Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure

Abstract

Pearson syndrome (PS) is a rare fatal mitochondrial disorder caused by single large-scale mitochondrial DNA deletions (SLSMDs). Most patients present with anemia in infancy. Bone marrow cytology with vacuolization in erythroid and myeloid precursors and ring-sideroblasts guides to the correct diagnosis, which is established by detection of SLSMDs. Non hematological symptoms suggesting a mitochondrial disease are often lacking at initial presentation, thus PS is an important differential diagnosis in isolated hypogenerative anemia in infancy. Spontaneous resolution of anemia occurs in two-third of patients at the age of 1-3 years, while multisystem non-hematological complications such as failure to thrive, muscle hypotonia, exocrine pancreas insufficiency, renal tubulopathy and cardiac dysfunction develop during the clinical course. Some patients with PS experience a phenotypical change to Kearns-Sayre syndrome. In the absence of curative therapy, the prognosis of patients with PS is dismal. Most patients die of acute lactic acidosis and multi-organ failure in early childhood. There is a great need for the development of novel therapies to alter the natural history of patients with PS.

Keywords: Mitochondrial DNA deletion; Natural history; Pearson syndrome.

Fig. 1

Hypothesis for the phenotypical change in Pearson syndrome. Hematological recovery is hypothesized to be due to a positive selection of hematopoietic stem cells harboring low load of deleted mitochondrial DNA (mtDNA). In contrast, deleted mtDNA accumulates in muscle, resulting in the development of Kearns-Sayre syndrome with muscular complications

Fig. 2

Bone marrow findings in patients with Pearson syndrome. Bone marrow can be hypocellular A or normocellular B. C + D: micromegakarocytes, E: dysplastic megakaryocyte with bi-nuclei. F: proerythroblast and myelocyte with vacuoles. G: proerythroblast with vacuoles, H: myelocyte with vacuoles, I: promyelocyte with vacuoles and double nuclei, J: macrocytic normoblast with disturbed hemoglobinization. K: erythroblast with lobulated nuclei. L: ring sideroblast (iron-staining)

Fig. 3

Diagnostic algorithm for suspected Pearson syndrome. Diagnosis of Pearson syndrome is suggested by patient history, clinical symptoms and laboratory findings. The key diagnostic procedures are genetic analysis to detect single large-scale mitochondrial DNA (mtDNA) deletions in blood cells and bone marrow examination. *The single large mtDNA deletion can be also be present in other tissues such as buccal swab and/or urinary epithelial cells in majority of patients [4]

Fig. 4

Initial presentation and complications during the clinical course in 25 patients with Pearson syndrome. Signs and symptoms at first presentation (blue), at time of diagnosis (red) or manifesting itself during the clinical course (green) are shown. The left axis provides the number of patients for each item. [6]