A 26-year-old female presented with features of chronic hemolysis and was on intermittent follow up. The clinical findings included pallor, icterus, unconjugated hyperbilirubinemia, hepato-splenomegaly, and cholelithiasis. She was only transfused twice, once during delivery and once three months back for severe anemia (3 g/dL). There was no history of similar illness in the family.
Complete blood count revealed
Hemoglobin 8 g/dl
Hematocrit 26.1%,
Red blood cell count 3.02x10^3/ µl L,
Mean corpuscular volume 86.4 fL, mean corpuscular hemoglobin 26.6 pg,
Mean corpuscular hemoglobin concentration 30.8 g%
Red cell distribution width 20%.
Platelet count was 40,000x10^3/µl (thrombocytopenia)
total leukocyte count 4000x 10^3/µl.
See figure 1 for abnormalities noted on the peripheral smear.
She had chronic moderate anemia from the age of 8 years, reticulocytosis and thrombocytopenia. Hemolytic workup was negative and detailed investigations on the blood sample of the patient ruled out hemoglobinopathies by Hb HPLC, G6PD deficiency and pyruvate kinase deficiency. Incubated osmotic fragility testing showed increased resistance to osmotic lysis. However, the flow cytometric eosin-5’-maleimide (EMA) dye-binding test was normal and hence ruling out hereditary spherocytosis. She had heterozygosity for alpha 3.7 bp deletion in HBA gene and homozygosity of [TA]7/7 repeats in UGT1A1 gene promoter which was consistent with Gilbert’s syndrome. The clinical manifestations raised the suspicion of stomatocytosis with macrothrombocytopenia. She had low levels of total cholesterol 117.48 mg/dL possibly due to chronic hemolysis. Additional NGS was performed (see figure 2).
A homozygous or compound heterozygous variant in the ABCG5/ABCG8 gene is known to predispose the patient to sitosterolemia or Mediterranean stomatocytosis/macrothrombocytopenia (OMIM: #210250). Mediterranean stomatocytosis/macrothrombocytopenia is described as the hematological manifestations of sitosterolemia. Usually, the typical features of sitosterolemia are absent and hematological feature consists of hemolytic anemia with the presence of stomatocytosis, reticulocytosis, and thrombocytopenia with large platelets. In our case, we have screened for the presence of any other potentially causal variant in the coding region of genes which predispose to other stomatocytic syndromes, dehydrated hereditary stomatocytosis (PIEZO1) and overhydrated hereditary stomatocytosis (RHAG).
Learning points
1. Mediterranean stomatocytosis/macrothrombocytopenia is the hematological manifestations of sitosterolemia.
2. As stomatocytes are usually disregarded as artefactual, multiple evaluations of the peripheral blood film are required to confirm the presence of disorder.
3. Presence of stomatocytes along with macrothrombocytopenia should raise the suspicion for the Mediterranean stomatocytosis/macrothrombocytopenia.
4. Patients usually have short stature, abdominal discomfort and protean manifestations like transient autoimmune markers being positive.
5. This disorder can often be misdiagnosed as hereditary spherocytosis because of the presence of spherocytes on peripheral blood film along with positivity for osmotic fragility test. EMA dye binding test is required to differentiate between the disorders in the laboratories where genetic testing is not available.
6. A critical evaluation of the peripheral blood film and astute characterization of phenotype is imperative for the diagnosis of this disorder
7. Patients are usually resistant to statin-based treatment, however, may respond to ezetimibe.
