Working Diagnosis:
Sickle Cell-Hereditary Persistence of Fetal Hemoglobin

Treatment:
No intervention was required

Outcome:
Hematology and neuromuscular specialists recommended return to duty with Sickle Cell Trait precautions.

Author's Comments:
Patients with Sickle Cell and Hereditary Persistence of Fetal Hemoglobin will test positive for Sickle Cell Disease on lab screening. Fetal hemoglobin (HgbF) protects red blood cells from sickling in patients with HgbS, with a higher percentage of fetal hemoglobin correlating inversely to severity of Sickle Cell Disease symptoms. This leads to a clinical absence of Sickle Cell Disease symptoms. Increased testing by the National Collegiate Athletic Association (NCAA) and military will identify more asymptomatic individuals with Sickle Cell-Hereditary Persistence of Fetal Hemoglobin.

Editor's Comments:
Fetal hemoglobin is a major hemoglobin during gestation, but is replaced almost completely by Hemoglobin A by the age of 12  months. After this transition, fetal hemoglobin is typically 3.1 ± 1.5% of hemoglobin distribution. In Hereditary Persistence of Fetal Hemoglobin (HPFH) fetal hemoglobin can range from 10–40%. There are multiple different mutations that lead to persistence of fetal hemoglobin, including deletions or single base substitutions in the HBB gene cluster and single nucleotide polymorphisms (SNPs) in the genes that encode repressors of fetal hemoglobin gene expression. Fetal hemoglobin inhibits sickle hemoglobin polymerization such that these patients usually have inconsequential hemolysis and few, if any, vasoocclusive events. Thus, individuals with hemoglobinopathies with concurrent high fetal hemoglobin can be asymptomatic. If screening of an asymptomatic individual uncovers sickle hemoglobin, Hereditary Persistence of Fetal Hemoglobin should be in the differential.

This case also highlights considerations to take in deciding which conditions to include in a screening program. Widespread screening of asymptomatic individuals will inevitably yield either false positives or inconsequential abnormalities. These results may lead to harm in the form of undue psychological stress and unnecessary further testing. Any screening program should be ready to address all positive results, and should be weighted against the potential benefit of uncovering treatable conditions.

References:
Steinberg MH. Fetal Hemoglobin in Sickle Hemoglobinopathies: High HbF Genotypes and Phenotypes. J. Clin. Med. 2020, 9(11), 3782.

Thein SL, Menzel S, Lathrop M, Garner C. Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. Hum Mol Genet. 2009 Oct 15; 18(R2): R216–R223.

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