Welcome to the ACMG Knowledge Nugget on newborn screening for alpha thalassemia. This activity is intended for educational purposes only. Neither I nor the planning committee have any disclosures. This session is approved for 0.25 CME. To obtain CMEs for this activity, you will need to pass the quiz with a score of at least 80% and complete the evaluation. This session is a companion to the Alpha Thalassemia Act Sheet, which is freely available at www.acmg.net slash ACT. Act Sheets are intended to be immediate resources for providers who encounter positive newborn screening results. Please keep in mind that a newborn screening result is just the first step in the diagnostic process. Further testing and evaluations are needed to determine if the newborn has the disease, a true positive result, or is unaffected, a false positive result. The Act Sheets are intended to provide an overview of the diseases identified by newborn screening and clear next steps for the management of a positive newborn screening result. This session will cover background information on alpha thalassemia, including clinical features and the underlying genetic cause, actions a primary care provider needs to take upon receiving a screen-positive test result for alpha thalassemia, clinical considerations, and supplemental resources. Alpha thalassemia is a genetic condition caused by pathogenic variants found in the HbA1 and or HbA2 genes. These genes contain the instructions for making the alpha-globin protein found on the alpha chains in normal hemoglobin. Normal hemoglobin is composed of two alpha chains containing alpha-globin and two beta chains containing beta-globin. In alpha thalassemia, there is a decrease in the amount of alpha-globin produced, which causes fewer alpha chains. Because of this, those with alpha thalassemia have a low number of red blood cells, as well as red blood cells that are smaller than normal or abnormally shaped. The severity of alpha thalassemia depends on how many alpha-globin genes are affected. The more alpha-globin genes that are affected, the less working hemoglobin is present and the more severe the signs and symptoms. There are four types of alpha thalassemia, severe, called alpha thalassemia major or hydrops fatalis, moderately severe, called HbH disease, mild, called alpha thalassemia trait, and asymptomatic, called alpha thalassemia silent carrier. Signs and symptoms vary widely based on the type of alpha thalassemia the baby has. Depending on how many alpha-globin genes are affected, signs may appear in utero or right at birth. In mild forms, signs will not appear until early childhood, if at all. Both severe and mild alpha thalassemia can cause low blood counts, or anemia, and small red blood cell size, microcytosis. In addition to these, early signs of severe alpha thalassemia can begin in utero and include excess fluid buildup in the body, or hydrops, an enlarged liver and spleen, or hepatosplenomegaly, bony changes of the face and head, yellowing of the skin and eyes, or jaundice, heart defects, and issues with the genital urinary system. Alpha thalassemia is inherited in a complex manner. An infant inherits two copies of the HbA1 and two copies of the HbA2 gene from each parent. The number of non-working copies of these genes that are passed on determines the severity and type of alpha thalassemia the child will have. This is shown in the table on the right. All states in the United States provide newborn screening for alpha thalassemia major, or hydrops fatalis, as well as HbH disease. States differ in the extent to which they report alpha thalassemia trait in silent carriers. A good resource for checking a state's newborn screening panel is the newbornscreening.hrsa.gov website. Screening for alpha thalassemia is performed by examining levels of Barts hemoglobin that is present in those with alpha thalassemia. Barts hemoglobin is an abnormal form of hemoglobin, caused when one or more of the four genes that produce alpha globin chains are dysfunctional. A quantitative assay, most commonly high-performance liquid chromatography, is used to quantify the amount of Barts hemoglobin present. Screening may be able to determine which type of alpha thalassemia an infant has. Now that you have an understanding of what alpha thalassemia is, let's talk about what to do if you have a patient screen positive for alpha thalassemia during newborn screening. You will need to take the following actions. First, contact the family and do the following. Inform the family of the screening result and that more testing is needed. Ascertain clinical status, which can range from asymptomatic to anemia, hepatosponomegaly, and or jaundice. Consult with your state's newborn screening program for a follow-up plan, which may include a referral to pediatric hematology and genetic counseling. Provide the family with basic information about alpha thalassemia. Second, take a family history. Biologic parents of affected newborns can also have alpha thalassemia. Third, arrange for appropriate referrals based on consultation with your newborn screening program. Referrals may include a comprehensive clinical evaluation, discussion of the treatment plan, and genetic counseling. The specialist is typically a pediatric hematologist. The clinical evaluations should include a comprehensive physical assessment by an experienced alpha thalassemia expert. Fourth, working with the appropriate specialist, take steps to ensure confirmation of the newborn screening result. Confirmation by molecular genetic testing is necessary to provide definitive diagnosis and to ascertain reproductive risk for those with alpha thalassemia trait or silent carrier. Fifth, report the final diagnostic outcome back to your state newborn screening program. Treatment of alpha thalassemia is dependent on the type of alpha thalassemia that is diagnosed. Those with alpha thalassemia silent carrier and alpha thalassemia trait can be followed by a primary care provider after referral to a genetic counselor. For those with moderate and severe forms of alpha thalassemia, blood transfusions for severe anemia, medication to reduce extra iron in the body, and avoidance of certain oxidative medications, such as antimalarial drugs and aspirin, may be necessary. Iron infusions generally do not improve anemia in this condition. As you continue to care for your patient with a positive newborn screen for alpha thalassemia, it is likely additional questions and concerns will come up. Here are some resources where you can obtain information on alpha thalassemia, appropriate laboratories and tests, and genetic specialists. Before we end today's session, let's have a quick review. First, alpha thalassemia is a serious condition, and identification of affected individuals is essential for the administration of early treatment. Second, newborn screening can identify the different types of alpha thalassemia, but molecular testing is needed for a definitive diagnosis and to help guide management. Third, ACT sheets are freely available on the ACMG website to review in the event of a screen-positive result. In addition to alpha thalassemia, ACT sheets are available for many other conditions that can be identified through newborn screening.

newborn screening

alpha thalassemia

genetic condition

hemoglobin production

early detection