Inherited thrombocytopenia and Occam’s razor

In this issue of Blood, Seo et al demonstrate that the extensive characterization of the inherited bone marrow failure syndromes (IBMFS) can lead to important insights into the biology of hematopoiesis.¹ 

As a nosology, the IBMFS comprise a group of hematologic disorders characterized by hypoplastic cytopenia(s), congenital anomalies, and cancer predisposition. The majority of the IBMFS can be broadly categorized as being either predominantly a pancytopenia or a single-cell cytopenia (see table). Despite these features common to most IBMFS, the molecular pathophysiology of these disorders is remarkably diverse. However, evaluating candidate genes inferred from the affected lineage(s) has, for the most part, proven to be unhelpful. Pancytopenias Fanconi anemia and dyskeratosis congenita result from faulty DNA repair and defective telomere maintenance, respectively. With regards to the single-cell cytopenias, the inherited pure red cell aplasia Diamond-Blackfan anemia (DBA) is a result, in the great majority of cases, of abnormal ribosome biogenesis and ribosomal RNA processing. Severe congenital neutropenia (SCN) arises from a number of distinct abnormalities, the most common being mutations in the gene encoding neutrophil elastase (ELANE). This mutation leads to cell death as a consequence of the neutrophil progenitor cell response to the resulting misfolded protein. Kostmann syndrome is caused by a proapoptotic mutation in HAX1 also resulting in neutropenia. Shwachman-Diamond syndrome, like DBA, is a ribosomopathy, in this case stemming from faulty ribosomal subunit assembly, and predominantly causes neutropenia, although anemia and thrombocytopenia are not uncommon. Other genetic causes of neutropenia abound but again few would a priori be seen as likely. Notably, thrombocytopenia absent radii (TAR) syndrome results unpredictably from defects in a subunit of the exon junction complex.²  Thus, it is clear that these rare disorders are for the most part caused by molecular lesions that result in complex biology and would be difficult to predict.

The oft-used principle of Occam’s razor states that a straightforward explanation is to be preferred over a more complex explanation. So, the mistaken belief that inherited BMF would be often explained by abnormalities in lineage-specific cytokines or their receptors serves to further debunk the notion that the simpler explanation is always to be favored.³  However, it seems fair that simple explanations do suffice for some IBMFS, just not as frequently as might be expected. There are indeed rare instances in which either a cytokine or its receptor is implicated. Most prominent among these is amegakaryocytic thrombocytopenia (AT), which results from mutations in c-mpl, the thrombopoietin (THPO) receptor, and would be predicted by its progression from amegakaryocytic thrombocytopenia to pancytopenia based upon the presence of c-mpl on early hematopoietic cells as well as the megakaryocyte lineage. There are also rare instances of SCN that occur as a consequence of abnormalities in the granulocyte colony-stimulating factor (GCSF) receptor.⁴  Over the past decade, relatively affordable DNA sequencing has permitted additional discovery. Very recently, a case of DBA has been linked to a mutation in erythropoietin (EPO) resulting in aberrant EPO receptor (EPOR) dimerization and failed signal transduction.⁵  We await the discovery of, no doubt, rare mutations in GCSF or EPOR resulting in marrow failure. The discovery of a mutation in THPO described by Seo and colleagues testifies to the existence of other inherited BMF syndromes that can be explained straightforwardly in terms of abnormalities in a lineage-specific cytokine or its receptor.

Nuanced and granular clinical research supported by international registries and patient cohorts combined with the skill of master clinicians have been hallmarks of progress in the understanding of the IBMFS. Collaborations between clinicians and clinical and laboratory researchers flourish to the benefit of investigators and their patients. The patients described by Seo and colleagues all presented with thrombocytopenia progressing to pancytopenia reminiscent of AT resulting from a c-mpl mutation. A complete evaluation, however, failed to reveal a diagnosis. Three of 5 patients from 3 families received allogeneic stem cell transplants from unrelated or hematologically normal related donors, all resulting in poor graft function despite evidence of complete donor chimerism. In 2 nontransplanted siblings and 1 transplanted proband who survived there was an excellent response to the THPO-mimetic romiplostim concordant with undetectable serum THPO levels. Next-generation DNA sequencing revealed 2 different autosomal-recessive inherited mutations (THPO R99W in 2 families and THPO R157X in the third), each resulting in a quantitative THPO defect. Although other reports of THPO mutations are referenced by the authors, this report describes treatment outcomes, failed transplant, and successful treatment with romiplostim, which would now lead a clinician to the diagnosis. Of note, these cases in many ways mirror the earlier observation of Kim et al⁵ ; they encountered a patient with presumed DBA with no genetic diagnosis who, despite achieving full chimerism post–hematopoietic stem cell transplantation, failed to correct the red cell failure. Unfortunately, this patient succumbed to transplant-related toxicity but a subsequent sibling was treated successfully with EPO after an EPO mutation (R150Q) was discovered with a qualitative defect in extracellular binding that resulted in abnormal downstream signaling. Furthermore, their study, based upon the presence of a faulty cytokine, resulted in significant insights into EPO binding and signaling.

The cases presented here by Seo et al and those of Kim et al⁵  represent the rare straightforward explanations for BMF that rarely occur. These observations, nuanced by exquisite clinical information provided by translational scientists, offer insights into biology as important and complex as those obtained from the study of inherited BMF caused by more complicated mechanisms. Thus, the report by Seo and colleagues reveals that the straightforward is not the mundane and that there is much to be learned by pursuing the elusive “simple” explanation of a disease phenotype.