Mimicry of inherited red cell disorders: the result of somatic mutations in a clonal myeloid disease

The mutations resulting from a clonal myeloid disease, usually a myelodysplastic syndrome, can lead to an abnormality of the red cell membrane, heme or globin synthesis or an enzyme pathway. These events can result in a syndrome that simulates the erythropoietic effects of a germline mutation.^1,2 The result can be a more complex cause of anemia than the disorder of erythropoiesis intrinsic to the chronic myeloid neoplasm itself. These acquired syndromes are shown in Table 1 and include hemoglobinopathies and hemolytic anemias. A superimposed protoporphyria syndrome may result from somatic mutation of the ferrochelatase gene (FECH) and another type of porphyria from an unidentified mutation. These effects may require therapy in addition to that used for the neoplasm. Whereas clonal hematopoiesis of indeterminate potential is, usually, a preclinical syndrome without a phenotype, in rare cases, the mutations may result in an acquired clinical disorder of the red cell that simulates a germline mutation, resulting in a phenotype, in this case the simulation of hereditary spherocytosis (Table 1). The (i) advanced age at presentation of the syndrome or (ii) the absence of any earlier laboratory or clinical evidence of the syndrome or both should heighten suspicion of such a somatic mutation.

This brief note provides a list of the reported phenotypes and the molecular abnormalities that should raise consideration of an acquired red cell disorder. The loci 8p11, 11p15, 14q23, 16p13, 18q21, Xq21 and Xq28 are noteworthy. In a few cases, the implicated genes were identified by next-generation sequencing in the absence of cytogenetic clues. The red cell alterations pointing to such a syndrome may be admixed with other red cell changes resulting from the clonal myeloid disease and not appreciated by the physician’s focus, understandably, on a life-threatening neoplasm making the diagnosis more difficult. In some cases, the mutations were considered secondary (passenger) mutations, but the high variant allele frequency mimicked that found in the germline mutation-induced inherited disease.¹⁴

The hematopathologist and hematological oncologist should consider acquired syndromes described here when alterations of the genes and/or chromosome loci noted in Table 1 occur in association with a chronic myeloid neoplasm or when the red cell morphology has features that are unusual, such as a heightened frequency or dominance of ovalocytes or spherocytes.

Table 1.Somatic mutations in chronic myeloid neoplasms leading to acquired red cell syndromes simulating germline mutations.

A clonal myeloid disease, especially a myelodysplastic syndrome, may also result in a profound disorder of erythropoiesis that leads to “red cell anarchy”.¹⁸ The latter is defined by an exaggerated combination of anisocytosis, anisochromia and poikilocytosis. Red cell anisocytosis (elevated red cell distribution width) predicts for a poor prognosis in acute myelogenous leukemia¹⁹ and in myelodysplastic syndrome.²⁰ Elevated red cell distribution width is also a risk factor for progression of age-related clonal hematopoiesis in otherwise healthy persons to acute myelogenous leukemia.²¹

Footnotes

• Received July 2, 2024
• Accepted July 10, 2024

Correspondence

M.A. LICHTMAN - marshall_lichtman@urmc.rochester.edu

Disclosures

No conflict of interest to disclose.