Pearson Syndrome 

Updated: Feb 01, 2019
Author: Zora R Rogers, MD; Chief Editor: Hassan M Yaish, MD 



Pearson marrow-pancreas syndrome, an often fatal disorder, was first described in 1979, by pediatric hematologist/oncologist Howard Pearson. Affected infants manifest a refractory, transfusion-dependent sideroblastic anemia, vacuolization of hematopoietic precursors, and exocrine pancreatic insufficiency.[1]  The last, although frequently encountered, may be absent in some cases of Pearson syndrome. The condition is now known to be a rare, multisystemic, mitochondrial cytopathy with anemia, neutropenia, and thrombocytopenia, as well as variable hepatic, renal, and endocrine failure. Death usually occurs early in life (before age 4 years). The most common causes of death are lactic acidemia (which may be triggered by infection) and liver or renal failure.[2]  Survivors after early childhood develop features of Kearns-Sayre syndrome (KSS), a mitochondriopathy characterized by progressive external ophthalmoplegia, weakness of skeletal muscle, atypical retinal pigmentation, and cardiac conduction defects.

The syndrome is due to mitochondrial DNA (mtDNA) deletions of variable size and location; mtDNA encodes for 13 of the respiratory chain enzymes, along with 24 RNA molecules used in intramitrochondrial protein synthesis. As a result, defective oxidative phosphorylation, as well as other defects (occurring in enzymes and RNA molecules), is involved in the syndrome's etiology. Patients may recover from the refractory anemia.



The mitochondriopathies comprise several diverse, overlapping syndromes caused by mutations of mitochondrial DNA.[3] Pearson syndrome is a specific clinical subset of these syndromes 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.

The specific mtDNA deletion includes deletion of the complete genes for ATPases 6 and 8, cytochrome c oxydase III, and NADH dehydrogenase 3, 4, 4L, and 5.[4, 5, 6, 7]

These defects cause cellular injury in target tissues.

Other mitochondriopathies, 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.[8, 9]

Defining features of Pearson syndrome

The first defining feature of Pearson syndrome is marrow failure. Sideroblastic anemia, usually macrocytic and frequently transfusion dependent, is observed in isolation or associated with neutropenia and thrombocytopenia. Bone marrow examination is hypoplastic with characteristic vacuolation of hematopoietic precursors and ringed sideroblasts (see the images below).

Characteristic vacuolization of a hematopoietic pr Characteristic vacuolization of a hematopoietic precursor in the bone marrow. (Light microscopy; 100x; Wright-Giemsa stain)
Electron photomicrograph of a hematopoietic precur Electron photomicrograph of a hematopoietic precursor (normoblast) with vacuolization. (Transmission electron microscopy; original 10,000x)

The second defining feature of Pearson syndrome is dysfunction of the exocrine pancreas due to fibrosis and acinar atrophy. The result is malabsorption, chronic diarrhea, and poor growth or failure to thrive. Studies have reported that 23-63% of patients with Pearson syndrome do not suffer from pancreatic insufficiency. In a retrospective cohort study by the Marrow Failure Study Group of the Associazione Italiana Emato-Oncologia Pediatrica (AIEOP), the investigators found no such insufficiency in 73% of patients.[10]

Another cardinal feature of Pearson syndrome is persistent or intermittent lactic acidemia, which is caused by defects in oxidative phosphorylation. Increased lactate/pyruvate ratio is observed along with increased urinary excretion of lactate and related organic acids.

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, may develop but are not usually part of the initial presentation.[11] The endocrine pancreas usually remains functional; however, a few patients develop diabetes mellitus and adrenal insufficiency. Splenic atrophy and impaired cardiac function have also been reported.[12, 13, 14, 15, 16]

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, abnormal myelinization, and possibly endocrinologic abnormalities.[17, 18]



United States

Pearson syndrome is rare. Less than 100 cases have been reported worldwide.


See United States.


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.


All races can be affected.


Pearson syndrome has no sex predilection.


Pearson syndrome is a progressive disease, and its features change with age. Neonates may be well at birth, but some 40% of patients present in the first year with persistent hypoplastic anemia, other cytopenias, low birth weight, microcephaly, and multiple organ system involvement (GI, neuromuscular, and metabolic).[17, 19, 20]  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 (elevated lactate:pyruvate ratio), 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 related 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. In the aforementioned AIEOP study, the investigators reported that, while all of the 11 patients in the study tested neurologically normal at birth, seven of them (64%) subsequently suffered from retardation of speech development, hypotonia, and muscle hypotrophy, with three patients eventually approaching a complete KSS phenotype.[10]




The history is nonspecific, with the constellation of symptoms guiding the evaluation. The patient may have been pale since birth, suggesting refractory anemia.

Birth weight may have been low, and the infant may not have gained weight well. This may be confirmed with a careful growth chart.

Chronic diarrhea and fatty stools may be noted and suggest pancreatic exocrine deficiency as a cause for failure to thrive.

Dietary history is important to exclude deficiencies of copper, riboflavin, and phenylalanine, which may cause anemia with vacuolization of hematopoietic precursors, similar to that observed in Pearson syndrome.

Previous illnesses or hospitalizations may include episodes of anorexia, vomiting, fever, and lethargy in association with electrolytic abnormalities, lactic acidosis, and hepatic dysfunction.

Development may be abnormal with the presence of neuromuscular abnormalities such as tremor, abnormal tone, and lethargy. Rarely corneal edema and hemispheric dysfunction has been reported, phenomena that are more commonly associated with KSS and MELAS.[21, 22]

History of medication exposure to rule out contact with drugs that may damage the bone marrow. For example, chloramphenicol can cause sideroblastic changes and vacuolization of hematopoietic precursors in the bone marrow, similar to the changes observed in individuals with Pearson syndrome.

Family history of unexplained pancytopenia, failure to thrive, acidosis, pancreatic insufficiency, neuromuscular dysfunction, or early death are important to document.

Some constitutional anemias and inherited bone marrow failure syndromes, such as X-linked sideroblastic anemia, Shwachman-Diamond syndrome, Fanconi anemia, and Diamond-Blackfan anemia, occur in families. A careful family history is vital to guiding investigation for these disorders.

Although mitochondriopathies can be inherited maternally, Pearson syndrome appears to be sporadic.


No pathognomonic physical characteristics are observed. Anemia causes pallor, and the patient's weight may be low for age; some patients may appear cachectic.

Hepatomegaly, often progressive, may occur. In the aforementioned AIEOP study, the investigators reported that out of 11 patients with Pearson syndrome, eight (73%) were found to have hepatomegaly, with the condition occurring in five of them before age 6 months; splenomegaly was found in just three patients (27%).[10]

Patchy erythema and photosensitivity are also reported.

Examine the patient for anomalies associated with other inherited bone marrow failure syndromes that present in the young child. For example, anomalies of the thumbs and radial ray may suggest Fanconi anemia, Diamond-Blackfan anemia,[23] or the thrombocytopenia-absent radii syndrome.


Abnormalities of mitochondrial DNA (mtDNA) (principally deletion, although rearrangements and duplications have also been reported) cause Pearson syndrome.

A study by Crippa et al suggested that in patients with Pearson syndrome, and possibly those with other mitochondrial diseases, ammonia and carbamoyl phosphate are “diverted from the urea cycle to the synthesis of nucleotides.” Biochemical analysis of four patients with Pearson syndrome found that, although low-normal ammonia levels were present, plasma levels of citrulline and arginine were low. Regression analysis indicated that each of the urea cycle’s intermediates was significantly correlated with the next, with the exception of ornithine (in its correlation with citrulline).[24]



Diagnostic Considerations

Shwachman-Diamond syndrome is the combination of pancreatic exocrine insufficiency and neutropenia. Epiphyseal and metaphyseal dysostosis also occur in Shwachman-Diamond syndrome. Patients with both syndromes may have cytopenias of all 3 lineages, but patients with Pearson syndrome have severe anemia as most characteristic finding although those with Shwachman-Diamond syndrome have neutropenia.

Fanconi anemia is a congenital bone marrow failure syndrome that can be distinguished from Pearson syndrome by the frequent presence of physical abnormalities, absence of pancreatic malabsorption, and by increased chromosomal fragility. Individuals with Fanconi anemia may have short stature, hyperpigmentation, anomalies of the thumb and radius, and other congenital abnormalities. No vacuolization of hematopoietic precursors occurs in Fanconi anemia, and chromosomes from patients with Fanconi anemia develop breaks when incubated with diepoxybutane. The cytopenias of Fanconi anemia usually start with thrombocytopenia and mild macrocytic anemia and often improve at least temporarily with androgen therapy.

Diamond-Blackfan anemia is congenital pure red cell aplasia characterized by isolated, severe, macrocytic anemia and often bony abnormalities of the thumbs and radii. Serum adenosine deaminase levels are usually increased in Diamond-Blackfan anemia, and no pancreatic insufficiency is observed. Many cases of Diamond-Blackfan anemia respond to glucocorticoid therapy.

Myelodysplastic syndrome (MDS), specifically the World Health Organization (WHO) classification refractory cytopenia of childhood, may also display cytoplasmic vacuolation. Patients with MDS may have additional cytogenetic abnormalities in the bone marrow and, of course, a negative genetic test for mtDNA deletion.[25]

Deletion of 22q11.2, usually associated with DiGeorge and velocardiofacial syndrome, may also display myelodysplastic features and cytoplasmic vacuolation.[26]

Hereditary sideroblastic anemia lacks the characteristic vacuolization of marrow precursors, and no concomitant pancreatic insufficiency occurs. Sideroblastic anemia may respond to pyridoxine or pyridoxal phosphate.

Copper deficiency, either primary or secondary on the basis of excess zinc intake, is associated with neuropathy, cytopenias, myelodysplastic features and cytoplasmic vacuolation.[27] Hypocupremia can be differentiated from Pearson syndrome on the basis of a low serum copper concentration and improvement with supplemental administration of copper.

Differential Diagnoses



Laboratory Studies

CBC count with differential and reticulocyte count

Patients with Pearson syndrome have macrocytic anemia.

The reticulocyte count is inappropriately low for the degree of anemia.

Some patients also have leukopenia, neutropenia, or thrombocytopenia.

Test of pancreatic exocrine function

Document evidence of pancreatic exocrine dysfunction.

Various direct and indirect tests are available, including the following:

  • Measurement of secretory capacity induced by exogenous hormones, a test meal, or a duodenal stimulant

  • Stool microscopy and analysis of fecal fat and nitrogen

  • Measurement of serum pancreatic isoamylase, trypsinogen, and lipase concentrations

Measurement of serum lactic acid

Patients may have lactic acidemia, most commonly seen during intercurrent illnesses.

The ratio of lactate to pyruvate may be increased at baseline.


Complex organic aciduria, including 3-methylglutaconic aciduria, has been reported.[28]

Some patients have proximal renal tubular dysfunction that causes urinary wasting of amino acids, glucose, bicarbonate, phosphate, citrate, and urate.

A retrospective study by Semeraro et al suggested that urinary organic acid profile analysis may aid in the diagnosis of Pearson syndrome. The investigators found almost constant alteration of the profile in seven patients with Pearson syndrome, determining the most frequent metabolites in the urine to be lactate, 3-hydroxybutyrate, 3-hydroxyisobutyrate, fumarate, pyruvate, 2-hydroxybutyrate, 2-ethyl-3-hydroxypropionate, and 3-methylglutaconate. The novel metabolites 3-methylglutarate, tiglylglycine, and 2-methyl-2,3-dihydroxybutyrate were also found. In contrast, the report frequently found normal profiles in eight patients with Kearns-Sayre syndrome.[29]

Hepatic study

Hepatic transaminase values may be increased in patients with hepatic involvement.

Bilirubin levels may be increased, and albumin concentrations and coagulation values (eg, prothrombin time) may reflect a defect in synthetic function.

Endocrinologic study

Some patients have evidence of having deficiencies of thyroid, parathyroid, or growth hormones.

Analysis of mitochondrial DNA

The causative deletions of mitochondrial DNA can be demonstrated with molecular genetic analysis. Because of heteroplasmy, not all tissues contain abundant amounts of mutant mitochondrial DNA. Peripheral blood cells are usually the first analytic sample. If Pearson syndrome is strongly suspected with normal findings in the blood, analysis of bone marrow should be performed.

Commercial testing is available for mtDNA deletions, and common point mutations A3243G, T3271C, G3460A, A8344G, T8356C, T8993G, T8993C, and G11778A1.

Imaging Studies

No specific imaging studies are needed to diagnose Pearson syndrome.

MRI of the brain may be performed to further investigate a phenotypic shift to a predominantly encephalopathic or myopathic condition, such as Kearns-Sayre syndrome, which may develop in older individuals with Pearson syndrome.


Bone marrow aspiration and biopsy are necessary to obtain bone marrow for histologic analysis.

Characteristic histologic findings of Pearson syndrome can be observed, and other causes of pancytopenia can be excluded.

Histologic Findings

The number of erythroid precursors in the bone marrow is normal or increased, and a characteristic vacuolization of hematopoietic precursors occurs (see the images below).

Characteristic vacuolization of a hematopoietic pr Characteristic vacuolization of a hematopoietic precursor in the bone marrow. (Light microscopy; 100x; Wright-Giemsa stain)
Electron photomicrograph of a hematopoietic precur Electron photomicrograph of a hematopoietic precursor (normoblast) with vacuolization. (Transmission electron microscopy; original 10,000x)

An increased number of sideroblasts with ringed sideroblasts may be observed on iron staining (see the image below).

Ringed sideroblast in the bone marrow (iron stain) Ringed sideroblast in the bone marrow (iron stain). The dark structures that form a ring around the nucleus are hemosiderin-laden mitochondria. (Light microscopy; 100x; iron stain)


Medical Care

No specific therapy is available for individuals with Pearson syndrome or other mitochondrial cytopathies. Awareness of possible complications and early intervention may prevent death and minimize morbidity.

Red blood cell transfusions are often needed to manage the macrocytic anemia, and patients may be dependent on transfusions. Erythropoietin has been tried to decrease the frequency of transfusions.

Pancreatic enzyme replacement is needed for patients with malabsorption due to exocrine pancreatic insufficiency. Supplementation with fat-soluble vitamins (ADEK) may also be needed.

Although without controlled evidence of benefit, many clinicians offer supplementation with coenzyme Q and additional supplementation with carnitine and riboflavin.

In neutropenic patients, fever higher than 101.5 º F should be evaluated promptly. Parenteral antibiotics should be administered after blood is obtained. Splenic atrophy may also increase the risk of bacteremia due to encapsulated organism. Granulocyte colony-stimulating factor (G-CSF) has been used in some patients to ameliorate severe neutropenia.[30]

Manage intermittent metabolic crises with hydration, correction of electrolyte abnormalities, correction of acidosis, and a search for underlying causes (eg, infection). Seek evidence of concomitant hepatic failure. Chronic bicarbonate supplementation and dichloroacetic acid have been used to treat persistent metabolic acidosis.

Patients may have hypothyroidism, hypoparathyroidism, diabetes mellitus, or growth hormone deficiency. These conditions should be screened for and treated, if present.

Stem cell transplantation has been reported in only one individual with Pearson syndrome.[31] Pearson syndrome is a multisystem disorder, thus, transplantation can only correct the hematologic manifestations of the disorder and cannot correct the dysfunction of other systems. Transplantation may be associated with unique or greater than expected toxicities as well.[31]

Surgical Care

No specific surgical management is needed for patients with Pearson syndrome.

Some patients may benefit from an indwelling venous catheter to facilitate frequent transfusions or infusions.


Patient should be seen in consultation by and managed in collaboration with an expert in metabolism and genetics in addition to a hematologist.

If endocrine, renal, or cardiac complications are present, appropriate specialists should be involved in comanagement.


No dietary restrictions or modifications are required.


No specific restrictions to activity are required.

Patients with neuromuscular manifestations may require appropriate support.



Medication Summary

No specific therapy is available for individuals with Pearson syndrome or other mitochondrial cytopathies. Attentive care and awareness of possible complications may prevent death and minimize morbidity. Anecdotal reports describe the use of long-term bicarbonate supplementation to manage persistent metabolic acidosis.


Questions & Answers


What is Pearson syndrome?

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What causes Pearson syndrome?


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How is Pearson syndrome differentiated from Diamond-Blackfan anemia?

How is Pearson syndrome differentiated from myelodysplastic syndrome (MDS)?

How is Pearson syndrome differentiated from DiGeorge and velocardiofacial syndrome?

How is Pearson syndrome differentiated from hereditary sideroblastic anemia?

How is Pearson syndrome differentiated from copper deficiency?

What are the differential diagnoses for Pearson Syndrome?


What is the role of blood tests in the workup of Pearson syndrome?

How is pancreatic exocrine dysfunction assessed in the workup of Pearson syndrome?

What is the role of serum lactic acid measurement in the workup of Pearson syndrome?

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What is Pearson syndrome?

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