Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are heterogeneous red blood cell (RBC) membrane disorders that result from mutations in the genes encoding α-spectrin (SPTA1), β-spectrin (SPTB), or protein 4.1R (EPB41). The resulting defects alter the horizontal cytoskeletal associations and affect RBC membrane stability and deformability causing shortened RBC survival. The clinical diagnosis of HE and HPP relies on identifying characteristic RBC morphology on peripheral blood smear and specific membrane biomechanical properties using osmotic gradient ektacytometry. However, this phenotypic diagnosis may not be readily available in patients requiring frequent transfusions, and does not predict disease course or severity. Using Next-Generation sequencing, we identified the causative genetic mutations in fifteen patients with clinically suspected HE or HPP and correlated the identified mutations with the clinical phenotype and ektacytometry profile. In addition to identifying three novel mutations, gene sequencing confirmed and, when the RBC morphology was not evaluable, identified the diagnosis. Moreover, genotypic differences justified the phenotypic differences within families with HE/HPP.
Objective: Several states are building infrastructure and data collection methods for longitudinal, population-based surveillance systems for selected hemoglobinopathies. The objective of our study was to improve an administrative case definition for sickle cell disease (SCD) to aid in longitudinal surveillance. Methods: We collected data from 3 administrative data sets (2004-2008) on 1998 patients aged 0-21 in Georgia who had ≥1 encounter in which an SCD International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code was recorded, and we compared these data with data from a laboratory and medical record review. We assessed performance (sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) of case definitions that differed by number and type of SCD-coded encounters; addition of SCD-associated treatments, procedures, and complications; and length of surveillance (1 vs 5 years). We identified correct diagnoses for patients who were incorrectly coded as having SCD. Results: The SCD case definition of ≥3 SCD-coded encounters in 5 years simplified and substantially improved the sensitivity (96.0% vs 85.8%) and NPV (68.2% vs 38.2%) of the original administrative case definition developed for 5-year, state-based surveillance (≥2 encounters in 5 years and ≥1 encounter for an SCD-related treatment, procedure, or complication), while maintaining a similar PPV (97.4% vs 97.4%) and specificity (76.5% vs 79.0%). Conclusions: This study supports an administrative case definition that specifies ≥3 ICD-9-CM–coded encounters to identify SCD with a high degree of accuracy in pediatric patients. This case definition can be used to help establish longitudinal SCD surveillance systems.
An asymptomatic infant of Ghanaian descent had hemoglobin F only detected on newborn screening. β-globin gene sequencing identified the intervening sequence (IVS)-II-849 (A → G) mutation with no normal β-globin gene. β-globin/δ-globin gene sequencing showed that both parents were heterozygous for the IVS-II-849 (A → G) mutation. The mother was heterozygous for the HbA2' δ-globin mutation (δ16 (A13) Gly → Arg), thus β-thalassemia trait was unrecognized due to coinheritance of HbA2'. The infant developed anemia, splenomegaly, and began transfusion therapy by the age 6 of months. This is the first report of β-thalassemia major with homozygous IVS-II-849 (A → G) mutations. This case highlights the importance of δ-globin gene mutations in prenatal testing.
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