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 Table of Contents  
Year : 2018  |  Volume : 9  |  Issue : 2  |  Page : 39-44

Primary familial and congenital polycythemia; The forgotten entity

Department of Pathology, Hematology Unit, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

Date of Web Publication18-Jun-2018

Correspondence Address:
Dr. Mansour S Aljabry
Department of Pathology, Hematology Unit, King Khalid University Hospital, King Saud University, P. O. Box 2925, Riyadh 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joah.joah_30_18

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Primary familial and congenital polycythemia (PFCP) is a rare autosomal dominant disorder caused by hypersensitivity of erythropoietin receptor of erythroid progenitors leading to increased rate of erythropoiesis at any given serum erythropoietin level. The hallmark of this disorder is isolated erythrocytosis with the absence of splenomegaly and lack of secondary causes of polycythemia. In this short review, we will shed light on various aspects of PFCP with special focus on molecular pathogenesis and diagnostic approach.

Keywords: Polycythemia, Polycythemia Vera, primary familial and congenital polycythemia

How to cite this article:
Aljabry MS. Primary familial and congenital polycythemia; The forgotten entity. J Appl Hematol 2018;9:39-44

How to cite this URL:
Aljabry MS. Primary familial and congenital polycythemia; The forgotten entity. J Appl Hematol [serial online] 2018 [cited 2023 Sep 22];9:39-44. Available from: https://www.jahjournal.org/text.asp?2018/9/2/39/234553

  Introduction Top

Primary familial and congenital polycythemia (PFCP) is a familial disorder characterized by isolated erythrocytosis due to the inheritance of mutated hypersensitive erythropoietin receptor (EPOR). The data regarding the true prevalence of PFCP are scarce and insufficient. However, it is likely to be underdiagnosed and underreported as definitive diagnosis requires molecular characterization of the implicated gene mutation, as well as exclusion of wide variety of closely related differential diagnoses. Moreover, some patients may undergo regular phlebotomies as symptomatic therapy for hyperviscosity related to polycythemia without further investigations.

  Molecular Pathogenesis Top

EPOR is an integral transmembrane glycoprotein composed of 508 amino acids belonging to cytokine receptor family. The structure of EPOR encompasses three integrated domains; an extracellular domain serving as receptor for EPO proliferative signals, a hydrophobic transmembrane domain that transmits the signal through the bilayers cell membrane, and a cytoplasmic domain which enables activation of Janus kinases 2 (JAK2) and subsequently phosphorylation of the tyrosine residues of STAT5 and RAS-MAPK signal transduction pathway.[1] On EPO stimulus, phosphorylation of the EPOR extracellular domain leads to conformational change, in which the EPO signal dissociate through the transmembrane domain and thereby activating the nonreceptor cytoplasmic tyrosine kinase JAK2 which, in turn, activates JAK-STAT pathway.[2] Negative regulation of EPOR is done through a group of suppressor molecules such as tyrosine phosphatase (SHP-1) and suppressor of cytokine signaling (SOCS) which facilitate dephosphorylation of signal transduction pathway and decrease the stability of receptor [3] [Figure 1].
Figure 1: Erythropoietin receptor and Janus kinases 2–STAT pathway: Activated: EPO signal phosphorylates Janus kinases 2 leading to activation of STAT5 and RAS-MAPK signal transduction pathway which in turn activates several nuclear transcription factors promoting proliferation of erythroid precursors. Inactivated: Recruitment of tyrosine phosphatase (SHP-1) and suppressor of cytokine signaling facilitates dephosphorylation of Janus kinases 2

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Control of EPO-EPOR signaling pathway is an essential mechanism for normal erythropoiesis. Studies on mice proved that congenital deficiency of EPO-EPOR signaling system is incompatible with life as deficient mice died of severe anemia during embryonic life.[4] On the other hand, gain-of-function mutations affecting EPOR domains induce deregulated erythrocytosis and are associated clinically with familial erythrocytosis type 1 which is more commonly known as PFCP.

Approximately 23 heterozygous pathologic variants involving EPOR gene have been identified in more than 116 patients.[5] The first EPOR mutation was found in a large Finnish family (29 members) with isolated erythrocytosis. The identified pathologic variant was a heterozygous nonsense mutation (G6002A) leading to early stop codon at Trp439, causing deficiency of C-terminal negative regulatory domain and truncation of cytoplasmic EPOR domain.[6]

The majority of reported pathological variants are nonsense or frameshift mutations either related to insertions or small deletions. Almost all of these mutations reside in exon 8 of EPOR gene which encodes the negative feedback regulatory domains of the receptor such as SHP-1 and SOCS.[5]

Lack of EPOR cytoplasmic suppressors results in overexpression of the receptor and thereby prolonged phosphorylation of JAK2 with excessive activation of STAT5 and RAS-MAPK signal transduction pathway. The upregulated signal transduction pathway promotes cell survival, enhances proliferation, and accelerates differentiation of erythroid precursors giving rise to primary polycythemia.[7]

Few missense mutations have also been described in some individuals with uncertain clinical significance. Chauveau et al. reported a point mutation (c. 1310G>A, p. Arg437His), which was detected in a 52-year-old patient with normal hemoglobin (Hb) concentration and normal RBC indices without any family history of polycythemia.[8] However, it was also found in a 35-year-old male polycythemic patient who required frequent phlebotomies.[9] The c. 1462C>T missense mutation is another variant which was reported in a 42-year-old male patient with primary polycythemia but also was detected in his nonpolycythemic mother and one of his siblings who was disease free.[10]

  Clinical Characteristics Top

PFCP is a familial disorder with autosomal dominant inheritance pattern, despite few sporadic cases described in the literature.[11] Clinical presentation of PFCP varies from an asymptomatic child diagnosed incidentally to severely ill elderly patient with arterial hypertension or myocardial infarction.[12],[13],[14],[15],[16] Of note, this clinical variability has been observed within the members of the same affected family.[6]

The vast majority of PFCP patients manifested clinically with mild hyperviscosity features such as fatigue, dizziness, headache, plethora, paresthesia, hypertension, and visual disturbances.[17] However, complications of PFCP might be severe and even life-threatening such as intracranial hemorrhage, coronary heart disease, and deep vein thrombosis.[18],[19] Laboratory findings typically reveal isolated high hematocrit (HCT) and Hb concentration above the average reference range for age and sex accompanied with increased red blood cell count. PFCP is characterized by the absence of splenomegaly, hepatomegaly, and lack of all secondary causes of erythrocytosis such as pulmonary, renal, or cardiac disorders. Serum EPO is usually below the normal range for reference values while Hb oxygen affinity, measured as P50, is normal.[20]

  Differential Diagnosis Top

Relative polycythemia

Concentration of Hb and HCT depends mainly on the plasma volume and red cell mass. Therefore, reduction of plasma volume due to dehydration or fluid loss can apparently elevate HCT and Hb concentration. Gaisbock's syndrome is a chronic state of reduced plasma volume due to shift of plasma fluid from intravascular toward interstitial compartment. This syndrome is commonly associated with uncontrolled hypertension, inappropriate use of diuretic therapy, and obesity.[21] Emamian et al. studied 9808 hypertensive patients and concluded that the majority of those patients had spurious increase of Hb and HCT concentration.[22] Diagnosis of relative polycythemia can be confirmed by measurement of total red cell mass using radiolabeled chromium-51.

Polycythemia vera

Polycythemia vera (PV) is a chronic stem cell myeloproliferative neoplasm (MPN) characterized by autonomous proliferation of erythropoiesis and other hematopoietic lineages due to gain-of-function mutation involving JAK2. PV is associated with splenomegaly and hypercellular bone marrow with panmyelosis, that is, prominent granulocytosis, hyperplastic erythropoiesis, and proliferation of pleomorphic megakaryocytes. Almost all PV patients carry JAK2 (V617F) or exon 12 mutation. The overall median survival for PV patient is around 13 years. Thrombotic complications are the most common cause of death; however, progression to acute leukemia or post-PV myelofibrosis has been reported in approximately 20% of PV patients.[23]

Although serum EPO level in PFCP is subnormal mimicking PV, it can be easily differentiated from PV by lack of MPN features and negative JAK2 mutations.

Secondary polycythemia

Secondary polycythemia encompasses a wide variety of clinical entities characterized by isolated erythrocytosis due to increased production of erythropoietin. According to the source of EPO production, it can be divided into extrinsic and intrinsic causes to erythroid precursors. Extrinsic causes are either related to hypoxia such as sleep apnea, chronic obstructive pulmonary disease, congenital heart disease, and renal artery stenosis or related to EPO secreting tumors such as renal or endocrine tumors.[24]

Intrinsic causes include rare congenital polycythemia disorders which might result from altered O2-sensing pathway or high-affinity Hb.

Altered oxygen-sensing pathway

At hypoxic state, erythropoiesis is triggered by hypoxia-inducible factor 1 (HIF-1) which exponentially stimulates the production of EPO and increases ATP and iron supply to erythroid progenitors. On normal O2 tension, HIF-1 is degraded by von Hippel–Lindau protein (VHL) and its cofactor prolyl hydroxylase PHD2.[25]

Chuvash polycythemia is an autosomal recessive disorder caused by a point mutation at codon 200 of the VHL gene leading to substitution of an arginine to tryptophan (vHL R200W). The net result of this mutation is loss of function of VHL protein, thereby lack of ubiquitination and degradation of α subunit of HIF-1. As a result, EPO is constitutively produced at any given O2 concentration.[26] Chuvash polycythemia is associated with early mortality attributed mainly to thrombotic and bleeding complications even not correlating with Hb level.[27],[28] In a follow-up of 103 patients for >20 years, 25% of patients died with cerebral hemorrhage or infarction by the age of 40 years.[29]

The other abnormality affecting O2 sensing pathway is an autosomal dominant mutation involving EGLN1 gene at chromosome 1q42.1. This mutation results in loss of function of PHD2 enzyme which regulates expression of HIF-1α in normal O2 status.[30] To date, more than 25 different mutations have been described in 32 patients with familial erythrocytosis.[31] Besides hyperviscosity complications, PHD2 mutations are characteristically associated with thrombophlebitis and pulmonary hypertension due to vascular proliferation.[32] Ladroue et al. described the PHD2 mutation in a polycythemic patient with recurrent paraganglioma and suggested that PHD2 might be a tumor-suppressor gene.[33]

A gain of function mutation involving EPAS1 gene, which encodes HIF-2α, has been described in some families with autosomal dominant pattern. This mutation has been described in 4 families and 8 sporadic cases with isolated erythrocytosis. Moreover, 2 patients developed paraganglioma suggesting the role of HIF-1 as a tumor suppressor gene as well.[5],[34]

Diagnosis of secondary polycythemia with altered O2 sensing pathway can be suspected in polycythemic patients with high EPO level and normal P50 after careful exclusion of extrinsic causes of high EPO level. Molecular studies for vHL, PHD2, and HIF-1 are required to establish the definitive diagnosis.

Altered affinity of hemoglobin

Inheritance of high-affinity Hb variants results in secondary polycythemia due to reduction in O2 supply to the tissues. To date, >100 Hb variants have been reported in the literature involving both α and β chains and inherited mainly as autosomal dominant.[34] Diagnosis can be established by measurement of P50 value on fresh blood followed by globin gene sequencing, because many of those variants are electrophoretically silent in Hb electrophoresis.[35]

Low level of 2,3-diphosphoglycerate (2,3-DPG) enzyme results in high affinity of Hb and thus leads to secondary polycythemia due to tissue hypoxia. 2,3-DPG deficiency is a rare autosomal recessive disorder caused by a compound heterozygous mutation involving DPGM gene at chromosome 7q33.[36] Estimation of 2,3-DPG enzyme and molecular characterization of DPGM gene should be performed for any patient with secondary polycythemia, low P50, and normal DNA gene sequencing for both α and β chains.[37]

Methemoglobinemia is a clinical condition in which the functional form of heme iron (ferrous Fe 2+) is oxidized to the inert form (ferric Fe 3+). Inherited methemoglobinemia is either related to NADH deficiency or due to inheritance of HbM and commonly presents with cyanosis.[38],[39] Few case reports have shown the association between methemoglobinemia and mild erythrocytosis mediated by altered oxyhemoglobin affinity.[40] Whenever methemoglobinemia is suspected, direct estimation of MetHb percentage in peripheral blood using Cooximetry should be considered. The definitive diagnosis can be established by the assessment of erythrocyte NADH-reductase (Cb5R) activity and Hb electrophoresis followed by DNA mutational analysis for Cb5R gene and sequencing for both α and β chains.[41]

  Diagnostic Approach Top

During the initial diagnostic workup, special attention should be paid to recent phlebotomy or any other local therapeutic procedures, such as cupping or Hijama, as it reduces Hb concentration and hence might mask polycythemia diagnosis. Careful family history is quite helpful in the diagnosis of PFCP as it being a familial disorder, and in some instances, it is crucial to draw a family pedigree, especially with rare or even novel mutations.[5]

Furthermore, persistence of an elevated Hb (>17.5 g/dl for men and >16 g/dl for women) and HCT should be documented on at least two separate occasions. RBC count is elevated as well, reflecting the increased RBC mass. Presence of leukocytosis and thrombocytosis is not a feature of PFCP but indicates myeloproliferative nature of the disorder and underlying PV.[23] In PFCP, physical findings usually include plethora with the absence of splenomegaly and signs of secondary polycythemia especially cardiopulmonary insufficiency features.[5]

The essential laboratory investigations should include the liver and renal function tests as hepatic and renal disease might lead to secondary erythrocytosis. Low serum ferritin and high B12 are commonly associated with primary polycythemia as compared with secondary polycythemia while high serum calcium could be related to parathyroid carcinoma or adenomas which secret EPO inappropriately.[42]

Arterial oxygen saturation, using pulse oximetry is the most sensitive indicator of peripheral hypoxia. However, it can be misleading in certain clinical conditions such as methemoglobinemia, high-affinity Hb and 2,3-DPG deficiency, and hence measurement of arterial blood gas (ABG) and O2 saturation by cooximetry should be considered.[43],[44]

Serum EPO level is characteristically low in PFCP and PV. In fact, subnormal EPO level exclude all hypoxia-driven polycythemias and has been considered a minor criterion for PV diagnosis.[22] Almost all secondary polycythemias are associated with high or normal EPO level.[45]

P50 is the partial pressure at which Hb is half saturated with oxygen. High-affinity Hb and low 2,3-DPG level shift the Hb oxygen dissociation curve to the left lowering the P50.[46] Furthermore, abnormal Hb variants, associated with altered oxyhemoglobin affinity or methemoglobinemia, can be detected by Hb electrophoresis. However, variants such as Olympia (β20Va → Met), Santa Clara (β97His → Asn), and Heathrow (β103Phe → Leu) are characterized by high affinity and erythrocytosis but electrophoretically silent.[36] Therefore, molecular testing is an indispensable tool for detection of these variants.

JAK2 V617 mutation is an acquired somatic gain of function missense mutation (valine to phenylalanine substitution at codon 617 in JH2) and leads to loss of autoinhibitory control over JAK2, and hence, rendering the mutated JAK2 in a constitutively active state. It has been reported in more than 95% PV patients. Although this mutation is not specific for PV, it is the gold standard to differentiate between clonal erythrocytosis in PV and other benign conditions. JAK2 exon 12 mutations are several gain-of-function mutations involving exon 12 in JAK2 gene reported in about 4% of PV and associated mainly with predominant erythroid proliferation. In a practical sense, molecular testing for JAK2 mutations in peripheral blood is the initial diagnostic step for erythrocytosis as being major criterion for PV.[47]

Bone marrow examination is not routinely required to establish the diagnosis for isolated erythrocytosis unless associated with atypical features such splenomegaly, panmyelosis, or positive JAK2 mutation.[45] In PFCP, bone marrow is usually mildly hypercellular with predominant erythropoiesis and normal megakaryocytes and granulopoiesis.[48]

DNA sequencing of the implicated genes is mandatory to establish the definitive diagnosis and can be directed by diagnostic algorithm which covers all potential causes of erythrocytosis [Figure 2].
Figure 2: Diagnostic algorithm for polycythemia. Hb = Hemoglobin, Epo = Erythropoietin, HD = Heart disease, PV = Polycythemia vera, COPD = Chronic obstructive pulmonary disease, Seq = sequencing, Poly = polycythemia

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  Prognosis and Management of Primary Familial and Congenital Polycythemia Top

The vast majority of published data regarding the prognosis and management of PFCP are obtained from case reports and opinion of experts and no specific guidelines have been issued yet. The most common complications are hypertension and thrombotic manifestations such as deep vein thrombosis, coronary heart disease, and even myocardial infarction. There are no reports of acute leukemia or myelofibrosis transformation among PFCP patients.[5]

The mainstay of disease management is to maintain good hydration and to avoid all exacerbating factors such as smoking, mountain climbing, and scuba diving. In most instances, no regular treatment is required. Phlebotomy is indicated to control the elevated HCT level if there is evidence of hyperviscosity features. The aim of phlebotomy is to maintain HCT lower than 45%.[45]

Low-dose aspirin should be considered for primary prevention of thromboembolic manifestations as 17% of patients in one series, died of cardiovascular complications.[45] Prchal and Sokolreported a patient who died at the age of 40 years because of MI despite being on regular venesections.[49] Lifelong anticoagulation should be considered only for patients with additional risk factors of thrombosis and if a thrombotic event has recurred.

  Concluding Remark Top

PFCP is a rare familial erythrocytosis disorder which can be easily misdiagnosed owing to the presence of wide variety of closely related differential diagnoses. Therefore, increase of awareness about the proper diagnostic approach to such rare disease among physician will help in accurate diagnosis and management.

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Conflicts of interest

There are no conflicts of interest.

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[Pubmed] | [DOI]


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