Pearson syndrome
Pearson syndrome is a rare and typically fatal disorder that primarily affects infants, characterized by defects in the hematopoietic system and the exocrine pancreas, along with potential kidney, liver, and endocrine complications. The condition is caused by deletions in mitochondrial DNA (mtDNA), which leads to energy deficits in cells due to impaired oxidative metabolism. Symptoms often emerge in early childhood and include bone marrow failure resulting in pancytopenia, digestive issues such as chronic diarrhea and malabsorption, and metabolic disturbances like lactic acidemia. Individuals with Pearson syndrome are commonly transfusion-dependent and may present with signs of anemia and failure to thrive.
Diagnosis typically involves analyzing bone marrow for mtDNA deletions, and while treatment focuses on managing specific symptoms—such as infections and metabolic imbalances—there is no definitive cure. Due to its sporadic nature, there are no established risk factors, and the condition does not show specific associations with race or sex. Unfortunately, most affected individuals do not survive past early childhood; however, rare survivors may develop additional mitochondrial-related syndromes later in life.
Pearson syndrome
ALSO KNOWN AS: Pearson’s syndrome; Pearson’s disease; Pearson’s marrow-pancreas syndrome
DEFINITION Pearson syndrome—named for Howard Pearson, a pediatric hematologist oncologist who first described the syndrome in 1979—is a rare, generally fatal disorder of infancy that affects the hematopoietic system and exocrine pancreas, with variable kidney, liver, and endocrine failure. Pearson syndrome is commonly caused by mitochondrial DNA (mtDNA) deletions, with high levels of heteroplasmy (proportion of mutant mitochondrial genomes) in the affected tissues.
Risk Factors
There are no specific risk factors for mtDNA deletions, which usually arise de novo, either in the oocyte or early in embryogenesis. There is no race or sex specific association for Pearson syndrome. Siblings of affected individuals are rarely affected.
Etiology and Genetics
Mitochondria are the cell’s energy-producing organelles. They contain hundreds to thousands of copies of mtDNA, a small double-stranded circular genome that encodes thirteen subunits of respiratory chain enzymes and part of the protein synthetic machinery necessary to translate these mitochondrial transcripts, two ribosomal RNA genes, and twenty-two transfer RNA genes. Pearson syndrome is caused by deletions of mtDNA. Depending on their size, mtDNA deletions can disrupt protein-coding sequences or decrease their expression by removing rRNA and tRNA genes. The proportion of deleted mitochondrial genomes varies between tissues and can change over time. When heteroplasmy levels reach a critical threshold, oxidative metabolism is impaired and cells experience an energy deficit. Abnormal iron metabolism also occurs in Pearson syndrome, which may contribute to cellular damage.
An important feature of mtDNA mutations is that, depending on the level of heteroplasmy and/or tissue-specific factors, a single mutation can cause different multisystemic disorders. MtDNA deletions are associated with three overlapping syndromes, with a general correspondence between the level of heteroplasmy and the affected tissue. Pearson syndrome primarily involves bone marrow and exocrine pancreas, but rare survivors may accumulate mtDNA deletions as the mitochondrial genome replicates in nerve and muscle, leading to Kearns-Sayre syndrome or progressive external ophthalmoplegia (paralysis of extraocular eye muscle).
Most mitochondrial diseases show maternal inheritance because mtDNA is transmitted exclusively in oocytes. However, mitochondrial DNA deletion syndromes usually occur sporadically. In rare inherited cases, mtDNA deletions are transmitted maternally, but the mother is usually affected with a later onset syndrome that involves other tissues, such as Kearns-Sayre syndrome.
Symptoms
The major symptoms of Pearson syndrome are bone marrow failure resulting in pancytopenia (reduced number of red and white blood cells and platelets) and exocrine pancreas dysfunction (problems with digestive enzymes, leading to chronic diarrhea and malabsorption). Typically sideroblastic anemia occurs despite the presence of sufficient iron (sideroblasts are nucleated erythrocytes with cytoplasmic iron granules because they cannot incorporate iron into hemoglobin). Often the patient is transfusion-dependent. Defective oxidative phosphorylation leads to lactic acidemia, which can be persistent or intermittent. The liver and kidneys are variably affected.
Symptoms begin during infancy and early childhood. Parents notice paleness due to anemia, chronic diarrhea and fatty stools, and failure to thrive. Death is usually caused from sepsis, hepatic failure, or metabolic crisis.
Screening and Diagnosis
In Pearson syndrome, mtDNA deletions are usually more common in blood than in muscle. However, bone marrow is the most reliable tissue for diagnosis, because less-involved tissues may have lower levels of heteroplasmy that can reduce the chance of detection. Although the junction-fragment created by an mtDNA deletion can be detected by polymerase chain reaction (PCR), deletions occur in normal individuals as part of the aging process, and PCR tests can thus give false positive results; Southern blot analysis is preferred. Molecular testing should be performed on blood isolated before transfusions to avoid false negative results caused by dilution of the patient’s abnormal blood with transfused donor blood.
Treatment and Therapy
There is no specific therapy, but individual symptoms have corresponding treatments: infection (antibiotics), metabolic acidosis (bicarbonate supplements or dichloracetic acid, which can be neurotoxic), pancytopenia (transfusions, with erythropoietin to possibly decrease their frequency), neutropenia (granulocyte colony-stimulating factor), and malabsorption (pancreatic replacement and vitamins). Other endocrine imbalances are treated with the appropriate hormones. One study suggests that high carbohydrate diets should be avoided, as those diets can stress the liver. Transplantation is not effective due to the multisystemic nature of the disease.
Prevention and Outcomes
Pearson syndrome is usually sporadic. Prenatal screening for women with mtDNA deletions is problematic because of unknown levels of heteroplasmy in untested fetal tissues. Pearson syndrome is often fatal in childhood, but survivors may develop Kearns-Sayre syndrome and should be monitored for cardiac and muscle function.
Bibliography
Bernes, S. M., et al. “Identical Mitochondrial DNA Deletion in Mother with Progressive External Ophthalmoplegia and Son with Pearson Marrow-Pancreas Syndrome.” Journal of Pediatrics 123 (1993): 598–602. Print.
Gagne, Katelyn E., et al. "Pearson Marrow Pancreas Syndrome in Patients Suspected to Have Diamond-Blackfan Anemia." Blood 124.3 (2014): 437–40. Print.
Kasbekar, Shivani A., et al. "Corneal Endothelial Dysfunction in Pearson Syndrome." Ophthalmic Genetics 34.1/2 (2013): 55–57. Print.
"Pearson Marrow-Pancreas Syndrome." Genetics Home Reference. National Library of Medicine, 4 Aug 2014. Web. 7 Aug. 2014.
Rotig, A., et al. “Pearson’s Marrow-Pancreas Syndrome: A Multisystem Mitochondrial Disorder in Infancy.” Journal of Clinical Investigation 86 (1990): 1601–08. Print.
Van den Ouweland, J. M. W., et al. “Characterization of a Novel Mitochondrial DNA Deletion in a Patient with a Variant of the Pearson Marrow-Pancreas Syndrome.” European Journal of Human Genetics 8 (2000): 195–203. Print.
Yoshimi, Ayami, et al. "Pearson Syndrome: A Multisystem Mitochondrial Disease with Bone Marrow Failure." Orphanet Journal of Rare Diseases, vol. 17, 17 Oct. 2022, p. 379, doi.org/10.1186%2Fs13023-022-02538-9. Accessed 9 Sept. 2024.