AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Background

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. 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.

Pathophysiology

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 Image 3). 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 Images 1-2). 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 60 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. 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

History

• Although the history is nonspecific, the astute clinician recognizes the need for further evaluation.
• Parents and/or caregivers may notice that the infant has been pale since birth, perhaps increasingly so; this finding indicates refractory anemia.
• Chronic diarrhea and fatty stools may be reported and indicate pancreatic exocrine deficiency.
• Inquire about previous illnesses or hospitalizations. Episodes of anorexia, vomiting, fever, and lethargy can occur. Associated dehydration, electrolytic abnormalities, lactic acidosis, and hepatic dysfunction may occur.
• Inquire about weight and obtain a growth chart. The birth weight may have been low, and the infant may fail to gain weight.
• A dietary history is important because deficiencies of copper, riboflavin, and phenylalanine may cause anemia with vacuolization of hematopoietic precursors, similar to changes observed in Pearson syndrome.
• Obtain a history of exposure to drugs. Certain drugs can damage the bone marrow. For example, chloramphenicol can cause sideroblastic changes and vacuolization of hematopoietic precursors, similar to its effects in individuals with Pearson syndrome.
• Obtain a family history.
• • Some anemias and syndromes of bone marrow failure, such as X-linked sideroblastic anemia and Diamond-Blackfan anemia, affect families. A good family history can alert the clinician to these possible diagnoses.
  • Although mitochondropathies can be inherited maternally, Pearson syndrome appears to be sporadic.

Physical

• No pathognomonic physical characteristics are observed.
• Anemia causes pallor.
• The patient's weight may be low for his or her age, and some patients are cachectic.
• Hepatomegaly, often progressive, occurs in patients with hepatic involvement.
• Patchy erythema and photosensitivity are also reported.
• Examine the patient for anomalies associated with other syndromes of bone marrow failure that present in the neonate or infant. For example, anomalies of the radii and thumb suggest Fanconi anemia, Diamond-Blackfan anemia, or the thrombocytopenia-absent radii syndrome.

Causes

Several types of abnormalities of mitochondrial DNA cause Pearson syndrome.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Shwachman-Diamond syndrome is the combination of pancreatic exocrine insufficiency and neutropenia. Epiphyseal and metaphyseal dysostosis also occur in Shwachman-Diamond syndrome. Patients with Pearson syndrome may be neutropenic, but severe anemia is most characteristic.

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 can be differentiated from Pearson syndrome on the basis of a low serum copper concentration and improvement with supplemental administration of copper.

Fanconi anemia is a congenital bone marrow failure syndrome that can be distinguished from Pearson syndrome by performing physical examination, by examining the bone marrow, and by testing for 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 often improve 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.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Lab Studies

• CBC count determination with differential and reticulocyte count
• • Patients with Pearson syndrome have macrocytic anemia.
  • The reticulocyte count is inappropriately low.
  • Some patients also have neutropenia, thrombocytopenia, or both.
• 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, though it may be intermittent.
  • The ratio of lactate to pyruvate may be increased.
• Urinalysis
• • Complex organic aciduria, including 3-methylglutaconic aciduria, is reported.
  • Some patients have proximal renal tubular dysfunction that causes urinary wasting of amino acids, glucose, bicarbonate, phosphate, citrate, and urate.
• 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 hypothyroid, hypoparathyroid, and a deficiency in growth hormone.
• 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.
  • Bone marrow cells are appropriate for sampling. Peripheral blood cells are also appropriate for mitochondrial DNA analysis. However, because of heteroplasmy, mutant DNA may not always be found. If Pearson syndrome is suspected despite normal findings in other tissues, analysis of bone marrow is prudent.

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, which may occur in older individuals with Pearson syndrome.

Procedures

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 Images 1-2). An increased number of sideroblasts with ringed sideroblasts may be observed on iron staining (see Image 3).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Medical Care

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.

• Patients with Pearson syndrome often need transfusions to manage anemia, and many are dependent on transfusions. Some hematologists use erythropoietin 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 may also be needed.
• Evaluate fever promptly. Parenteral antimicrobials, after the blood is cultured, are required for patients who are neutropenic. Splenic atrophy may increase the risk of bacterial sepsis. Granulocyte colony-stimulating factor (G-CSF) has been used in some patients to prevent or treat severe neutropenia.
• 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 need appropriate treatment.
• Stem cell transplantation has been reported in only one individual with Pearson syndrome.¹ 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.¹

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.

Consultations

Consultation and collaboration with an expert in metabolism and genetics are prudent.

Diet

No dietary restrictions or modifications are required.

Activity

No specific restrictions to activity are required. Patients with neuromuscular manifestations may require appropriate support.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

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 and dichloroacetic acid to manage persistent metabolic acidosis.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

Because Pearson syndrome is a rare disease, many physicians may not be aware of it.

Special Concerns

The collaboration of a multidisciplinary team is needed for patients with Pearson syndrome.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Media file 1:  Characteristic vacuolization of a hematopoietic precursor in the bone marrow. (Light microscopy; 100x; Wright-Giemsa stain)
	View Full Size Image
Media type:  Micrograph

Media file 2:  Electron photomicrograph of a hematopoietic precursor (normoblast) with vacuolization. (Transmission electron microscopy; original 10,000x)
	View Full Size Image
Media type:  Electron Microscopy

Media file 3:  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)
	View Full Size Image
Media type:  Micrograph

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

1. Faraci M, Cuzzubbo D, Micalizzi C, et al. Allogeneic bone marrow transplantation for Pearson's syndrome. Bone Marrow Transplant. May 2007;39(9):563-5. [Medline].
2. Blaw ME, Mize CE. Juvenile Pearson syndrome. J Child Neurol. Jul 1990;5(3):187-90. [Medline].
3. Cormier V, Rotig A, Quartino AR, et al. Widespread multi-tissue deletions of the mitochondrial genome in the Pearson marrow-pancreas syndrome. J Pediatr. Oct 1990;117(4):599-602. [Medline].
4. De Vivo DC. The expanding clinical spectrum of mitochondrial diseases. Brain Dev. Jan-Feb 1993;15(1):1-22. [Medline].
5. Gibson KM, Bennett MJ, Mize CE, et al. 3-Methylglutaconic aciduria associated with Pearson syndrome and respiratory chain defects. J Pediatr. Dec 1992;121(6):940-2. [Medline].
6. Harding AE, Hammans SR. Deletions of the mitochondrial genome. J Inherit Metab Dis. 1992;15(4):480-6. [Medline].
7. Kerr DS. Protean manifestations of mitochondrial diseases: a minireview. J Pediatr Hematol Oncol. Jul-Aug 1997;19(4):279-86. [Medline].
8. Knerr I, Metzler M, Niemeyer CM, et al. Hematologic features and clinical course of an infant with Pearson syndrome caused by a novel deletion of mitochondrial DNA. J Pediatr Hematol Oncol. Dec 2003;25(12):948-51. [Medline].
9. Krauch G, Wilichowski E, Schmidt KG, Mayatepek E. Pearson marrow-pancreas syndrome with worsening cardiac function caused by pleiotropic rearrangement of mitochondrial DNA. Am J Med Genet. Jun 1 2002;110(1):57-61. [Medline].
10. Lee HF, Lee HJ, Chi CS, Tsai CR, Chang TK, Wang CJ. The neurological evolution of Pearson syndrome: Case report and literature review. Eur J Paediatr Neurol. Apr 13 2007;[Medline].
11. McShane MA, Hammans SR, Sweeney M, et al. Pearson syndrome and mitochondrial encephalomyopathy in a patient with a deletion of mtDNA. Am J Hum Genet. Jan 1991;48(1):39-42. [Medline].
12. Muraki K, Nishimura S, Goto Y, et al. The association between haematological manifestation and mtDNA deletions in Pearson syndrome. J Inherit Metab Dis. Sep 1997;20(5):697-703. [Medline].
13. Pearson HA, Lobel JS, Kocoshis SA, et al. A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. J Pediatr. Dec 1979;95(6):976-84. [Medline].
14. Rotig A, Bourgeron T, Chretien D, et al. Spectrum of mitochondrial DNA rearrangements in the Pearson marrow-pancreas syndrome. Hum Mol Genet. Aug 1995;4(8):1327-30. [Medline].
15. Rötig A, Cormier V, Blanche S, et al. Pearson's marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy. J Clin Invest. Nov 1990;86(5):1601-8. [Medline].
16. Rotig A, Cormier V, Koll F, et al. Site-specific deletions of the mitochondrial genome in the Pearson marrow-pancreas syndrome. Genomics. Jun 1991;10(2):502-4. [Medline].
17. Seneca S, De Meirleir L, De Schepper J, et al. Pearson marrow pancreas syndrome: a molecular study and clinical management. Clin Genet. May 1997;51(5):338-42. [Medline].
18. Stacpoole PW, Kerr DS, Barnes C, et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. May 2006;117(5):1519-31. [Medline].
19. Stoddard RA, McCurnin DC, Shultenover SJ, et al. Syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction presenting in the neonate. J Pediatr. Aug 1981;99(2):259-61. [Medline].
20. Superti-Furga A, Schoenle E, Tuchschmid P, et al. Pearson bone marrow-pancreas syndrome with insulin-dependent diabetes, progressive renal tubulopathy, organic aciduria and elevated fetal haemoglobin caused by deletion and duplication of mitochondrial DNA. Eur J Pediatr. Jan 1993;152(1):44-50. [Medline].

Article Last Updated: Jul 31, 2007