What are the signs and symptoms of copper deficiency in individuals of all ages, particularly in infants, young children, and those with malabsorptive disorders?

Signs of Copper Deficiency

Copper deficiency presents with a characteristic triad of hematologic abnormalities (anemia, neutropenia, leukopenia), neurologic manifestations (psychomotor retardation, hypotonia, myelopathy), and skeletal changes (metaphyseal abnormalities, osteopenia, pathologic fractures). 1

Age-Specific Risk Windows

Full-term infants younger than 6 months and preterm infants younger than 2.5 months are unlikely to develop copper deficiency due to adequate fetal copper stores accumulated during the third trimester. 2, 1 Copper is accumulated at a faster rate during the last trimester, meaning preterm infants are born with lower stores than term infants but remain protected for approximately 2.5 months. 2

After these protective windows, copper deficiency becomes clinically relevant, particularly in high-risk populations. 1

Hematologic Manifestations

The most striking hematologic abnormalities include:

• Sideroblastic anemia (often macrocytic or microcytic) that does not respond to iron supplementation 2, 3, 4
• Neutropenia and leukopenia, which can be severe enough to mimic myelodysplastic syndrome 1, 3, 4
• Thrombocytopenia or pancytopenia in severe cases 3
• Nuclear maturation defects in erythroid precursors that cannot be explained solely by defective iron transport 4

A critical pitfall: copper deficiency frequently masquerades as myelodysplastic syndrome, leading to inappropriate referrals for stem cell transplantation. 1 Always check copper status before pursuing aggressive hematologic interventions in at-risk patients.

Neurologic Signs

Neurologic manifestations are particularly concerning because they may be irreversible even with copper supplementation, unlike hematologic abnormalities which typically correct rapidly. 5, 6

Key neurologic features include:

• Psychomotor retardation and developmental delay 2, 1
• Hypotonia (decreased muscle tone) 2, 1
• Myelopathy with progressive gait abnormalities and ataxia 5, 6
• Paresthesias of upper and lower extremities 5
• Progressive weakness of extremities 5, 6

Physical Examination Findings

Beyond neurologic examination, look for:

• Hypopigmentation of skin and hair 2, 1
• Pallor (from anemia) 2, 1
• Failure to thrive or poor growth 1

Skeletal/Radiologic Abnormalities

Bone changes appear at approximately 3-9 months of age in at-risk infants and include: 7

• Cupping and fraying of metaphyses 2, 1
• Sickle-shaped metaphyseal spurs 2, 1
• Significant demineralization/osteopenia (generalized bone changes) 2, 1, 7
• Subperiosteal new bone formation 2, 1
• Metaphyseal fragmentation that may be difficult to distinguish from fractures caused by abuse 2, 1
• Pathologic fractures can occur with normal handling 2

These radiologic changes improve rapidly after therapeutic copper supplementation. 7

High-Risk Clinical Scenarios

Suspect copper deficiency in:

• Severe nutritional disorders including liver failure or short gut syndrome 2, 1
• Long-term parenteral nutrition without adequate copper supplementation 2, 1, 3
• High gastrointestinal fluid losses from diarrhea, stoma losses (especially ileostomy), or fistulas 2, 1
• Malabsorptive states including gastric bypass surgery, gastrectomy, subtotal colectomy, or small bowel resections 5, 6
• Premature infants on prolonged parenteral nutrition 3, 4, 7
• Severely malnourished children 3
• Adolescents following bariatric surgery 1

Distinguishing Copper Deficiency from Menkes Disease

Menkes disease shares many features with dietary copper deficiency but notably lacks anemia, which is a key distinguishing feature. 1, 8 Menkes disease is an X-linked recessive condition occurring only in males and presents with: 2, 8

• Sparse, kinky hair (pathognomonic sign) 2, 8
• Calvarial wormian bones 2, 8
• Tortuous cerebral vessels (characteristic finding) 2
• Intracranial hemorrhage (can occur in Menkes but not reported in dietary copper deficiency) 2
• Anterior rib flaring 2
• Absence of anemia despite severe copper deficiency 2, 1, 8

Diagnostic Approach

When copper deficiency is suspected, measure: 1, 9

• Serum copper and ceruloplasmin simultaneously 1, 9
• Complete blood count with differential (looking specifically for neutrophil count, anemia, leukopenia, thrombocytopenia) 1, 9
• C-reactive protein (CRP) alongside ceruloplasmin, because ceruloplasmin is an acute phase reactant—inflammation falsely elevates levels and can mask underlying copper deficiency 9
• Cu-Zn superoxide dismutase (SOD) activity in erythrocytes is a more sensitive indicator than plasma copper or ceruloplasmin alone 2, 9

Never diagnose or rule out copper deficiency based solely on ceruloplasmin or serum copper without checking CRP and CBC. 9