• 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.
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.
Family history as a guide to genetic disease
|General (ask all patients)|
|Are your parents alive?|
Do you have any siblings?
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:
|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
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
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.
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
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.