{"doi":"10.1002/ajh.26121","title":"Novel mechanism of hereditary pyropoikilocytosis phenotype due to co‐inheritance of β globin and α spectrin mutations","abstract":"To the Editor: Co-existence of red blood cell (RBC) membrane disorders and hemoglobinopathies are rare and may present a diagnostic challenge due to overlap of clinical findings. We describe a novel mechanism for the phenotype of hereditary pyropoikilocytosis (HPP), associated with dominant β-thalassemia due to a novel β-globin gene (HBB) mutation, exacerbated by co-inheritance of two α-spectrin gene (SPTA1) mutations in trans. Beta-thalassemia is generally an autosomal recessive disorder caused by HBB mutations, which affect the production of the β-globin subunit of hemoglobin. Frameshift or nonsense mutations in HBB exons 1 and 2 are common, resulting in abnormal termination codons, which trigger nonsense-mediated mRNA decay (NMD) that eliminates the defective mRNA.1 Individuals who are heterozygous for mutations in HBB generally have β-thalassemia minor or a trait with microcytosis and mild or no anemia. However, there are rare HBB mutations that lead to a dominantly inherited form of β-thalassemia causing moderate to severe symptomatic anemia. Splenomegaly is often present and hemolysis may be prominent. More than 40 of these mutations have been described, ranging from heterogeneous missense mutations to frameshift mutations, caused by small insertions and deletions, resulting in truncated or elongated β-globin variants.1 Most of these mutations are located in the distal part of HBB exon 2 or 3 and tend to escape NMD. This leads to an accumulation of defective peptides, which are hyper-unstable, non-functional and toxic when combined with normal α/β globin dimers. These variants may exhibit heterogeneous clinical phenotypes within families.2 Hereditary pyropoikilocytosis is a rare severe hemolytic disorder characterized by unique poikilocytic and microspherocytic erythrocytes.3 The HPP patients are typically homozygous or compound heterozygotes for mutations in SPTA1, which markedly reduce the “horizontal interactions” of spectrin αβ heterodimers to form tetramers, the main structural unit of the RBC membrane skeleton, that regulates the shape and deformability of the cell.4 These abnormalities severely weaken the skeleton resulting in poikilocyte formation during circulatory shear stress. Hereditary pyropoikilocytosis patients also exhibit a decreased amount of spectrin, which interferes with the “vertical interactions” between the skeleton and the lipid bilayer and leads to loss of membrane and microspherocytes. This combination of qualitative and quantitative defects of spectrin is a hallmark of HPP.4 Here we describe a 59-year-old Dominican male who presented with life-long history of severe microcytic hypochromic anemia and jaundice, with his hemoglobin ranging from 5–7 g/dL requiring occasional RBC transfusions, without iron deficiency. The clinical and laboratory findings are shown in Figure 1(A). His peripheral blood smear (Figure 1(B)) revealed typical HPP RBC morphology. After initial evaluation, the proband became progressively severely anemic. Ten months later, he underwent bone marrow biopsy that was compatible with myelodysplastic syndrome, confirmed by cytogenetic abnormalities. He was then lost to follow up. We performed several investigations as outlined in supplementary data. Sequencing of the HBB gene revealed a novel pathogenic frameshift β-thalassemia mutation in exon 2, HBB282delT, coding for β-globin Cys93fs. No large deletions or duplications were detected by multiplex ligation-dependent probe amplification (MLPA) analysis. Computational algorithms predicted that intron 2 splicing is not affected, and the mutant HBB transcript was confirmed by Sanger sequencing using cDNA obtained from the patient's peripheral blood granulocyte RNA. As we could not obtain sufficient reticulocyte RNA, we performed in vitro expansion of erythroid progenitors in 3-week liquid erythroid cultures. Initially, most of the peripheral blood mononuclear cells were lymphoid cells. At day 7, most lymphoid cells were dead, and t","journal":"American Journal of Hematology","year":2021,"id":202114,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":301175,"name":"Jihyun Song","orcid":"0000-0002-1269-0892","position":1,"is_corresponding":false},{"id":452826,"name":"N. Scott Reading","orcid":"0000-0003-0806-5661","position":2,"is_corresponding":false},{"id":782171,"name":"Julio Lautersztain","orcid":null,"position":3,"is_corresponding":false},{"id":538008,"name":"Abdullah Kutlar","orcid":"0000-0002-5482-8087","position":4,"is_corresponding":false},{"id":686450,"name":"Archana M. Agarwal","orcid":"0000-0001-5896-5719","position":5,"is_corresponding":false},{"id":782172,"name":"Thérèsa L. Coetzer","orcid":null,"position":6,"is_corresponding":false},{"id":301181,"name":"Josef T. Prchal","orcid":"0000-0002-8019-2940","position":7,"is_corresponding":false},{"id":301176,"name":"Soo Jin Kim","orcid":"0000-0002-4174-1679","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-18T23:51:05.955461Z","pmid":"33556202","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}