless an environmental "trigger" causes symptom onset. In many cases, no specific therapy is needed other than monitoring for  and watching for signs and symptoms.[8] Moderately and severely affected people are likely to benefit from splenectomy.
  • Most people who undergo splenectomy are able to maintain a normal hemoglobin level.[4] However, people with severe HS may remain anemic post-splenectomy, and may need blood transfusions during an infection.

Diagnosis

Diagnostic Criteria

  1. Newly diagnosed patients with a family history of HS, typical clinical features and laboratory investigations (spherocytes, raised mean corpuscular haemoglobin concentration [MCHC], increase in reticulocytes) do not require any additional tests (grade 1 recommendation, grade A evidence).
  2.  If the diagnosis is equivocal, a screening test with high predictive value for HS is helpful. The recommended screening tests are the cryohaemolysis test and EMA binding (grade 1 recommendation, grade A evidence). (Confirmation).
  3.  Gel electrophoresis analysis of erythrocyte membranes is the method of choice for diagnosis of atypical cases.

History and Symptoms

Physical Examination

  • Splenomegaly is the rule in HS. Palpable spleens have been detected in more than 75% of affected subjects. The liver is normal in size and function.
  • Other important clues are jaundice and upper right abdominal pain indicative of gallbladder disease. This is especially important if the patient has a family history of gallbladder disease.
  • Any patient who presents with profound and sudden anemia and reticulocytopenia with the aforementioned physical findings also should have HS in the differential diagnosis.

Laboratory Findings

Initial testing

Confirmatory tests

  • EMA bindingOsmotic fragility ●Glycerol lysisCryohemolysis

Imaging Findings:

  • There are no particular other imaging findings associated with HS.

Other Diagnostic Studies:

    • In certain atypical cases in which further characterization of the RBC cytoskeletal/membrane proteins is needed, gel electrophoresis can be done using RBC ghosts, or DNA sequencing can be performed.

Treatment

Medical Therapy

  • As with most inherited hemolytic anemias, treatment is directed at preventing or minimizing complications of chronic hemolysis and anemia. There are no specific treatments directed at the underlying red blood cell (RBC) membrane defect.
  • If a neonate is suspected of having HS (eg, based on positive family history and neonatal jaundice), treatment can be initiated for HS without awaiting diagnostic confirmation. This may include therapy for hyperbilirubinemia and, in severe cases, transfusion or even exchange transfusion [83
  • The goals of pharmacotherapy for hereditary spherocytosis are to reduce morbidity and prevent complications. Folic acid supplementation is indicated to prevent megaloblastic crisis.

Surgery

  • Generally, the treatment of HS involves presplenectomy care, splenectomy, and management of postsplenectomy complications.
  • In pediatric cases, splenectomy ideally should not be performed until a child is older than 6 years because of the increased incidence of postsplenectomy infections with encapsulated organisms such as S pneumoniae and H influenzae in young children.
  • Partial splenectomies are increasingly used in pediatric patients, as this approach appears to both control hemolysis and preserve splenic function.

Prevention

In general, once the diagnosis and baseline severity of HS in a child are established, it is not necessary to perform repeated blood tests unless there is an additional clinical indication (such as intercurrent infection and pallor, or an increase in jaundice). A routine annual review is usually sufficient together with an open door policy for potential complications such as parvovirus infection, or abdominal pain, which may trigger investigation for gallstones.

Case Studies

Case #1

Related Chapters

External links

References

  1. Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. 
  2. Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. 
  3. 3.0 3.1 Bolton-Maggs, P H B (2004). "Hereditary spherocytosis; new guidelines". Archives of Disease in Childhood. 89 (9): 809–812. ISSN 0003-9888. doi:10.1136/adc.2003.034587. 
  4. He, Ben-Jin; Liao, Lin; Deng, Zeng-Fu; Tao, Yi-Feng; Xu, Yu-Chan; Lin, Fa-Quan (2018). "Molecular Genetic Mechanisms of Hereditary Spherocytosis: Current Perspectives". Acta Haematologica. 139 (1): 60–66. ISSN 0001-5792. doi:10.1159/000486229. 
  5. 5.0 5.1 5.2 Perrotta, Silverio; Gallagher, Patrick G; Mohandas, Narla (2008). "Hereditary spherocytosis". The Lancet. 372 (9647): 1411–1426. ISSN 0140-6736. doi:10.1016/S0140-6736(08)61588-3. 
  6. Robert D. Christensen, Hassan M. Yaish & Patrick G. Gallagher (2015). "A pediatrician's practical guide to diagnosing and treating hereditary spherocytosis in neonates". Pediatrics. 135 (6): 1107–1114. PMID 26009624. doi:10.1542/peds.2014-3516. 
  7. Silverio Perrotta, Patrick G. Gallagher & Narla Mohandas (2008). "Hereditary spherocytosis". Lancet (London, England). 372 (9647): 1411–1426. PMID 18940465. doi:10.1016/S0140-6736(08)61588-3. 
  8. Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. 
  9. Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. 
  10. Sayeeda Huq, Mark A. C. Pietroni, Hafizur Rahman & Mohammad Tariqul Alam (2010). "Hereditary spherocytosis". Journal of health, population, and nutrition. 28 (1): 107–109. PMID 20214092. 

he:ספרוציטוזיס תורשתי sr:Сфероцитоза


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