Genetic blood disorders: Questions you need to ask

,

Applied Evidence

Genetic blood disorders: Questions you need to ask

J Fam Pract. 2012 January;61(1):30-37

By

Paul S. Starr, MD

No one is better positioned than you to look for evidence of inherited diseases—especially when you consider that many FPs care for 2, or even 3, generations of a single family.

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References

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3. Ingram VM. Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin. Nature. 1957;180:326-328.

4. National Heart, Lung, and Blood Institute. What is sickle cell anemia? Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/sca/. Accessed December 14, 2011.

5. National Center for Biotechnology Information. Sickle cell disease. Gene Reviews. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1377/. Accessed December 14, 2011.

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7. National Heart, Lung, and Blood Institute. What are the signs and symptoms of sickle cell disease. Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/sca/signs.html. Accessed December 14, 2011.

8. Candrilli SD, O’Brien SH, Ware RE, et al. Hydroxyurea adherence and associated outcomes among Medicaid enrollees with sickle cell disease. Am J Hematol. 2011;86:273-277.

9. Hoffer LJ. Folate supplementation in sickle cell anemia. N Engl J Med. 2003;349:813.-

10. ClinicalTrials.gov. Evaluating the safety and effectiveness of bone marrow transplants in children with sickle cell disease (BMT CTN #0601) (The SCURT study). Available at: http://clinicaltrials.gov/ct2/show/NCT00745420?term=sickle+cell+bone+marrow+transplant&rank=1. Accessed December 15, 2011.

11. McKerrell TD, Cohen HW, Billett HH. The older sickle cell patient. Am J Hematol. 2004;76:101-106.

12. Cooley TB, Lee P. Series of cases of splenomegaly in children with anemia and peculiar bon changes. Trans Am Pediatr Soc. 1925;37:29.-

13. Thalassemia. Stedman’s Medical Dictionary. 24th ed. Baltimore, Md: Williams & Wilkins; 1982:1435.

14. Johnson CS, Tegos C, Beutler E. Alpha thalassemia; prevalence and hematologic findings in American blacks. Arch Intern Med. 1982;142:1280-1282.

15. Al-Awamy BH. Thalassemia syndromes in Saudi Arabia; meta-analysis of local studies. Saudi Med J. 2000;21:8-17.

16. Lie-Injo L. Alpha-chain thalassemia and hydrops fetalis in Malaya: report of five cases. Blood. 1962;20:581-590.

17. Chouliaris G, Berdoukas V, Ladis V, et al. Impact of magnetic resonance imaging on cardiac mortality in thalassemia major. J Magn Reson Imaging. 2011;34:56-59.

18. Mendilcioglu I, Yakut S, Keser I, et al. Prenatal diagnosis of beta-thalassemia and other hemoglobinopathies in southwestern Turkey. Hemoglobin. 2011;35:47-55.

19. Vichinsky EP. Changing patterns of thalassemia worldwide. Ann NY Acad Sci. 2005;1054:18-24.

20. Cao A, Moi P, Galanello R. Recent advances in beta-thalassemias. Pediatr Rep. 2011;3:e17.-

21. Texas Department of State Health Services. Sickle cell + thalassemia. Available at: http://www.dshs.state.tx.us/newborn/thala.shtm. Accessed December 14, 2011.

22. Weatherall DJ. History of genetic disease: thalassaemia: the long road from bedside to genome. Nat Rev Genet. 2004;5:625-631.

23. Jaffe EK, Stith L. ALAD porphyria is a conformational disease. Am J Hum Genet. 2007;80:329-337.

24. Thunell S, Floderus Y, Henrichson A, et al. Porphyria in Sweden. Physiol Res. 2006;55(suppl 2):S109-S118.

25. James WD, Berger T, Elston D. Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa: Saunders; 2006.

26. Gross U, Hoffman GF, Doss MO. Erythropoietic and hepatic porphyries. J Inherit Metab Dis. 2000;23:641-661.

27. American Porphyria Foundation. About porphyria. Available at: http://www.porphyriafoundation.com/about_porphyria. Accessed December 19, 2011.

28. Boffey PM. Rare disease proposed as cause for “vampires.” New York Times. May 31, 1985. Available at: http://www.nytimes.com/1985/05/31/us/rare-disease-proposed-as-cause-for-vampires.html. Accessed December 15, 2011.

29. Khachemoune A, Blyumin M. Red urine and photosensitive skin rash. J Fam Pract. 2009;58:200-202.

30. Lin CS, Lee NJ, Park SB, et al. Purple pigments: the pathophysiology of acute porphyric neuropathy. Clin Neurophysiol. 2011;122:2336-2344.

31. Seubert S, Seubert A, Stella AM, et al. Results of treatment of porphyria cutanea tarda with bloodletting and chloroquine. Z Hautkr. 1990;65:223-225.

32. Sassa S. Modern diagnosis and management of the porphyrias. Br J Haematol. 2006;135:281-292.

33. Cainelli T, Di Padova C, Marchesi L, et al. Hydroxychloroquine versus phlebotomy in the treatment of porphyria cutanea tarda. Br J Dermatol. 1983;108:593-600.

34. McKusick-Nathans Institute of Genetic Medicine. Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders. Vol .3. Baltimore, Md: Johns Hopkins University; 1998:2305.

35. National Digestive Diseases National Clearinghouse. Hemochromatosis. Available at: http://digestive.niddk.nih.gov/diseases/pubs/hemochromatosis. Accessed December 14, 2011.

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38. Rocchi E, Gibertini P, Cassanelli M, et al. Iron removal therapy in porphyria cutanea tarda: phlebotomy versus slow subcutaneous desferrioxamine infusion. Br J Dermatol. 1986;114:621-629.

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PRACTICE RECOMMENDATIONS

• Advise patients at risk for genetic disorders to be tested before starting a family, as carrier status identified at birth is often lost to follow up. C

• Keep genetic blood disorders in mind for patients of all ages; the most common form of porphyria, as well as hereditary hemochromatosis, often remains hidden until well into adulthood. C

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

Some inherited diseases are found as a result of routine neonatal screening. Others remain hidden for years—until a pregnant woman is tested, an older patient receives a particular laboratory test, or signs and symptoms of a previously undetected disorder emerge.

To recognize the signs and respond appropriately, you need to know which patient populations are at heightened risk for which inherited diseases. It is crucial, too, to routinely obtain a comprehensive medical history.

FAST TRACK

Bone marrow transplantation offers hope for patients with sickle cell disease and other potentially fatal inherited blood disorders.

General questions about the health status of family members may be sufficient when there is no reason to suspect a genetic disease. When you have evidence or a reasonable suspicion of a particular disorder, however, a targeted family history (TABLE) is essential. It is crucial, too, to thoroughly document any evidence of an inherited condition found at birth, as well as to advise patients of reproductive age who may be carriers to seek genetic testing or counseling when they begin thinking about starting a family. This review focuses on inherited blood disorders, but these principles apply to other genetic diseases, as well.

TABLE
Family history as a guide to genetic disease

General (ask all patients)
Are your parents alive? - If so, how old are they? What is the status of their health? - If not, what did they die of, and at what age? Do you have any siblings? - If so, what are their ages and the status of their health? - If they are deceased, what caused their death and at what age? Are there any diseases that run in your family (eg, breast or colon cancer, heart disease, type 2 diabetes, or genetic disorders)?
Targeted family history (tailored to diagnosis or suspected disorder)
Has anyone else in your family had this disease? Has anyone in the family: - required frequent blood transfusions? - donated blood or been told by a doctor to give blood frequently? - been extremely sensitive to the sun? - had a bronzed appearance not related to sun exposure or purposeful tanning?
Family/social history
Who is living in the home with you (or your child)? Are there any children who may be affected or may be silent carriers? Would you be willing to see a genetic counselor?

Sickle cell disease

FAST TRACK

About one in 500 African Americans are born with sickle cell disease— perhaps the best-known inherited blood disorder.

About one in 500 African Americans are born with sickle cell disease (SCD)—perhaps the best-known inherited blood disorder. Far more (approximately one in 12) are carriers. SCD also affects people of Hispanic origin, although the incidence (about one in 36,000) is much lower than that of blacks. Overall, an estimated 70,000 to 100,000 US residents have SCD.^1,2

Inheritance
The genetics of SCD are fairly straightforward: A mutation in the hemoglobin beta chain results in a single amino acid substitution of the normal glutamic acid.³ The mode of inheritance is autosomal recessive. Simply put, patients with SCD have 2 abnormal genes (one from each parent) that cause their red blood cells to change shape. People with sickle cell trait have only one abnormal gene. They cannot develop SCD themselves, but they are carriers of the disease.

Testing
SCD is typically diagnosed as a result of routine neonatal screening (screening newborns for SCD is mandatory in every state).⁴ The gold standard test is hemoglobin electrophoresis. Although gene sequencing can be used to distinguish SCD from other hemoglobinopathies in equivocal cases, this is rarely necessary.⁵

Clinical presentation
Infants with SCD are typically asymptomatic for the first few months of life. This is because of the persistence of fetal hemoglobin, which is not predisposed to sickling.⁶

In many cases, hand/mouth syndrome—a painful swelling of the hands and feet—is the first physical manifestation of SCD and is treated with pain medication and an increase in fluids. The clinical course of SCD, although somewhat variable, is characterized by sickle cell and pain crises.

Sickle cell crisis occurs when a precipitating factor, such as a temperature change, dehydration, or infection, induces the abnormal genes to polymerize and deform the red blood cells, which then hemolyze. Microinfarctions can occur throughout the body, causing intense pain. The hematocrit may fall precipitously. If the bone marrow is unable to replace the hemolyzed red blood cells, an aplastic crisis may result.