# Severe Pain Phenotype in Hemoglobin C (HbC)/Beta-Zero (β⁰) Thalassemia Without Hemoglobin S (HbS): A Clinical and Diagnostic Challenge

## TL;DR

A rare hemoglobin disorder combining HbC and β⁰-thalassemia causes severe pain despite lacking typical sickling, highlighting a diagnostic and treatment challenge.

## Contribution

This case report highlights the unusual severe pain phenotype in HbC/β⁰-thalassemia, a rarely studied genotype.

## Key findings

- A patient with HbC/β⁰-thalassemia experienced severe pain without evidence of vaso-occlusion or acute hemolysis.
- Extramedullary hematopoiesis is a possible explanation for the pain, but the severity remains unexplained.
- Management of pain in this condition is challenging and requires further research into its mechanisms.

## Abstract

Abnormalities in the synthesis or structure of globin chains are known as hemoglobinopathies, and they produce a wide range of clinical phenotypes. When both alleles of the same gene carry different hemoglobin variants, this results in compound heterozygosity. The condition described in this case report (hemoglobin C (HbC)/beta-zero (β⁰)-thalassemia) is one such example. On their own, neither HbC nor β⁰-thalassemia is typically associated with acute vaso-occlusive crises, and the combination of HbC/β⁰-thalassemia has not been well characterized. Limited reports indicate that this genotype is not known to cause pain episodes resembling those seen in HbSC disease. Here, we describe a 32-year-old woman with DNA-confirmed HbC/β⁰-thalassemia. She has chronic transfusion dependence, marrow expansion, and anemia, with a baseline hemoglobin of about 8 g/dL. Despite treatment with hydroxyurea and opioid therapy, she has persistent diffuse bone pain. During the current admission, she presented with worsening pain, nausea, and vomiting. Laboratory findings showed stable hemoglobin compared to her baseline, without leukocytosis or sickling, and imaging revealed no acute pathology. Her pain was managed with intravenous hydromorphone, with plans to transition to oral methadone and oxycodone as needed before discharge. This case illustrates the difficulty of managing severe pain in HbC/β⁰-thalassemia, particularly when symptoms occur with high intensity but without evidence of vaso-occlusion or acute hemolysis. While extramedullary hematopoiesis is a leading explanation for her pain, the degree of pain she experienced is unusual in the absence of acute sickling. Given the rarity of this genotype and the limited amount of published data, management remains challenging. Further research is needed to clarify the mechanisms of pain in HbC/β⁰-thalassemia and to distinguish organic causes from central sensitization in patients with chronic opioid use.