Newborn Screening and Clinical Management of Children with Sickle Cell Disease

Maria del Pilar Aguinaga

Abstract

Newborn screening (NBS) in the United States of America (USA) is a federalstate partnership with the goal of identifying at birth, infants that are affected with genetic and congenital disorders, for proper follow-up testing, genetic counseling, education and treatment. NBS should be followed by access to medical care to decrease the morbidity and mortality associated with these disorders. Prompt clinical management of the affected newborns ensures their survival. Today, the most common genetic disorder identified by NBS in the USA is sickle cell disease (SCD). NBS Diagnostic tests, follow-up and pediatric guidelines for detection and treatment of infants with SCD are discussed in this report.

Abstracto

El tamizaje genético neonatal o muestreo del recién nacido (MRN) en los Estados Unidos de América (EEUU) es una asociación entre el gobierno federal y estatal con el objetivo de identificar al nacer a infantes afectados con enfermedades genéticas y congénitas, para el seguimiento apropiado que incluye confirmación del diagnóstico clínico, consejería genética, educación y tratamiento. El seguimiento del MRN debe incluir acceso al cuidado médico para poder bajar la morbilidad y mortalidad asociada con estos desórdenes. El pronto manejo clínico de estos recién nacidos asegura su supervivencia. Actualmente en

138

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los EEUU, la Anemia falciforme (sickle cell) es el desorden genético más común detectado en el MRN. Exámenes de diagnóstico para el MRN, seguimiento y directivas para la detección y tratamiento de infantes afectados con anemia falciforme son discutidos en este reporte.

Newborn Screening (NBS) involves a series of laboratory and medical tests performed mainly in blood collected by heel prick within 48 hours after birth. The newborn’s blood is spotted on paper cards, also known as Guthrie Spots1, allowed to dry and then sent to the State Public Health Laboratories or another Participating Laboratory for testing. NBS is performed to detect genetic and congenital disorders in newborns, with the ultimate goal of treating the disease to prevent the morbidity and mortality associated with these disorders. In the USA, NBS started in the 1960s with the screening of a handful of genetic disorders for populations at risk. In 1972, following the passage of the National Sickle Cell Anemia Control Act by President Nixon, along with the passage of the National Genetic Disease Act in 1978, funding was provided for the establishment of Sickle Cell Centers around the country. The Meharry Sickle Cell Center was established in 1972, with a subcontract from the state of Tennessee (TN) to provide SCD screening and education to both, the population at risk and health care providers. In the mid 1980s, universal screening for SCD became a reality due to the political influence exerted by the Civil Rights Movement of the 1960s, the advent of new and affordable clinical laboratory tests for the diagnosis of SCD, and the discovery that prophylactic penicillin prolonged survival of SCD children2 that otherwise would have succumbed to infections. Early identification of affected infants through NBS for SCD prevents the mortality associated with pneumococcal sepsis and splenic sequestration during childhood. Like several states, TN started NBS in the late 1960s and in 1988 implemented universal NBS for hemoglobinopathies. Since this time, The Meharry Sickle Cell Center (MSCC) became the Hemoglobinopathy Confirmatory and Reference Laboratory for the state’s NBS Program. Every year, approximately 4 million infants in the USA are tested by NBS for an array of genetic and congenital disorders, such as inborn errors of metabolism, congenital hypothyroidism, hemoglobinopathies and congenital hearing loss3. The later screening has recently been implemented in several states, including TN. This test is the only NBS exam that does not require

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blood but rather involves placing tiny earphones in the baby’s ear to detect the baby’s response to sound. Hearing loss occurs more frequently than any other genetic disorder. According to the National Center for Hearing Assessment and Management, every year about 12,000 infants are born in the USA with permanent hearing loss. Other NBS tests include but are not limited to biotinidase deficiency, congenital adrenal hyperplasia, galactosemia, homocystinuria, maple syrup urine disease, medium-chain acyl coenzyme A dehydrogenase deficiency, phenylketonuria, SCD and other hemoglobinopathies, cystic fibrosis and tyrosinemia. The state of TN, a leader in NBS in the country, currently screens for 46 genetic disorders, mostly by tandem mass spectrometry. NBS for cystic fibrosis will soon be added to the screening panel in TN. Yearly, NBS in the USA detects approximately five-thousand newborns with severe genetic disorders. NBS Fees are collected by most states from parents, health care professionals, birthing facilities or third-party payers. The NBS fees range from $140.00 (state of Alabama) to zero (states of Kansas, New York, Pennsylvania and West Virginia). Recently, the State of TN has been considering raising its NBS fee from $47.50 to $75 per screening panel.

Incidence of SCD in the USA

Today, SCD is the most common genetic disorder detected by NBS in the USA population, with an incidence of 1: 2000 to 1:2500 individuals3. Its incidence in the minority population is strikingly high. In the African American population 1 out of every 375 births is affected by SCD. In the Eastern USA Hispanic population 1 out of every 1114 infants are born with SCD. SCD is also prevalent in people of Mediterranean, Middle Eastern Indian, Caribbean, and South American descent4. SCD is found in the Native American and Caucasian population as well, with an incidence of 36.20 and 1.72 per 100,000 population respectively4. Since its inception, NBS in TN has been confirming between 65 to 85 infants per year with SCD, out of 79,000 - 82,000 births per year. The number of confirmed traits (HbAS) averages 2,500 yearly. Tables 1, and 2 depict detailed data on hemoglobinopathies identified in the state of TN. Fig. 1 shows the regional map of the state of TN.

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Table 1: State of TN Presumptive Positives and Confirmed Disease Cases for Hemoglobinopathies and Traits from 2004 to First Quarter of 2007 NBS primary test usually detects more cases than those that are actually confirmed at the Reference and Confirmatory Laboratory. Disease cases include SCD and other hemoglobinopathies. Traits on this table include sickle cell trait and other hemoglobin variant heterozygotes.

2004

Hemoglobinopathy

2005

2006

2007

(Jan-Mar)

Presumed

Confirmed

Presumed

Confirmed

Presumed

Confirmed

Presumed

Confirmed

Positives

Positives

Positives

Positives

Positives

Positives

Positives

Positives

161

82

167

66

261

69

86

22

Hemoglobin Traits

2,630

2,804

2,491

664

Total Births

79,572

81,720

Not available

Not available

Figure 1. Map of the State of Tennesse by Regions. West TN (lime), Middle-TN (light blue), East TN (seagreen), and South East TN (violet). The MSCC performs the hemoglobinopathy confirmatory diagnosis for the State NBS Program. The MSCC also does the NBS follow-up for the Middle-TN region. There are three other regional Sickle Cell Centers in the state of TN (population 5.5 million inhabitants).

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Table 2. Hemoglobin Types in Adults and Children Classified by Regions in the State of TN. These hemoglobins were confirmed at the MSCC from 10/2001 to 10/2003. Other, includes Hb Hasharon, Hb OPadova, Hb Russ and other rare variants.

AA AC AD B-thal AHPFH FAC AC^F FAD AE FAE A^F AF/FA AG AS AS^F FABarts FAG FAS FS/SF FSC FSA SC SS SD S/B-thal Other * Total

West Region 2,431 153 6 15

Middle Region 2,231 39 7 22

East Region 1,596 28 9 18

South East Region 6,266 21 2 15

Total 12,524 241 24 70

8 391 13 7 5 16 130 833 7 269 68

2 182 6 27 7 68 46 122 7 142 34

4 65 0 28 5 13 79 389 4 95 22

2 31 0 6 3 7 57 95 1 57 7

16 669 19 68 20 104 312 1439 19 563 131

1 11 1,203 45 25 15 3 3 0 2 3 5,663

3 11 610 27 11 3 15 16 2 1 3 3,644

1 6 322 7 2 1 1 1 0 0 0 2,696

1 1 137 2 2 0 0 1 1 0 1 6,716

6 29 2,272 81 40 19 19 21 3 3 7 18,719

Sickle Cell Disease: Definition and Pathophysiology

SCD is a serious genetic disorder caused by a mutation in the β-globin gene involving the substitution of glutamic acid with valine at position of amino acid six of the β-globin chain, giving rise to sickle hemoglobin (HbS) inside the red blood cells (RBC). When the concentration of Hb S (sickle hemoglobin) is greater than 50%, the condition is called sickle cell disease, which includes the homozygote state (sickle cell anemia, Hb SS), the sickle beta-thalassemia states (sickle-beta plus, HbSβ+ and sickle-beta zero, HbSβ0) and combinations

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of HbS with other hemoglobins, i.e HbSC, HbSE, HbSD, and HbSOArab. If the amount of HbS inside the red blood cells is less than 50%, the condition is called sickle cell trait (HbAS) which is the heterozygote state, and the red blood cells in these individuals contain HbS (usually 35-45%) and normal adult hemoglobin HbA (55-65%). Deoxygenating conditions trigger polymerization of Hb S inside the red blood cells, which lead to the formation of sickle cells (sickling), which is a key event in the pathophysiology of SCD. Even though SCD is a monogenic disorder, it shows a wide heterogeneity in the severity of its clinical manifestations. The main clinical manifestations of SCD are a chronic hemolytic anemia and recurrent painful vaso-occlusive episodes. The number of pain episodes per year are a measure of the clinical severity of SCD and correlates with early death5. Secondary complications in SCD include infection, stroke, organ failure, acute chest syndrome, kidney disease, gout, osteomyelitis, gallstones, pulmonary embolism, osteoarthritis, and an overall impaired quality of life (QOL) with a reduced life expectancy. The median survival age for SCD patients is 42 years for males and 48 years for females; a reduction of 25-30 years in life expectancy5. Still, life expectancy is longer than it was in the past, particularly related to the inclusion of hydroxyurea (HU), phrophylactic penicillin and pneumococcal immunizations in the treatment regimen6,7.

Newborn Screening Follow-Up

The identification of SCD or sickle cell trait (SCT) newborns is done efficiently at birth through the NBS Program at state public health screening laboratories. Follow-up of SCD and SCT involves confirmatory diagnosis, genetic counseling, education and clinical management. After confirmation, trait follow-up counseling is done through a letter communicating the newborn carrier status, or through a face to face meeting, if requested by the family. SCD counseling follow-up is done through a home visit by the genetic counselor and/or follow-up nurse or by appointment at the Sickle Cell Center. Assessment of knowledge of the adult individual carrier status is necessary after childhood, especially at reproductive age or during the pre-conceptual period. A national antenatal diagnosis of sickle cell disease in combination with newborn screening for population at risk has just started in England8. This approach, although expensive, has the advantage for parents to

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know whether or not they are carrying a child with SCD. If two SCT individuals decide to have children, they need to understand the risks of having a child affected with SCD. Several improvements could be done in this aspect, like the use of a permanent card to remind these individuals of their carrier status, high-school surveys about carrier status among the children, community screening of the adult population that may not have been tested as newborns. In addition, there is a need to screen immigrant children and adults, since most likely they have not been screened at birth by NBS. In the past few years, in the state of Tennessee along with other states, there has been a large Hispanic population influx, and SCT is not uncommon in this population, with incidences ranging from 0.55 to 5.7% according to published data in similar Hispanic populations9. In order to prevent SCD, it is necessary to implement proper education and counseling techniques to make the SCT individuals aware of their risk of having children with SCD. It also becomes necessary to provide the state follow-up letters, educational and counseling materials in Spanish for the Hispanic families that have SCT or SCD. Family protocols that provide SCD knowledge and coping techniques, and involve the extended family members of the affected individuals will increase family awareness and support of the primary caregivers. Innovative and effective educational methods, that are age appropriate for individuals with SCD need to be developed as well. Summer camps and mini-camps have been effective ways to teach and give emotional support to children with SCD.

Confirmatory Diagnosis After the State Public Health Laboratory has identified an infant with SCD, SCT or any other hemoglobinopathy using dried blood; the follow-up nurse makes sure that a second blood sample (fresh liquid blood) is sent for confirmatory testing to the Hemoglobinopathy Reference and Confirmatory Laboratory. The laboratory methods used are isoelectric focusing electrophoresis, alkaline, acid and neutral electrophoresis, high performance liquid chromatography and DNA testing for rare hemoglobin variants10-12.

Clinical Management of Infants and Children with SCD

Several factors have contributed to the increased in life expectancy for sickle cell disease. They are related primarily to early identification of the disease and proper health care management, including penicillin prophylaxis,

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immunizations against pneumococcal infections, and folate administration13, even though there is no real evidence that sickle cell patients are folate deficient. The management of sickle cell disease has to be done with age appropriate protocols, starting with pediatric primary and hematologic care, from birth to 15 years of age, then transitional protocols into adult care. Proper health care management from birth to 6 months of age include confirmatory testing, age appropriate immunizations starting at 2 months, DPT/Hib OC (Diphteria Pertusis Tetanus/Haemophylus influenza Type b) , PCV 7 (heptavalent pneumococcal-conjugated vaccine at 2, 4, 6 and 12 months of age), IPV (Inactivated Polio Vaccine (IPV), and HBV (hepatitis B vaccine). By 2 months of age, prophylactic penicillin (PCN) at 125mg BID (bis in die, twice a day) should be started and continued until 3 years of age, when it can be increased to 250mg BID and given until 5 years of age, when it should be reassessed. A developmental and nutritional assessment should be done, along with referral to a sickle cell center. Parents and the primary care giver should be taught about the symptoms of sickle cell disease. From 6 to 12 months of age: periodic screening with CBC (complete blood count ) and reticulocyte counts, UA (urinalysis), SMA-20 (sequential multi channel analysis for 20 chemical tests), age appropriate immunizations and influenza vaccine at 12 months, a PPD test (purified protein derivative or Tuberculin test) and hepatitis B surface antigen status. The caregivers should be taught about SCD symptoms like fever, splenic sequestration, priapism, and dehydration. From 12 months to 3 years of age: periodic screening with CBC and reticulocyte counts, UA, and SMA-20. A basal transcranial doppler (TCD), and an increase in the PCN dose to 250 mg BID at 3 years of age, as mentioned above. The medical care provider needs to give PCV23 (23-valent pneumococcal polysaccharide vaccine) at 2 years and 5 years of age. Hydroxyurea (HU) may be beneficial at this age for some children that present a severe course of the disease. Since there are no clinical studies on the effect of hydroxyurea (at therapeutic doses) on the reproductive system of male SCD patients (pediatric and adult), caution should be excised in those patients undergoing long-term hydroxyurea therapy. Some reports have described azoospermia in male patients on HU14,15. To date, HU is the only FDA-approved drug for the treatment of sickle cell disease. From 3 years to 5 years of age, the periodic screening with CBC and reticulocyte counts, UA and SMA-20 should be continued. Magnetic resonance imaging (MRI) should be conducted only if indicated by the results of the TCD.

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Medical care providers should explain pain management for SCD to the parents and care givers. At this point, if the child is going to start school, a letter to the school could be sent by the medical care providers explaining SCD, and educational materials like a SCD parent/teacher guide to school should be given to teachers and school officials who regularly interact with children with SCD. Parents should meet with school staff to set realistic educational goals for their child16. From 5 years to 10 years of age, medical care providers need to evaluate for PCN phrophylaxis, do a TCD, perform a yearly ophthalmological evaluation, do an assessment of pneumococcal titers, and revaccination at 10 years of age, perform an assessment for avascular necrosis of the hip and shoulder. If the child is been transfused, the medical care providers need to test for Hepatitis C and HIV (Human Immunodeficiency Virus). Pain management and stress reduction and possibly delay in puberty should be discussed with the parents. From 10 years to 15 years of age: the medical care providers should perform an MRI/MRA (Magnetic Resonance Imaging/Magnetic Resonance Angiogram) if indicated by the TCD results. HU may be considered in children with a severe course of the disease. Pneumococcal titers need to be checked and vaccine needs to be repeated at 15 years of age. The medical care provider should look for symptoms of illness like priapism, and discuss preventive care, and crisis management with the child’s caregivers. Also, the medical care provider should discuss with girls the possible complications during pregnancy, and with the parents and child the genetics of inheritance of hemoglobinopathies. Pain management, pain tolerance and narcotic use can be discussed as well. From 15 years of age and older, the physician should discuss the adult complications of SCD, like renal disease, skin ulcers, pulmonary disease, aseptic necrosis, retinal disease, central nervous system, and priapism. Transition to adult care should also be discussed, as the child transitions into the care of the adult hematologist. Career choices can also be discussed for persons with disabilities due to chronic disease. Adjunctive therapy for pain management and stress reduction should be discussed, and given if needed. Most sickle cell disease patients receive blood transfusions at some point in their lives for symptomatic anemia, aplastic crisis, splenic or hepatic sequestration, acute chest syndrome or acute organ failure, and in preparation for surgery. Red cell exchange transfusion is recommended for acute stroke, acute chest syndrome, and multi-organ failure. Iron chelators like

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desferoxamine or dederasirox are used in patients that are having iron overload.

Acknowledgements

This work was supported in part by contract# GR 06-16979-00 from the Tennessee Department of Health and Research Triangle International Subcontract # 3-312-0210355 from the Health Resources and Services Administration. I would like to thank the TN NBS Program and the Meharry Sickle Cell Center Staff for data sharing. I am grateful to my mentor Dr. Alberto Cazorla Talleri for shaping my early scientific development and for his valuable teachings.

References

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