Dehydrated hereditary stomatocytosis

Other Names: Desiccytosis hereditary; Xerocytosis hereditary; Hereditary xerocytosis Dehydrated hereditary stomatocytosis (DHS) is a rare hemolytic anemia characterized by a decreased red cell osmotic fragility due to a defect in cation permeability, resulting in red cell dehydration and mild to moderate compensated hemolysis. Pseudohyperkalemia (loss of potassium ions from red cells on storage at room temperature) is sometimes observed.

Epidemiology

The prevalence of DHS is unknown but to date, about 20 families with DHS have been described in the literature.

Cause

Most reported DHS cases are caused by gain-of-function mutations in the gene PIEZO1 (16q24.3) which encodes part of a mechanosensitive ion channel. This results in increased red cell membrane permeability for cations that consequently leads to cation depletion, dehydration and shortened red cell survival. Rare atypical forms have been associated with mutations in SLC4A1 (17q21.31), coding for the Band 3 anion transport protein, or KCNN4 (19q13.2) which codes for the putative Gardos channel.

Signs and symptoms

Onset of DHS may occur during the perinatal period with occurrence of edema and ascites (most often not related to an underlying anemia) that usually resolve spontaneously during the first weeks of life but may rarely lead to hydrops fetalis . Most adult patients present a mild anemia or a totally compensated hemolysis, with fatigue, icterus, splenomegaly and risks of secondary complications including cholelithiasis. Patients can also be referred for unexplained hemochromatosis, since iron overload is frequently associated with the disease. Thrombotic complications (arterial and venous events, including portal vein thrombosis and pulmonary hypertension) have been described at a high rate after splenectomy.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Increased red cell osmotic fragility
• Nonspherocytic hemolytic anemia

30%-79% of people have these symptoms

• Abnormal blood potassium concentration
• Cholelithiasis(Gallstones)
• Increased lactate dehydrogenase level
• Increased serum ferritin(Increased serum ferritin level)
• Increased total bilirubin(High bili total)
• Macrocytic anemia
• Schistocytosis
• Splenomegaly(Increased spleen size)

5%-29% of people have these symptoms

• Abdominal pain(Pain in stomach)
• Congenital hemolytic anemia
• Edema(Fluid retention)
• Episodic fatigue
• Hemoglobinuria(Hemoglobin in urine)
• Hepatitis(Liver inflammation)
• Hepatomegaly(Enlarged liver)
• Increased hemoglobin concentration
• Increased mean corpuscular volume
• Intermittent jaundice(Intermittent yellow skin)
• Jaundice(Yellow skin)
• Neonatal hyperbilirubinemia
• Pallor
• Thromboembolism

1%-4% of people have these symptoms

• Conjunctival icterus(Yellowing of the whites of the eyes)
• Polycythemia(Increased red blood cells)
• Portal vein thrombosis(Blood clot in portal vein)
• Pulmonary venous hypertension

Diagnosis

Diagnosis relies on laboratory findings. The typical presentation includes normal hemoglobin level or mild [[anemia, normal mean cell volume (MCV) or mild macrocytosis, normal or elevated mean corpuscular hemoglobin concentration (MCHC), elevated reticulocytosis, and a small number of stomatocytes (<10% of red cells). A diagnosis of DHS must be evoked in patients with unexplained iron overload, even if hemoglobin levels are normal, as well as in patients with unexplained hemolysis (before splenectomy) or those presenting with thrombotic events, if already splenectomized.

Osmolar gradient ektacytometry is the best phenotypic diagnosis method, showing a leftward shift of the bell-shaped curve with a normal maximum deformability index and a decreased hypo and hyper-osmotic point, reflecting decreased osmotic fragility and cell dehydration, respectively. In some cases, an increased serum potassium level is observed, which results from in vitro leakage and is clinically irrelevant. Measurement of ferritin level and liver magnetic resonance imaging (MRI) are performed to evaluate iron overload. Genetic screening of the causative genes can be performed after phenotypic investigations.

Differential diagnosis

Differential diagnoses include other causes of hemolysis, including hereditary spherocytosis, overhydrated hereditary stomatocytosis, hemoglobinopathy or red cell enzyme deficiencies such as hemolytic anemia due to red cell pyruvate kinase deficiency.

Treatment

Treatment is mainly symptomatic. Occurrence of cholelithiasis should be regularly monitored. Folic acid supplementation should be proposed in case of anemia. Pregnancy should be closely monitored. Iron status should be regularly monitored by serum ferritinemia and liver MRI.

Iron depletion, most often by phlebotomy, is proposed when ferritinemia reaches the threshold of 1000 ng/ml or when iron liver overload is present. Splenectomy is contraindicated in DHS due to an elevated risk of life threatening arterial and venous thrombotic events. is mainly symptomatic. Occurrence of cholelithiasis should be regularly monitored.

Folic acid supplementation should be proposed in case of anemia. Pregnancy should be closely monitored. Iron status should be regularly monitored by serum ferritinemia and liver MRI. Iron depletion, most often by phlebotomy, is proposed when ferritinemia reaches the threshold of 1000 ng/ml or when iron liver overload is present. Splenectomy is contraindicated in DHS due to an elevated risk of life threatening arterial and venous thrombotic events.

Prognosis

Overall prognosis is favorable in well managed patients (not splenectomized and with regular monitoring of their iron status). Splenectomized patients are at risk of early or late thrombotic events.

NIH genetic and rare disease info

• NIH info on Dehydrated hereditary stomatocytosis

Dehydrated hereditary stomatocytosis is a rare disease.