Case Presentation

A 2-month-old South Asian boy was evaluated for persistent pancytopenia, severe transfusion-requiring anemia, failure to thrive, feeding difficulty, intermittent diarrhea, and metabolic acidosis. He had been born growth-restricted at 2.1 kg and developed severe anemia shortly after birth. His neonatal course included metabolic derangements, generalized seizures, and a hypoxic cardiac arrest requiring resuscitation.

The family history immediately complicated the diagnostic reasoning. His parents were consanguineous. Three siblings had died during infancy with severe anemia, recurrent illness, diarrhea, or failure to thrive, while a surviving sister had been diagnosed with congenital megaloblastic anemia.

Teaching Pause 1

What diagnostic categories should initially be considered in an infant with pancytopenia and failure to thrive?

The early differential should remain broad:

• Congenital bone marrow failure syndromes
• Nutritional megaloblastic anemia
• Congenital sideroblastic anemia
• Diamond–Blackfan anemia
• Severe infection or inflammatory disease
• Hemophagocytic lymphohistiocytosis
• Inborn errors of metabolism
• Mitochondrial cytopathies
• Less commonly, infiltrative or malignant marrow disorders

The family history and consanguinity reasonably raise suspicion for an autosomal-recessive disorder. However, this is a diagnostic clue, not a diagnosis, and should not override the emerging phenotype.

The First Diagnostic Turn: This Is a Hypoproliferative Anemia

The hemoglobin was 7.7 g/dL, platelets 30 × 10⁹/L, and reticulocyte count only 0.3%. Corrected and absolute reticulocyte measurements likewise demonstrated markedly inadequate erythropoietic compensation. Iron availability appeared adequate, and a trial of vitamin B12 and folate had failed to produce a hematologic response.

Teaching Pause 2

Why is the reticulocyte count particularly useful here?

Profound anemia should normally produce a substantial reticulocytosis if marrow production is intact. A very low reticulocyte response shifts the reasoning away from isolated peripheral destruction or blood loss and toward ineffective or suppressed hematopoiesis.

The diagnostic center of gravity therefore moves toward congenital marrow disorders, metabolic disease, and mitochondrial dysfunction.

Could This Be HLH?

Hemophagocytosis was identified in the marrow, and HLH had been suspected at the referring hospital.

But the child satisfied only three HLH-2004 criteria: cytopenias, hypofibrinogenemia, and hemophagocytosis. He lacked fever, splenomegaly, hypertriglyceridemia, and hyperferritinemia; the reported ferritin was only 100 ng/mL. The authors therefore rejected HLH as the unifying diagnosis.

Clinical Reasoning Pearl

Hemophagocytosis is not synonymous with HLH.

It is a morphologic finding that must be interpreted in its clinical context. Anchoring on marrow hemophagocytosis alone could have diverted attention from the much more diagnostically specific marrow abnormalities that followed.

The Decisive Clue: Look at the Marrow

Bone marrow examination demonstrated:

• Relative erythroid hyperplasia
• Megaloblastoid change
• Dyserythropoiesis
• Prominent cytoplasmic vacuolization of erythroid precursors
• Similar vacuolization in myeloid precursors
• Dysplastic megakaryocytes
• Increased storage iron
• More than 15% ring sideroblasts

The marrow images on page 4 illustrate the combination particularly well: abnormal erythroid maturation, vacuolated erythroid and myeloid precursors, and megakaryocytic abnormalities. The Perl stain on page 5 demonstrates the ring sideroblasts.

Teaching Pause 3

Which disease should immediately move toward the top of the differential when an infant has refractory anemia, vacuolated marrow precursors, and ring sideroblasts?

Pearson marrow-pancreas syndrome.

Pearson syndrome is a mitochondrial cytopathy classically associated with single large-scale mitochondrial DNA deletions. Its hematologic hallmark is refractory sideroblastic anemia with ineffective erythropoiesis and characteristic marrow vacuolization.

But one more part of the phenotype needs to be established.

The Second Organ System: The Pancreas

The infant had chronic feeding difficulty, intermittent diarrhea, and profound failure to thrive.

Stool examination demonstrated fat globules consistent with steatorrhea, providing clinical evidence of malabsorption and exocrine pancreatic dysfunction. Fecal elastase was unavailable.

The combination was now highly characteristic:

Bone marrow failure + vacuolated marrow precursors + ring sideroblasts + exocrine pancreatic dysfunction

This pattern strongly points toward Pearson syndrome.

What About the Metabolic Abnormalities?

The patient also had metabolic acidosis, with pH 7.32 and bicarbonate 12 mmol/L. Lactate was not consistently elevated. Renal tubular dysfunction was considered, but urinary electrolyte and organic-acid studies were unavailable.

This is an important reasoning point: normal lactate does not exclude mitochondrial disease.

The diagnosis rests on the complete phenotype rather than on any single biochemical abnormality.

The Diagnostic Limitation

Molecular testing for a mitochondrial DNA deletion was not available.

The authors considered the clinical and marrow constellation diagnostic of Pearson syndrome, citing pancytopenia with reticulocytopenia, vacuolated erythroid and myeloid precursors, ring sideroblasts, and exocrine pancreatic insufficiency.

For contemporary clinical practice, however, this distinction is important:

The phenotype is highly suggestive of Pearson syndrome, but molecular demonstration of a single large-scale mtDNA deletion provides definitive etiologic confirmation whenever testing is accessible.

The Family History: Helpful or Misleading?

The consanguinity and clustering of childhood anemia initially suggest Mendelian inheritance.

That is somewhat discordant with classic Pearson syndrome because the responsible large-scale mtDNA deletions are usually sporadic rather than conventionally inherited. The authors appropriately acknowledge this tension and propose possible modifying nuclear factors or phenotypic variability.

The practical lesson is that a compelling family history should broaden genetic investigation rather than force the phenotype into a familiar inheritance pattern.

Management

There is no curative therapy for Pearson syndrome. Treatment is primarily supportive.

At nine months, the child was receiving:

• Regular packed red-cell transfusions
• Pancreatic enzyme replacement
• Nutritional supplementation
• Multivitamins
• Supportive metabolic care
• Genetic counseling for the family

Clinical improvement was reported with this regimen.

Survivors require longitudinal surveillance because the phenotype may evolve, including neurologic, renal, cardiac, endocrine, and neuromuscular manifestations. Some patients surviving the early marrow-pancreas phenotype later develop features within the Kearns–Sayre spectrum.

Clinical Pearls

1. Think beyond nutritional anemia when severe infantile anemia is accompanied by reticulocytopenia and multisystem disease.
2. Marrow vacuolization is a major diagnostic clue. Vacuolated erythroid and myeloid precursors together with ring sideroblasts strongly suggest mitochondrial dysfunction.
3. Pancreatic disease completes the pattern. Failure to thrive and steatorrhea accompanying sideroblastic marrow failure should raise immediate concern for Pearson syndrome.
4. Hemophagocytosis does not establish HLH. Apply accepted diagnostic criteria rather than anchoring on a single morphologic observation.
5. Normal lactate does not exclude mitochondrial disease.
6. Consanguinity can mislead diagnostic reasoning. Pearson syndrome is usually caused by sporadic large-scale mtDNA deletions despite an apparently genetic clinical presentation.
7. Molecular confirmation remains important. A characteristic phenotype may establish a strong presumptive diagnosis when resources are limited, but mtDNA deletion analysis provides etiologic confirmation.

Pitfalls to Avoid

• Attributing refractory anemia to iron, folate, or B12 deficiency despite an inadequate reticulocyte response.
• Diagnosing HLH solely because hemophagocytosis is present.
• Ignoring gastrointestinal and growth abnormalities while concentrating exclusively on the CBC.
• Assuming that mitochondrial disease must produce persistent lactic acidosis.
• Assuming a conventional recessive disorder solely because the parents are consanguineous.
• Treating stabilization of the hematologic phenotype as resolution of the mitochondrial disorder.

CARE-Style Timeline

Birth: Growth restriction and low birth weight; severe anemia and metabolic disturbance requiring exchange transfusion.

Neonatal period: Seizures associated with metabolic abnormalities, followed by hypoxic cardiac arrest and resuscitation.

First months: Persistent anemia, thrombocytopenia, feeding difficulty, diarrhea, failure to thrive, and recurrent hospitalizations.

2 months: Pancytopenia with marked reticulocytopenia; metabolic acidosis; unsuccessful vitamin B12/folate therapy.

Diagnostic evaluation: Bone marrow demonstrates dyserythropoiesis, vacuolated erythroid and myeloid precursors, and >15% ring sideroblasts; stool fat supports exocrine pancreatic dysfunction.

Diagnosis: Clinical diagnosis of Pearson syndrome; molecular mtDNA deletion testing unavailable.

By 9 months: Ongoing transfusion support, pancreatic enzyme replacement, nutritional therapy, and genetic counseling with reported clinical improvement.

Board-Style Questions

1. Which bone marrow finding is most characteristic of Pearson syndrome in this clinical setting?

A. Isolated erythroid aplasia
B. Vacuolated erythroid precursors with ring sideroblasts
C. Extensive lymphoblast infiltration
D. Pure megakaryocytic hyperplasia
E. Marrow fibrosis

Answer: B.

The characteristic combination is ineffective erythropoiesis with cytoplasmic vacuolization of marrow precursors and ring sideroblast formation.

2. Which additional manifestation most strongly supports Pearson syndrome in an infant with sideroblastic anemia?

A. Nephrotic syndrome
B. Exocrine pancreatic insufficiency
C. Autoimmune thyroiditis
D. Splenic sequestration
E. Hemarthrosis

Answer: B.

Pearson syndrome classically combines marrow dysfunction with exocrine pancreatic dysfunction.

3. Hemophagocytosis is demonstrated in the marrow. What is the best next step in reasoning?

A. Diagnose HLH immediately
B. Begin chemotherapy for leukemia
C. Determine whether established HLH diagnostic criteria are fulfilled
D. Assume bacterial sepsis
E. Repeat the marrow until hemophagocytosis disappears

Answer: C.

Hemophagocytosis is neither specific nor sufficient for HLH.

4. Which genetic abnormality is classically associated with Pearson syndrome?

A. Trisomy 21
B. BCR::ABL1 translocation
C. Single large-scale mitochondrial DNA deletion
D. Factor VIII mutation
E. SMN1 deletion

Answer: C.

Pearson syndrome belongs to the spectrum of disorders caused by single large-scale mtDNA deletions.

5. Which statement regarding long-term follow-up is most appropriate?

A. Hematologic improvement indicates cure
B. Follow-up can cease after transfusion independence
C. Survivors may develop additional multisystem mitochondrial manifestations
D. Pancreatic dysfunction invariably resolves before age 1
E. Neurologic involvement excludes Pearson syndrome

Answer: C.

The phenotype can evolve with age, and surviving children may subsequently develop neurologic, renal, endocrine, cardiac, or Kearns–Sayre–spectrum manifestations.

Clinical Take-Home Message

In an infant with refractory hypoproliferative anemia or pancytopenia, the combination of marrow precursor vacuolization, ring sideroblasts, failure to thrive, and exocrine pancreatic dysfunction should immediately raise suspicion for Pearson syndrome. The key to diagnosis is recognizing the multisystem pattern rather than treating each abnormality in isolation.

Journal of Medical Case Reports is the world’s first international, PubMed-listed, medical journal devoted to publishing case reports from all medical disciplines and will consider any original case report that expands the field of general medical knowledge, and original research relating to case reports. The journal is open access, and strongly endorses the CARE guidelines for case reports, requiring authors to submit populated CARE checklists with submissions to improve transparency in reporting.