Rare Polycythemias (Chuvash, PFCP, TEMPI)

Quick comparison

Chuvash polycythemia

• Mechanism: an abnormality of cellular oxygen sensing, with decreased serum hepcidin. A mutation in the VHL gene producing an R200W amino-acid substitution leads to increased hypoxia-inducible factor (HIF)-1 and HIF-2 and upregulation of the hypoxic response even when oxygen levels are normal → ↑EPO → ↑Hb. This makes it a secondary (EPO-driven) erythrocytosis.
• Inheritance / epidemiology: autosomal recessive; seen in the Chuvash region of central European Russia.
• Symptoms: thrombotic and hemorrhagic vascular complications that lead to early mortality.
• Treatment: not well defined and individualized. Phlebotomy only for attributable hyperviscosity symptoms, with caution (thrombosis in Chuvash is not hematocrit-driven and prior phlebotomy has been associated with increased thrombosis). Low-dose aspirin may be considered (benefit unproven). Antihistamines treat only pruritus.
• Contrast with congenital EPOR disease: C-terminal EPOR truncations remove the negative regulatory (SHP-1 binding) domain, prolonging EPO-triggered signaling and making erythroid progenitors hypersensitive to EPO; signaling remains EPO-dependent, not constitutive, whereas Chuvash-type polycythemia is characterized by normal or high EPO levels.

Primary familial and congenital polycythemia (PFCP)

• Definition: isolated erythrocytosis in an individual with a normal-sized spleen and no disorder causing secondary erythrocytosis.
• Clinical manifestations: relate to the erythrocytosis, and can include plethora and the hyperviscosity syndrome (headache, dizziness, fatigue, lassitude, visual and auditory disturbances, paresthesia, myalgia), altered mental status, and arterial and/or venous thromboembolic events.
• Diagnosis: isolated erythrocytosis, normal hemoglobin-oxygen affinity (normal P50), EPO serum level below or in the lower-normal range, and a family history consistent with autosomal dominant inheritance. Confirmed in 12% to 15% of individuals by a heterozygous pathogenic variant in EPOR.
• Distinguishing from PV: PV is associated with a low EPO level; if EPO is low but there is NO JAK2 mutation and there is a family history suggestive of autosomal dominant inheritance, PFCP is the most likely diagnosis.
• Treatment: no published management guidelines. Most individuals need no regular treatment; some undergo phlebotomy to treat hyperviscosity symptoms or to maintain a near-normal hematocrit; some require antihypertensive therapy. Low-dose aspirin can be considered for thromboembolic prevention, though no evidence of efficacy exists.

TEMPI syndrome

• Acronym:
  • Telangiectasias
  • Erythrocytosis with an elevated EPO
  • Monoclonal gammopathy
  • Perinephric fluid collections
  • Intrapulmonary shunting
• The pathophysiology underlying the telangiectasia formation and intrapulmonary shunting is not clear.
• EPO: patients have a characteristically elevated serum erythropoietin level, elevated to 10 to 500 times the upper limit of normal.
• Treatment: partial or complete responses have been seen with the proteasome inhibitor bortezomib.

High-yield pearl

• In a patient with erythrocytosis and a LOW EPO level, JAK2 V617F is a major criterion for polycythemia vera; if JAK2 (V617F and exon 12) is negative, test EPOR (PFCP); VHL (Chuvash) and other oxygen-sensing gene defects are evaluated when EPO is normal or high.