Pearson Syndrome 

In 1979, Pearson et al described a previously unrecognized, often fatal disorder of infants with transfusion-dependent sideroblastic anemia, vacuolization of hematopoietic precursors, and exocrine pancreatic insufficiency.^[1] The large deletions of the mitochondrial genome that cause the disorder were discovered a decade later.

Pearson syndrome is currently recognized as a rare, multisystemic, mitochondrial cytopathy. Its features are refractory sideroblastic anemia, pancytopenia, defective oxidative phosphorylation, exocrine pancreatic insufficiency, and variable hepatic, renal, and endocrine failure. Death often occurs in infancy or early childhood due to infection or metabolic crisis. Patients may recover from the refractory anemia. Older survivors have Kearns-Sayre syndrome (KSS), which is a mitochondropathy characterized by progressive external ophthalmoplegia and weakness of skeletal muscle.

Mitochondropathies

The mitochondropathies comprise several diverse, overlapping syndromes caused by mutations of mitochondrial DNA. Pearson syndrome is a specific clinical subset of these syndromes that in which involvement of the bone marrow and exocrine pancreas is prominent. The pathogenesis of Pearson syndrome is complex and not well understood. Deletions of certain components of the electron transport chain, encoded by mitochondrial DNA, cause a defect in cellular oxidative metabolism. Certain transfer RNAs (tRNAs) may also be deleted, and their deletion impairs the translation of messenger RNAs (mRNAs) to proteins. Abnormal metabolism of iron, evidenced by sideroblastosis and hemosiderosis, may also be a key feature (see the image below).

These defects cause cellular injury in target tissues.

Other mitochondropathies, such as KSS and the mitochondrial myopathies, have deletions of mitochondrial DNA that may be similar or identical to those detected in Pearson syndrome. How similar abnormalities of mitochondrial DNA cause such diverse disorders is not well understood. The distinct phenotypes are probably the result of differences in the amount and in the tissue-specific distribution of abnormal mitochondrial DNA, the evolution of this distribution over time, and the effects of tissue-specific nuclear modifier genes.

Defining features of Pearson syndrome

The first defining feature of Pearson syndrome is marrow failure. Macrocytic sideroblastic anemia occurs with the characteristic vacuolation of hematopoietic precursors (see the images below).

The anemia is refractory, and patients may be transfusion dependent. Neutropenia and thrombocytopenia may also be present.

The second defining feature of Pearson syndrome is dysfunction of the exocrine pancreas due to fibrosis and acinar atrophy. The result is malabsorption and chronic diarrhea.

Another cardinal feature of Pearson syndrome is persistent or intermittent lactic acidemia, which is caused by a defect in oxidative phosphorylation.

Other organ systems are affected in various ways. Hepatic involvement may cause increases in transaminase, bilirubin, and lipid levels, as well as in steatosis. Some patients develop hepatic failure. Renal involvement is common and manifests as a tubulopathy, such as Fanconi syndrome. Endocrinologic disturbances, such as growth hormone deficiency, hypothyroidism, and hypoparathyroidism, are relatively uncommon. The endocrine pancreas usually remains functional; however, a few patients develop diabetes mellitus. Splenic atrophy and impaired cardiac function have also been reported.

Failure to thrive is common. Several factors are likely contributory. Such factors include a defect in cellular metabolic energy, malabsorption due to exocrine pancreatic failure, hepatic and renal insufficiency, and, perhaps, concomitant endocrinologic abnormalities.

Frequency

United States

Pearson syndrome is rare. Approximately 80 cases have been reported worldwide.

International

See United States.

Mortality/Morbidity

Pearson syndrome is often fatal in infancy or early childhood. The usual causes of death are bacterial sepsis due to neutropenia, metabolic crisis, and hepatic failure.

Race

All races can be affected.

Sex

Pearson syndrome has no sex predilection.

Age

Pearson syndrome is a progressive disease, and its features change with age. Neonates may be well at birth, but some neonates with Pearson syndrome have low birth weight, pallor, and anemia.^{[2, 3]}Hydrops fetalis has also been reported. Anemic newborns may need transfusion.

During infancy and early childhood, failure to thrive, chronic diarrhea, and progressive hepatomegaly often occur in individuals with Pearson syndrome. These conditions are punctuated by episodic crises characterized by somnolence, vomiting, electrolytic abnormalities, lactic acidosis, and hepatic insufficiency. The lactic acidosis may become persistent with time. Typical causes of death in infants and young children with Pearson syndrome are metabolic crisis, hepatic failure, and overwhelming sepsis due to neutropenia.

Some patients survive infancy and early childhood and spontaneously recover from the hematologic dysfunction. Case reports document a shift in the phenotype of these individuals to a predominantly myopathic or encephalopathic condition. For example, some patients who survive early childhood may develop KSS or Leigh syndrome, whereas others may be neurologically healthy.