CONGENITAL ERYTHROCYTOSIS. Mary Frances McMullin
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1 CONGENITAL ERYTHROCYTOSIS Mary Frances McMullin
2 Disclosures No relevant disclosures
3 Learning outcomes Describe the mechanism of red cell production following signalling from the erythropoietin receptor List the causes of primary and secondary congenital erythrocytosis Perform an investigation of a young patient with erythrocytosis to find the cause Propose possible management options in a patient with congenital erythrocytosis
4
5 Haemoglobin and red cell mass (males) Johansson Pl et al. Br. J. Haem. 2005; 129, 701-5
6 Erythrocytosis Apparent: Raised haematocrit with a red cell mass within the reference range Relative: Raised haematocrit with a red cell mass within the reference range and reduced plasma volume Absolute: Increase in the red cell mass >125% of predicted value
7 Classification of an Erythrocytosis Primary erythrocytosis Congenital EPO receptor mutations Acquired Polycythemia vera LNK mutations (congenital and acquired) Secondary erythrocytosis Congenital Acquired EPO mediated Hypoxia driven Central hypoxic process Local hypoxia Pathologic EPO production Exogenous EPO Idiopathic erythrocytosis
8 Congenital erythrocytosis Primary EPO receptor mutations Secondary Oxygen sensing pathway mutations VHL gene mutations PHD2 mutations HIF -2a mutations Bisphosphoglycerate mutase deficiency High oxygen-affinity haemoglobin Methaemoglobinaemia Hereditary ATP increase
9 Erythropoietin Receptor EPO Signal Transduction EPO Down modulation EPO Truncated EPOR EPO Receptor Receptor Receptor JAK2 JAK2 SHP-1 JAK2 STAT5 SHP-1 SHP-1 active STAT5 dimers
10
11 EPOR truncation mutation T C T T G C G T C C A T G G A C A C T G T G De novo G to A at base 6002 Stop codon at aa 439 T C T T G C G T C C A T N G A C A C T G T G Individual Teenage boy Hb PCV WBC Platelets EPO Level (g/l) (x10 9 /L) x10 9 /L) (miu/ml) (NR )
12 Erythropoietin Receptor Truncations Mutation Amino Acid Truncation Reference G5881T 110 Arcasoy, 2002 Deletion Petersen, 2004 G5959T 84 Kralovics, 1997 C5964G 83 Kralovics, 1998, Cario, 2006 Insertion T Kralovics, 1997 Tandem duplication Watowich, 1999 Insertion G Sokol, 1995 Deletion Kralovics, 1997, Arcasoy, 1995 C5986T 74 Furukawa, 1997 G6002A 70 de la Chapelle, 1993 and Percy, 1998 G6003A 70 Cario, 2006 Adapted from Percy, 2007
13 E208X E208E G229S G220R T274A P155L E20 8Q G220V F287S p.i568t E487de PH SH2 Q72fs S186I E208X A223V pq423x p.r551w A215V D234N L510VfsX35(+)L510F Mutations in LNK (SH2B3) in Myeloproliferative Neoplasms
14 Hypoxia Sensing Normoxia Hypoxia O 2 O 2 O 2 O 2 O 2 Pro.H Fe HIF-a HIF-b O 2 OH Epo VEGF HIF-a Glut1, PGK VHL HIF -a HIF-b Transferrin Degradation CGTG Courtesy of J Prchal
15 VHL mutational screen Normal >100 patients A A A G A C C T G G A G C G G C T G A C A C A G G Homozygous C598T/Arg200Trp 9 Asian families A A A G A C C T G G A G T G G C T G A C A C A G G
16 Chuvash Pakistan Bangladesh
17 VHL mutations Amino acid change Clinical comments References C598T/wild type Arg200Trp Percy 2003, Cario 2005, Perrotta 2006 Homozygotes C571G/C571G His191Asp Pastore 2003 C598T/C598T Arg200Trp Ang, 2002, Percy 2003 Perrotta 2006, Pastore 2003, Cario 2005, Bento 2005 C413T/C413T Phe138Lys Piterkova, 2012 Compound Heterozygotes C235T/C562G Arg79Cys/Leu 188Val Bento 2005 G388C/C598T Val130Leu/Arg200Trp Pastore 2003 G430C/C598T Gly144Arg/Arg200Trp Percy 2005 C562G/C598T Leu188Val/Arg200Trp Pastore 2003 C574T/C598T Pro192Ser/Arg200Trp Pastore 2003 C574A/C598T Pro192Thr/Arg200Trp Percy 2007 Heterozygotes G311T/wild type Gly104VAL Cario 2005 G376T/wild type Asp126Tyr Some features of VHL syndrome G430A/wild type Gly144Arg Mother and sister with mutation unaffected Pastore 2003 Randi 2005 A523G/wild type Try175Cys Ataxia telangectasia Gento 2005 C562G/wild type Leu188Val Percy 2007
18 Family with hereditary erythrocytosis Father Daughter Son Mother Hemoglobin g/dl RBC x /l 6.4 N/A Hct WBC x 10 9 /l N/A Platelets x 10 9 /l Erythropoietin mu/ml N/A N/A (normal range 5-25 mu/ml) RBC red blood cell, Hct hematocrit, WBC white blood cell, N/A not available black = Hb (values as shown)
19 Sequencing exon 2 of PHD2 Normal sequence Father G T T G A T A A T C C A A A T G G A G G T T G A T A A T C C A A A T G G A G Mother C to G change at base 950 Proline to arginine at codon 317 Son G T T G A T A A T C C A A A T G G A G Daughter G T T G A T A A T C C A A A T G G A G G T T G A T A A T C C A A A T G G A G
20 P317R impairs HIF hydroxylase activity In vitro translated wild type or P317R Flag PHD2 or control Incubated with immobilized GST-HIF-1alpha and 35 S labeled in vitro translated VHL Assessed binding of VHL to HIF P317R PHD2 variant reduced binding of HIF to VHL Impairment of hydroxylation
21 G1112A mutation Arg371His
22 PHD2 mutation Amino acid change Clinical events Reference G471C P200Q Cln157His (SNP) Pro200Gln Homozygous for JAK2 V617F Albiero delG Met202IlefsX71 Inflammatory arthomyalgia, visual symptoms, hypertension C609G 840_841insA A872T Asn203Lys Lys204Glu Asp254His Arg281ThrfsX3 Gly285Arg Lys291Ile Pro304Leu JAK2 exon insL+154F547dup8 Cardiac disease Ladroue, 2011 Al-Sheikh 2007 Albiero 2009 Database Ladroue 2011 Tinnitus Al-Sheikh 2007 Database Albiero 2009 Database C950G Pro317Arg Superficial thrombophlebitis Percy 2006 Val338serfX18 TIA Database G1112A Arg371His Sagittal sinus thrombosis Percy 2007 A1121G C1129T His374Arg Gln377X Hypertension paraganglioma Ladroue 2008 Al-Sheikh 2007 A1267G Arg398X Lys423Glu Ladroue, 2011 Albiero 2009
23 Erythrocytosis family proband Grandmother Father Mother Unaffected Son Affected Son Epo Hct Hb Age Grandmother Father Mother Unaffected Son Affected Son Epo Hct Hb Age
24 Sequencing of HIF-2alpha ODD G to T change at base 1609 Gly to Trp at codon 537 Normal sequence
25 Hydroxylation of Gly537Trp variant
26 MUTATION CODON AMINO ACID EXCHANGE REFERENCE Phe374Y Thyrosine Lorenzo, 2012 c.1588g>a Ala530 Threonine Zhuang 2012 c.1589c>t Ala530 Valine c.1591c>t Pro531 Favier, 2012 c.1601c>t Pro-534 Leucine Furlow, 2009 c.1603a>g Met-535 Valine Percy, 2008 c.1604t>c Met-535 Threonine c.1605g>a Met-535 Isoleucine Martini, 2008 c.1609g>a Gly-537 Arginine Percy, 20008, Gale 2008, Perrotta 2008 c.1609g>t Gly-537 Tryptophan Percy 2008 c.1617c>g Asp-539 Glutamic acid Van Wijk 2009 c.1620c>g Phe-540 Leucine
27 Biphosphoglycerate mutase Converts 1,2 BPG to 2,3 BPG 2,3BPG binds to the Hb tetramer and converts Hb molecule to low affinity state for oxygen Lack of 2,3 BPG Hb tetramer in high oxygen affinity state and oxygen dissociation curve shifted to the left Low 2,3 BPG levels Deficiency of biphosphoglycerate mutase Autosomal dominant or recessive
28 DNA sequence analysis detected a heterozygous G>A substitution at nucleotide c.269, in the patient and his mother but not his father. Nayia Petousi et al. Haematologica 2014;99:e201-e204 n
29 Structural effects. Nayia Petousi et al. Haematologica 2014;99:e201-e204
30 Oxygen Dissociation Curve
31 High Oxygen affinity Haemoglobins Haemoglobin Chesapeake (1966) Over 90 variants with altered oxygen affinity a and b globin defects Stable and unstable Do not release oxygen easily to tissues Hypoxia, raised EPO and erythrocytosis Sequence the globin genes?
32 High Affinity Haemoglobins UPN Hb Olympia Olympia Pierre Benite Heathrow Santa Clara Age at presentation (yrs) Haemoglobin (g/l) Hct WBC (x 10 9 /l) Pts (x10 9 /l) Epo (miu/ml) N/A N/A
33 Congenital Methaemoglobinaemia Abnormal M Haemoglobin variant Deficiency of a cytochrome reductase Recessive congenital methaemoglobinaemia: cytochrome b5 reductase deficiency
34 Erythrocytosis Measure Epo levels Primary Secondary Intrinsic defect of the erythroid cell Erythropoietin driven
35 Diagnostic pathway History and examination
36 Investigation Repeat confirmatory FBP Red Cell Mass Erythropoietin level P 50 - Oxygen dissociation curve Haemoglobin electrophoresis Sequencing of known gene mutations
37 Clinical events in congenital erythrocytoses Homozygotes with Chuvash polycythaemia: increased mortality from cerebrovascular events and mesenteric thrombosis PHD2 and HIF2A mutations associated with thromboembolic events Pulmonary hypertension may occur
38 Management issues in congenital erythrocytosis Assess each individual patient Prophylaxis for any thromboembolic risks Consider low dose aspirin Consider venesection to an achievable target
39 Smyth,PLOS, 2005,3,e290
40 Recommendations: High oxygen affinity haemoglobins Possible indications for Venesection include: Presence of symptoms such as dizziness, dyspnoea or angina, for which a raised Hct is considered to be a contributory factor. One or more previous thrombotic episodes. Asymptomatic individuals in whom a family member with a high oxygen affinity haemoglobin, similar haemoglobin concentration, and comparable risk factors for thrombosis has developed a thrombotic problem.
41 High oxygen affinity haemoglobins Consideration of a partial exchange transfusion should be given for individuals with a Hct >0.60 requiring major surgery Do not attempt to reduce the Hct to within the normal range. Venesection to maintain the Hct <0.60 has been recommended. When thrombosis or symptoms compatible with hyperviscosity develop at a lower Hct, a target Hct of 0.52 has been suggested.
42 Russell, Nat Med , 845
43 Conclusions Rare individuals with an increased red cell mass may have a congenital erythrocytosis They often present at a young age and have a family history An investigation for known molecular defects should be carried out Venesection and low dose aspirin are possible management options
44 Acknowledgements Queen s University and Belfast City Hospital University of Pennsylvania, Frank Lee UK Collaborators Tony Green University of Cambridge Claire Harrison, Guys and St Thomas All the clinicians and scientists who provided blood samples and clinical information
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