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Sickle Cell Disease Case Study CC: Pain and tenderness in lower extremities; unable to bear weight on feet HPI: 24 month old female presents to ER with a recent h/o painful welling in lower extremities. Findings of last visit were normal, with exception of low hemoglobin level and mildly enlarged spleen. PMH: No history of fever, infection, or trauma; otherwise unremarkable. FH: Patient's parent's are of Caribbean ancestry and had siblings that died at a young age from infection and others who may have had sickle cell disease. SH: No significant social history. ROS: Besides swelling and enlarged spleen, patient presents with a low hemoglobin count (anemia). Possible acute bone pain crisis, which typically presents wth progressive pain, most commonly in the humerus, tibia, and femur. However, patients with acute bone pain crisis typically present with fever, leukoyctyosis and tenderness or effusion in the affected joints; none of which were present. PE: No significant clinical findings besides palpable spleen tip (splenomegaly) and swollen feet (possible aseptic dactylitis, or Foot-Hand Syndrome). Laboratory Testing: Based on the aforementioned symptoms, request made for hemoglobin electrophoresis testing to identify the types of hemoglobin in the patient’s blood.

Symptoms

SICKLE CELL CASES BY COUNTRY 

Anemia/Aplastic crisis

Splenic sequestration

Infection

Effects on growth and maturation

Hand-foot syndrome

Acute chest syndrome

Central nervous system involvement

Prognosis: HbSS genotype is normally fatal

Progression

Methods of Diagnosis Replacement of a negatively-charged glutamic acid in the standard HbA beta-globin by a neutral valine in Hemoglobin S (HbS) results in a protein with a slightly reduced negative charge. Two techniques utilize this Hemoglobin Electrophoresis: A blood sample is separated according to the relative electric charges of its constituents. Specifically, the HbA tetramer electrophoreses as a single "fast" band, and the HbS tetramer as a single "slow" band. Another separate band appears if Hemoglobin C (HbC) is present. This test result documented sickle cell hemoglobin, Hb S, in the specimen collected from the patient. Isoelectric Focusing: Similar to the previous in that difference in electric charge is utilized to detect HbS. Here, however, the plate has a fixed pH gradient. Differently charged cells will migrate to predetermined points along the gradient according to their isoelectric point. This method is more sensitive than the previous. High Performance Liquid Chromatography: Also based on differences in polarity. This method is completely automated, unlike the rest, and is the quickest method of testing. Screening: Before any tests are run, at risk newborns undergo a screening test. In this test, their blood is isolated and deoxygenated by addition of chemicals. The depressed level of oxygen causes affected cells to sickle. This screening cannot differentiate between heterozygous/homozygous individuals.

Hemoglobin A

Hemoglobin S

Results of HBB Mutation

Incidence and Prevalence

For the first 6 months, infants are normally protected by elevated levels of Fetal Hemoglobin (Hemoglobin F) which gives them the ability to bind oxygen at a greater affinity than normal adult hemoglobin. After 6 months to Age 10, complications will begin. One of the most common issues is vaso-occlusive crisis. Between the ages of 6 months to 3 years, Hand-foot syndrome may occur, which leads to strong pain and swelling in the hand and feet area. Between ages 2-4, children will have a higher chance of having acute chest syndrome and will continute to have it into their adolescent years. Fevers, cough, leukoctosis, tachypnea, dyspnea, hypoxia and sputum production. Bacteremia is also common at age 4. Hand-foot syndrome will go away by age 5, however other conditions will begin. Acute chest syndrome in young children is very common for sickle cell patients. Other problems may occur like kidneys losing concentration capacity and dehydration to kidney failure. Cell death or infarction can lead to problems in all areas such as loss of vision, leg ulcers, possible liver failure, bone pain, soft tissue damage, splenic sequestration crisis leading to painful enlargement and damage to the spleen, eventually leading to asplenia (absence of normal spleen function). As an effect, the patient is very vulnerable to infections. Puberty occurs slower than normal children. A study conducted by the Cooperative Study of Sickle Cell Disease reported patients who were homozygous tend to have an average of a 1.4 year growth delay in growth spurts compared to children who had normal blood cells. Constant fatigue in muscles as low oxygen concentrations continue to be caused by the shape and blockage of Sickle Cells will eventually manifest to stroke issues. 30% of children and 11% of patients will experience stroke issues by 20 years of age. As a result, patients who are homozygous recessive have do not have a long life -span. Survival rate was averaged around 14.3 years of age where 20% of the deaths would occur in the first 2 years, another 33 percent of deaths would occur before age 5 and 50% would live before age 30 and 16% would live beyond age 30. Of these patients who did not live pass age 20 died between age 1-3 normally from Streptococcus pneumonia infection. Deaths after age 10 were mainly caused by acute chest syndrome. However, since 1973, research and development towards fighting Sickle Cell Disease have improved dramatically. 85.6% of homozygous recessive patients now survive pass 18 years of age and patients with a milder rate of Sickle Cell survive pass 18 by 97.4%. In the case of people with heterozygous SCD, patients will live a normal life with uncommon episodes of SCD traits. If under a condition of exercise, homozygous SCD symptoms will occur.

Areas Most affected: Usually in areas that also have Malaria Sub-Saharan Africa India South America Cuba Central America United States

Mediterranean countries Greece Turkey Saudi Arabia Sicily South Italy

-Healthy carriers with Sickle-cell trait range between 10% and 40% across the regions around the equator. -North African coast: Sickle Cell carriers ranges between 1% and 2% -South Africa: Sickle Cell carriers are less than 1%

Sickle Cell Disease Incidence Worldwide:

Brazil: 7%-10% Cuba: 5% Greece: 8%-27% India: 9%-38%

Trends:

-Comparing to the malaria map, this distribution gives supportive evidence that natural selection favors the sickle-cell trait in areas with high levels of

Southern Italy: 10% Puerto Rico: 5% Panama: 12%-14% Saudi Arabia 5%-25%

Two Extremes Sickle Cell Crisis and Malaria induced anemia represent the two extremes of the variance in genotype.

References Arnold, MD, J, et al. "Sickle Cell Anemia Clinical Presentation." Medscape Reference, 2001. Web. 6 Nov 2011. <http://emedicine.medscape.com/article/205926-clinical Ballas, S. K., Lewis, C. N., Noone, A. M., Krasnow, S. H., Kamarulzaman, E., Burka, E. R. Clinical, hematological, and biochemical features of Hb SC disease. Am. J. Hemat. 13: 37-51, 1982 http://pubget.com/paper/7137165 Chang, Shung Ho, Karen M. Gooding, and Fred E. Reginer. "High-performance Liquid Chromatography of Proteins." Journal of Chromatography 125.1 (1976): 103-14. Print. Charache S, Page DL. Infarction of bone marrow in the sickle cell disorders. Ann Intern Med1967;67:1195-1200

Genetics of Sickle Cell Disease The pathophysiology of sickle cell disease (SCD) is attributed to a missense mutation on the HBB gene locus, located on chromosome 11, that replaces hydrophilic glutamic acid with hydrophobic valine at amino acid 6 on the β subunits of hemoglobin. The change in amino acid produces a hemoglobin that transforms into a sickle shape when subjected to low levels of oxygen. SCD is a homozygous recessive disease, and heterzyogtes (HbAS) who have both a normal and sickle allele poses a resistance to infection by Plasmodium falciparum, known as heterzygote advantage. Similar pathologies arise from other heterzygote combinations. HbS exists in combination with other hemoglobins in a double heterozygous state. The clinically important diseases involved, observed in patients in the United States, are HbSC and Hb-beta thalassemia. HbSC disease is a milder sickling disorder where symptoms are less aggressive and consistent. It is present in 1 in 1100 African Americans. In the HbC mutation, lysine replaces glutamic acid in position 6 on the beta chain.

Hemoglobin and Hemoglobin Variants The most common types of normal hemoglobin are: Hemoglobin F (fetal hemoglobin). This type is normally found in fetuses and newborn babies. Hemoglobin F is replaced by hemoglobin A (adult hemoglobin) shortly after birth; only very small amounts of hemoglobin F are made after birth. Some diseases, such as sickle cell disease, aplastic anemia, and leukemia, have abnormal types of hemoglobin and higher amounts of hemoglobin F. Hemoglobin A. This is the most common type of hemoglobin found normally in adults. Some diseases, such as severe forms of thalassemia, may cause hemoglobin A levels to be low and hemoglobin F levels to be high. Hemoglobin A2. This is a normal type of hemoglobin found in small amounts in adults. More than 400 different types of abnormal hemoglobin have been found, but the most common are: Hemoglobin S. This type of hemoglobin is present in sickle cell disease. Hemoglobin C. This type of hemoglobin does not carry oxygen well. Hemoglobin E. This type of hemoglobin is found in people of Southeast Asian descent. Hemoglobin D. This type of hemoglobin is present in a sickle cell disorder. Hemoglobin H (heavy hemoglobin). This type of hemoglobin may be present in certain types of thalassemia. Hemoglobin S and hemoglobin C are the most common types of abnormal hemoglobins that may be found by an electrophoresis test.

Natural History of Disease (Pleiotropy)

Eli C. Minkoff, 1983 Evolutionary Biology , 1st Edition, Addison-Wesley, ISBN 0-201-15890-6

Treatment Everyday care: Those with Sickle cell have to deal with pain on a daily basis. Pain management consists of OTC pain relievers as well as temperature management and massage, which all help by increasing the quantity of oxygen to tissues. Hydration and warmth are key — when sickle cells are dehydrated, the concentration of HbS increases, leading their polymerization and subsequent sickling. Infectious diseases are always a concern, as sickle cell leads to increased susceptibility to disease resultant from damage to the spleen. Blood transfusions are performed in patients experiencing severe pain crises. They can also be used as a preventative measure. However, transfusions are merely preventative, not curative. HbS will still be regenerated. The risks involved with transfusiosn are not minor, and include blood clots, iron overload, and blood-born infections. Bone marrow transplants can cure sickle cell. Replacement of sickle cell bone marrow with healthy bone marrow results in the generation of healthy blood cells. It is difficult, however, to find a sufficient number of donors. The treatment must take place while the patient is still young, but has an efficacy rate close to 90%. Hydroxyurea: A drug initially used in the treatment of Leukemia, it has been found to be extremely effective in sickle cell treatment. Although a cytotoxin, it has a side effect of causing the body to generate HbF, thus reducing the relative concentration of HbS and subsequently reducing the effects of sickle cell. Treatment requires at least 2 months to be beneficial, and once taken, must be taken consistently. Patients taking it had a much lower frequency of pain crises and chest syndrome. Long term effects are still not known, and it has the side effect of decreasing the body’s ability to generate white blood cells, so this treatment is only recommended for severe cases. Blood

Transfusions are During a blood transfusion, a person (the recipient) receives healthy blood from another person (the donor). The donated blood is carefully screened for diseases before it is used. Before receiving a blood transfusion, the recipient's blood is analyzed closely (using blood type) to make sure the donor blood is a close match to the recipient's. Blood is transfused into an arm vein slowly over 1 to 4 hours (except in an emergency when blood is transfused more quickly). Blood transfusions can: Treat a sudden or short-term condition related to sickle cell disease.  Treat severe complications of sickle cell disease. 

Prevent complications of sickle cell disease.

Lower the risk of stroke in infants and children. Blood transfusions aren't usually used to treat uncomplicated painful events or mild to moderate anemia.

“Hydroxyurea Significance” Image from: //Charache, et al., 1995. The effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 332:1317-1322. Google Image result for: http://sickle.bwh.harvard.edu/msh.html “Hydrated vs Non-Hydrated Cell” Image from: http://www.bio.davidson.edu/people/midorcas/animalphysiology/websites/2005/eppolito/treatment.htm Lane, PA. "Sickle Cell Disease." NCBI. Pediatric Clinic of North America. Web. <1996 Jun;43(3):639-64.>. Leikin SL, Gallagher D, Kinney TR, Sloane D, Klug P, Rida W. “Mortality in children and adolescents with sickle cell disease.” Pediatrics 1989;84:500-508 Lekhwani S, Vaswani ND.Hemoglobin Variants Detection by HPLC (High Performance Liquid Chromatography) Method . Pediatric Oncall [serial online] 2010 [cited 2010 January 1];7 Art # 1 available from:http://www.pediatriconcall.com/fordoctor/diseasesandcondition/PEDIATRIC_HEMATOLOGY/ chromatography.asp McKusick , Victor, et al. "Hemoglobin, Beta Locus; HBB." OMIM Gene Map . NCBI, 1986. Web. 6 Nov 2011. <http://omim.org/entry/141900 Nussbaum, R.L., McInnes, R.R., Willard, H.F. 2007. Thompson & Thompson Genetics in Medicine. 7th ed. Philadelphia: Saunders Elsevier Neel, J. V. "The Inheritance of Sickle Cell Anemia." Science 110.2846 (1949): 64-66.Science Magazine. Web. <http://www.sciencemag.org/content/110/2846/64.short>. Odenheimer DJ, Whitten CF, Rucknagel DA, Sarnaik SA, Sing CF. “Stability over time of hematological variables in 197 children with sickle cell anemia.” Am J Mednet1984;18:461-470 http://www.ncbi.nlm.nih.gov/pubmed/6206724?dopt=Abstract Rees, D. C., Williams, T. N., Gladwin, M. T. “Sickle-Cell Disease.” (2010) The Lancet, 376 (9757), pp. 2018-2031 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61029-X/fulltext# Samuel Charache, M.D., Michael L. Terrin, M.D., Richard D. Moore, M.D., George J. Dover, M.D., Franca B. Barton, M.S., Susan V. Eckert, Robert P. McMahon, Ph.D., Duane R. Bonds, M.D., and the Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. “ Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia.” N Engl J Med 1995; 332:13171322May 18, 1995 http://www.nejm.org/doi/full/10.1056/NEJM199505183322001#t=references Shafer, FE, F. Lorey, GC Cunningham, C. Klump, E. Vicinsky, and B. Lubin. "Newborn Screening for Sickle Cell Disease: 4 Years of Experience from California's Newborn Screening Program." U.S. Gov't, P.H.S. Journal of Pediatric Hematology/oncology. Web. <http://ukpmc.ac.uk/abstract/MED/8556368>. "Spleen with Sickle Cell Disease" Image from: //Sanders, Melissa. "Spleen with Sickle Cell Disease." Online image. Jan. Google Image Result for http://pathweb.uchc.edu/eAtlas/Images/ HEM/6382b.gif.15 Feb. 2007 <http://tinyurl.com/2dn45p>.// "Sickle Cell Diease." CDC, 2011. Web. 6 Nov 2011. <http://www.cdc.gov/ncbddd/sicklecell/traits.html>. "Spleen with Sickle Cell Disease" Image from: //Sanders, Melissa. "Spleen with Sickle Cell Disease." Online image. Jan. Google Image Result for http://pathweb.uchc.edu/eAtlas/Images/ HEM/6382b.gif.15 Feb. 2007 <http://tinyurl.com/2dn45p>.// Telfer P, Coen P, Chakravorty S, Wilkey O, Evans J, Newell H, et al. Clinical outcomes in children with sickle cell disease living in England: a neonatal cohort in East London. Haematologica. Jul 2007;92(7):905-12 Williams, Thomas N., Tabitha W. Mwangli, Sammy Wambual, and Moses Kortok. "Sickle Cell Trait and the Risk of Plasmodium Falciparum Malaria and Other Childhood Diseases." The Journal of Infectious Disease 1st ser. 192 (2005): 178-86. Print.


Sickle Cell Disease