Getting the Right Diagnosis and Understanding Lab Results

The journey to an Imerslund-Gräsbeck syndrome (IGS) diagnosis often involves several rounds of lab work as doctors rule out more common causes of anemia. Because IGS is a rare “selective” absorption disorder, your child’s diet may be perfectly healthy, but the lab results will tell a different story of a body that is functionally starving for Vitamin B12 ^[1][2].

Blood Count Basics: The CBC

The Complete Blood Count (CBC) is usually the first window into IGS.

• Macrocytic Anemia: In classic IGS, the red blood cells are larger than normal but lower in number ^[3]. This is called macrocytosis, and the size is measured by the MCV (Mean Corpuscular Volume) ^[1].
• Pancytopenia: In more severe cases, all three types of blood cells—red cells, white cells, and platelets—may be low ^[3][1].
• Megaloblastic Changes: Under a microscope, doctors may see “hypersegmented neutrophils” (white blood cells with too many sections), which is a classic fingerprint of B12 deficiency ^[3].

Functional Markers: MMA and Homocysteine

While a simple Vitamin B12 level will typically be low in IGS, doctors also look at “functional markers” to see if the body is struggling without B12 inside its cells ^[1][4].

• Methylmalonic Acid (MMA): This level can rise significantly when the body lacks B12 ^[3].
• Homocysteine: This amino acid also increases when B12 is missing ^[3]. High levels of both MMA and homocysteine strongly support a B12 deficiency diagnosis ^[5].

Important Context: These markers are not perfect. MMA and homocysteine can also rise due to poor kidney function, and homocysteine can be affected by low folate or other conditions. Your doctor will interpret these alongside the full clinical picture.

The Clue in the Urine: Proteinuria

One of the most unique signs of IGS is finding proteinuria (protein in the urine) alongside a Vitamin B12 deficiency ^[3][6]. Doctors check this using a protein-to-creatinine ratio test. If a child has low B12 and protein in their urine, IGS is often suspected. This protein loss persists even after the anemia is treated ^[6][3].

Genetic Testing: The Final Confirmation

While blood and urine tests point the way, discuss confirmatory genetic testing with your metabolic, hematology, or genetics team ^[7].

• CUBN and AMN Genes: Labs look for pathogenic variants in both copies of either the CUBN or AMN gene ^[7][8].
• Do Not Delay Treatment: If your child has severe B12 deficiency with neurological or hematologic findings, treatment should begin immediately. Do not delay starting B12 injections while waiting for genetic test results to come back. Additionally, genetic tests may occasionally yield a “variant of uncertain significance” which requires a specialist to interpret ^[8][9].

Common Diagnostic Pitfalls

Because IGS is so rare, it is frequently mistaken for other conditions:

• The MCV Mask: If a child also has alpha-thalassemia (a common genetic blood trait), their red blood cells might appear small or normal-sized, “masking” the large cells doctors expect to see in B12 deficiency ^[2][10].
• Pseudo-TMA: Severe IGS can cause high levels of LDH and low platelets, mimicking a life-threatening emergency called TTP (Thrombotic Thrombocytopenic Purpura) ^[11][12]. TTP is an emergency that may require plasma exchange. This treatment should not be withheld while doctors work to determine if the true cause is IGS ^[12].
• Simple Iron Deficiency: Because fatigue and paleness are common in iron deficiency, children may be given iron supplements first, which do not fix the underlying B12 problem in IGS ^[2].