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| '''For patient information click [[Hereditary spherocytosis (patient information)|here]]''' | | '''For patient information click [[Hereditary spherocytosis (patient information)|here]]''' |
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| {{CMG}} {{ZAS}} | | {{CMG}}; {{AE}} {{ZAS}} |
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| ==[[Hereditary spherocytosis overview|Overview]]== | | ==[[Hereditary spherocytosis overview|Overview]]== |
| '''Hereditary spherocytosis''' is a genetically-transmitted form of [[spherocytosis]], an auto-[[Hemolysis|hemolytic]] [[anemia]] characterized by the production of red blood cells that are sphere-shaped rather than donut-shaped, and therefore more prone to [[hemolysis]].
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| == Historical Perspective == | | == [[hereditary spherocytosis historical perspective|Historical Perspective]] == |
| * Hereditary spherocytosis was first described in 1871.<ref>{{Cite journal
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| | author = [[Sayeeda Huq]], [[Mark A. C. Pietroni]], [[Hafizur Rahman]] & [[Mohammad Tariqul Alam]]
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| | title = Hereditary spherocytosis
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| | journal = [[Journal of health, population, and nutrition]]
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| | volume = 28
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| | issue = 1
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| | pages = 107–109
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| | year = 2010
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| | month = February
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| | pmid = 20214092
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| }}</ref>
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| * It is the commonest cause of inherited chronic hemolysis in the northern europe and north america.<ref>{{Cite journal
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| | author = [[Sayeeda Huq]], [[Mark A. C. Pietroni]], [[Hafizur Rahman]] & [[Mohammad Tariqul Alam]]
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| | title = Hereditary spherocytosis
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| | journal = [[Journal of health, population, and nutrition]]
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| | volume = 28
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| | issue = 1
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| | pages = 107–109
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| | year = 2010
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| | month = February
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| | pmid = 20214092
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| }}</ref>
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| == Classification == | | == [[hereditary spherocytosis classification|Classification]] == |
| * Hereditary Spherocytosis classified on basis of underlying defect in protein and also on the basis of severity of hemolysis.
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| * Classification of hereditary spherocytosis on the basis of clinical severity.<ref name="Bolton-Maggs2004">{{cite journal|last1=Bolton-Maggs|first1=P H B|title=Hereditary spherocytosis; new guidelines|journal=Archives of Disease in Childhood|volume=89|issue=9|year=2004|pages=809–812|issn=0003-9888|doi=10.1136/adc.2003.034587}}</ref>{{cite web |url=http://www.ncbi.nlm.nih.gov/books/NBK1116/ |title=GeneReviews® - NCBI Bookshelf |format= |work= |accessdate=}}
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| {| class="wikitable"
| | == [[hereditary spherocytosis pathophysiology|Pathophysiology]] == |
| |+
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| ! Locus
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| ! Gene
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| ! Protein
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| ! Inheritance
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| ! Severity
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| ! Comment
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| |-
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| | SPH1
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| | ANK1
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| | Ankyrin-1
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| | AD/AR
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| | mild-moderate/moderately severe-severe
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| | often transfusion dependant
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| |-
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| | SPH2
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| | SPTB
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| | Spectrin beta chain,erythrocytic
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| | AD/AR
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| | mild-moderate/severe
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| | 1 fatal infantile case described
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| |-
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| | SPH3
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| | SPTA1
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| | Spectrin alpha chain,erythrocytic1
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| | AR
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| | severe
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| | transfusion dependant
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| |-
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| | SPH4
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| | SLC4A1
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| | Band3(anion transport protein)
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| | AD
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| | mild-moderate
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| | certain SLC4A1 variants cause disease only when biallelic
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| |-
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| | SPH5
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| | EPB42
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| | Protein 4.2
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| | AR
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| | mild-moderate
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| | 1 moderately severe case described
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| |}
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| {| class="wikitable"
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| |+
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| ! Classification
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| ! Mild
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| ! Moderate
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| ! Severe
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| |-
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| ! Hemoglobin (g/dl)
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| | 110-150
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| | 80-120
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| | 60-80
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| |-
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| ! Reticulocyte count (%)
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| | 3-6
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| | >6
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| | >10
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| |-
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| ! Bilirubin (ug/l)
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| | 17-34
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| | >34
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| | >51
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| |-
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| ! Splenectomy
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| | usually not required
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| | indicated during school age, usually before puberty
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| | necessary - delay until 6 years of age if possible
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| |}
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| == Pathophysiology == | | == [[hereditary spherocytosis causes|Causes]] == |
| * The defects in hereditary spherocytosis lie in the cell membrane.<ref name="Bolton-Maggs2004">{{cite journal|last1=Bolton-Maggs|first1=P H B|title=Hereditary spherocytosis; new guidelines|journal=Archives of Disease in Childhood|volume=89|issue=9|year=2004|pages=809–812|issn=0003-9888|doi=10.1136/adc.2003.034587}}</ref>
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| * 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).
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| * 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.
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| * The destabilization of membrane leads to both abnormal morphology and reduced red cell life span.
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| * The shorter the life span of red blood cells, the worse the clinical effects.
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| * 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.
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| == Causes == | | == [[Hereditary spherocytosis differential diagnosis|Differentiating Hereditary Spherocytosis from Other Diseases]] == |
| * Hereditary spherocytosis is caused by a variety of genetic mutations.<ref name="HeLiao2018">{{cite journal|last1=He|first1=Ben-Jin|last2=Liao|first2=Lin|last3=Deng|first3=Zeng-Fu|last4=Tao|first4=Yi-Feng|last5=Xu|first5=Yu-Chan|last6=Lin|first6=Fa-Quan|title=Molecular Genetic Mechanisms of Hereditary Spherocytosis: Current Perspectives|journal=Acta Haematologica|volume=139|issue=1|year=2018|pages=60–66|issn=0001-5792|doi=10.1159/000486229}}</ref>
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| * There are 05 genes associated with hereditary spherocytosis including, alpha spectrin (SPTA1), beta spectrin (SPTB), ankyrin (ANK1), band3 (SLC4A1) and protein 4.2 (EPB42).
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| * Mutations in one or more of hereditary spherocytosis related genes can cause membrane protein deficiency leading to hereditary spherocytosis.
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| {| class="wikitable"
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| |+Molecular and Genetic Characteristics of 5 Erythrocyte Membrane Protein Genes
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| |}
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| == Differentiating Hereditary spherocytosis overview from Other Diseases == | | == [[hereditary spherocytosis epidemiology and demographics|Epidemiology and Demographics]] == |
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| == Epidemiology and Demographics == | | == [[hereditary spherocytosis risk factors|Risk Factors]] == |
| * HS is seen in all populations but appears to be especially common in people of northern European ancestry.
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| * In the United States, the incidence of the disorder is approximately one case in 5000 people.
| | == [[hereditary spherocytosis screening|Screening]] == |
| ** In northern European, HS affects as many as 1 in 2000 to 1 in 5000 (prevalence, approximately 0.02 to 0.05 percent).
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| == Risk Factors == | | == [[hereditary spherocytosis natural history, complications and prognosis|Natural History, Complications, and Prognosis]] == |
| * The risk factors for this condition have not yet been properly identified.
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| * However, having a family member with this condition can increase your susceptibility to this disease. The condition is also most common in individuals of North European origin although it has been found to arise in people of all races.
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| == Screening == | | == [[hereditary spherocytosis diagnostic study of choice|Diagnosis]] == |
| * 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.
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| == Natural History, Complications, and Prognosis == | | == [[Hereditary spherocytosis history and symptoms|History and Symptoms]] == |
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| === Natural History === | | == [[hereditary spherocytosis physical examination|Physical Examination]] == |
| * '''Disease severity and age of presentation''' — [[Hereditary spherocytosis|HS]] 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.
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| * The majority of affected individuals have mild or moderate hemolysis or [[hemolytic anemia]] and a known family history, making diagnosis and treatment relatively straightforward. Individuals with significant severe hemolysis may develop additional complications such as [[jaundice]]/[[hyperbilirubinemia]], [[folate deficiency]], or [[splenomegaly]].
| | == [[hereditary spherocytosis laboratory findings|Laboratory Findings]] == |
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| === Complications === | | == [[hereditary spherocytosis chest x ray|Chest X ray]] == |
| Common complications of [[hemolysis]] include [[neonatal jaundice]], [[splenomegaly]], and pigment gallstones.
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| * '''[[Neonatal jaundice]]''' — [[Hereditary spherocytosis|HS]] 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 [[Hereditary spherocytosis|HS]] is underdiagnosed as a cause of [[neonatal jaundice]]. A requirement for [[phototherapy]] and/or [[exchange transfusion]] during this period is common.
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| * '''[[Splenomegaly]]''' — [[Splenomegaly]] is rare in neonates, but can often be seen in older children and adults with [[Hereditary spherocytosis|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.
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| * '''Pigment gallstones''' — Pigment (bilirubin) [[gallstones]] are common in individuals with [[Hereditary spherocytosis|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]].
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| === Prognosis === | | == [[hereditary spherocytosis CT|CT]] == |
| * 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.
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| * People with very mild [[Hereditary spherocytosis|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.
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| * Most people who undergo [[splenectomy]] are able to maintain a normal [[hemoglobin]] level.[4] However, people with severe [[Hereditary spherocytosis|HS]] may remain anemic post-splenectomy, and may need [[blood transfusions]] during an infection.
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| == Diagnosis == | | == [[hereditary spherocytosis MRI|MRI]] == |
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| === Diagnostic Criteria === | | == [[hereditary spherocytosis echocardiography or ultrasound| Echocardiography or Ultrasound]] == |
| # 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).
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| # 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).
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| # Gel electrophoresis analysis of erythrocyte membranes is the method of choice for diagnosis of atypical cases.
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| === History and Symptoms === | | == [[hereditary spherocytosis other imaging findings|Other Imaging Findings]] == |
| * As in any other chronic hemolytic states, the signs and symptoms of [[Hereditary spherocytosis|hereditary spherocytosis (HS]]) include mild [[pallor]], intermittent [[jaundice]], and [[splenomegaly]]. However, signs and symptoms are highly variable. [[Anemia]] or [[hyperbilirubinemia]] may be of such magnitude as to require [[exchange transfusion]] in the neonatal period. The disorder also may escape clinical recognition altogether. [[Anemia]] usually is mild to moderate, but is sometimes very severe and sometimes not present.
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| * Symptoms of hereditary spherocytosis include:
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| ** Yellowing of the skin and eyes (jaundice)
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| ** [[Pallor|Pale coloring (pallor)]]
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| ** [[Fatigue]]
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| ** Irritability
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| ** [[Shortness of breath]]
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| ** [[Weakness]]
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| === Physical Examination === | | == [[hereditary spherocytosis other diagnostic studies|Other Diagnostic Studies]] == |
| * [[Splenomegaly]] is the rule in [[Hereditary spherocytosis|HS]]. Palpable [[Spleen|spleens]] have been detected in more than 75% of affected subjects. The [[liver]] is normal in size and function.
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| * 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|gallbladder disease.]]
| | == [[hereditary spherocytosis medical therapy|Treatment]] == |
| * Any patient who presents with profound and sudden [[anemia]] and [[reticulocytopenia]] with the aforementioned physical findings also should have [[Hereditary spherocytosis|HS]] in the differential diagnosis.
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| === Laboratory Findings === | | == [[hereditary spherocytosis medical therapy|Medical Therapy]] == |
| '''Initial testing'''
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| *<nowiki/>'''CBC and RBC indices''' – All individuals with suspected [[Hereditary spherocytosis|HS]] based on [[family history]], [[neonatal jaundice]], or other findings should have a [[Complete blood count|complete blood count (CBC)]] with [[reticulocyte count]] and [[Red blood cell|red blood cell (RBC)]] indices. The [[Mean corpuscular hemoglobin concentration|mean corpuscular hemoglobin concentration (MCHC)]] is often the most useful parameter for assessing [[spherocytosis]]; an MCHC ≥36 g/dL is consistent with [[Spherocyte|spherocytes]]. A low [[Mean corpuscular volume|mean corpuscular volume (MCV)]] is also helpful in some cases, especially in [[neonates]], but variable degrees of [[reticulocytosis]] make the [[MCV]]<nowiki/>less useful in older children and adults.
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| * '''[[Blood smear]] review''' – All individuals with suspected [[Hereditary spherocytosis|HS]] should have a [[blood smear]] reviewed by an experienced individual. In a [[peripheral blood smear]], the abnormally small [[Red blood cell|red blood cells]] lacking the central pallor i.e. spherocytes are seen. Other abnormal [[RBC]] shapes, and the degree of polychromatophilia, which reflects [[reticulocytosis]].
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| * '''[[Coombs test|Coombs testing]]''' – If [[hemolysis]] is present, Coombs testing (also called direct antiglobulin testing [DAT]) is usually done to eliminate the possibility of immune-mediated hemolysis, which <nowiki/>may be due to [[Hemolytic disease of newborn|hemolytic disease of the fetus and newborn (HDFN)]] in neonates or [[Autoimmune hemolytic anemia|autoimmune hemolytic anemia (AIHA)]] in older children and adults. The results of testing may also be useful to the [[transfusion]] service if [[transfusion]] is indicated. [[Coombs test|Coombs testing]] in [[Hereditary spherocytosis|HS]] is negative.
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| '''Confirmatory tests'''
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| * '''EMA binding''' ●'''Osmotic fragility''' '''●Glycerol lysis''' ●'''Cryohemolysis'''
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| === Imaging Findings: === | | == [[hereditary spherocytosis surgery|Surgery]] == |
| * There are no particular other imaging findings associated with HS.
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| === Other Diagnostic Studies: === | | ==[[hereditary spherocytosis primary prevention|Primary Prevention]] == |
| ** 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.
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| == Treatment == | | == [[hereditary spherocytosis secondary prevention|Secondary Prevention]]== |
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| === Medical Therapy === | | == [[hereditary spherocytosis cost-effectiveness of therapy|Cost-Effectiveness of 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.
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| * 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
| | == [[hereditary spherocytosis future or investigational therapies|Future or Investigational Therapies]] == |
| * The goals of pharmacotherapy for hereditary spherocytosis are to reduce morbidity and prevent complications. Folic acid supplementation is indicated to prevent megaloblastic crisis.
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| === Surgery === | | == [[Hereditary spherocytosis case study one|Case Studies]] == |
| * Generally, the treatment of HS involves presplenectomy care, splenectomy, and management of postsplenectomy complications.
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| * 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.
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| * Partial splenectomies are increasingly used in pediatric patients, as this approach appears to both control hemolysis and preserve splenic function.
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| === Prevention ===
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| 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.
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| ==Case Studies==
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| [[Hereditary spherocytosis case study one|Case #1]] | | [[Hereditary spherocytosis case study one|Case #1]] |
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