Case series: a rare dominant form of β-thalassemia successfully treated by luspatercept

TL;DR

A rare dominant form of β-thalassemia caused by a novel HBB mutation was successfully treated with luspatercept and hydroxyurea in a multigenerational family.

Contribution

A novel heterozygous HBB mutation causing dominant β-thalassemia is described, along with successful treatment using luspatercept and hydroxyurea.

Findings

Luspatercept improved hemoglobin levels and reduced transfusion needs in affected family members.

Hydroxyurea stabilized hemoglobin levels in one patient.

The mutation causes a broad clinical spectrum of β-thalassemia within a single family.

Abstract

Beta-thalassemia is typically inherited in an autosomal recessive manner and can result from a wide range of mutations affecting all stages of the gene expression pathway. Nonsense and frameshift mutations usually trigger nonsense-mediated mRNA decay (NMD). In rare cases, however, such mutations can lead to dominant β-thalassemia when NMD is bypassed, allowing the synthesis of truncated β-globin chains with dominant-negative effects. We describe a multigenerational family with a novel heterozygous two–base pair insertion in the HBB gene (c.287_288insAC), resulting in a frameshift and a premature stop codon located downstream of the NMD threshold. This mutation causes dominantly inherited β-thalassemia with a broad clinical spectrum, ranging from mild anemia to transfusion dependency. The index patients‘ mother presented with anemia, splenomegaly, iron overload, and ultimately became transfusion-dependent. Her three children, all carriers of the same variant, exhibited variable degrees of anemia; two developed symptoms during adolescence that required pharmacological intervention. Luspatercept was effective in the affected mother and her daughter, improving hemoglobin levels, alleviating symptoms, and reducing transfusion requirements. Hydroxyurea was successfully used in the second daughter to stabilize hemoglobin levels. This case series expands the known spectrum of dominant β-thalassemia mutations and highlights the marked phenotypic variability even within a single family. Our findings support the use of Luspatercept and Hydroxyurea as therapeutic options. Long-term monitoring, including surveillance for complications related to iron overload, is essential for optimal clinical management.

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