Congenital erythrocytosis is a very rare disorder of hematopoiesis that is typified by the presence of elevated red cell mass and puts patients at an increased risk of blood clots, heart attacks and stroke. Diagnosis is complicated because many environmental/lifestyle factors can also affect red blood cell levels but ultimately comes down to genetic screening to try to find pathologic variants of the involved genes. CLI chatted to Dr Frances Smith (Synnovis Molecular Pathology Laboratory, King’s College Hospital, London, UK) to find out more about the disease and how diagnosis is achieved.

What is congenital erythrocytosis?

So, congenital erythrocytosis is one subtype of a much more broad category of disorders which are characterized by elevated red cell mass, which therefore causes an elevated hemoglobin level and hematocrit. The clinical findings are often around blood hyperviscosity – an increased risk of blood clots, heart attacks and strokes. Patients can present with dizziness, tiredness and a red flushed colour. Amongst the different subtypes of erythrocytosis, congenital erythrocytosis is definitely the most rare – it is a very rare condition.

Clinically, congenital erythrocytosis is distinct from the somatic acquired types of erythrocytosis. Broadly, erythrocytosis is divided into two types. Primary erythrocytosis encompasses conditions that are caused by defects in the intrinsic red cell progenitor cells. Secondary erythrocytosis is characterized by a raised erythropoietin level, so these patients often have a defect in the oxygen-sensing pathway. Erythropoietin (EPO) is the key driver of red cell production (erythropoiesis) and it acts in the bone marrow on the erythroid progenitor cells. Erythropoiesis is a very complex, very highly regulated system that achieves a balance in your red blood cell production and maintenance to ensure that your body can respond to changes in oxygen in your environment. Determining the exact cause of a patient’s erythrocytosis therefore involves an analysis of that whole pathway.

By far the most common cause of somatic erythrocytosis is a JAK2 somatic mutation. The Janus kinase 2 (JAK-2) protein is one of the major players in the transduction of the signal from EPO, as the binding of EPO to its receptor (EpoR) triggers the JAK2–STAT (signal transducer and activator of transcription) signalling pathway which drives erythropoiesis.

The genes that are involved in the congenital erythrocytosis conditions can be divided up into two sections. The first are associated with primary congenital erythrocytosis and include mutations in the EPO receptor gene and the SH2B3 gene, which encodes the SH2B adapter protein 3 and is a negative regulator of that JAK2–STAT signalling pathway. The second set of genes are associated with secondary congenital erythrocytosis and involve mutations in genes involved in the oxygen-sensing pathway, such as the genes for the hypoxia-inducible factor (HIF) complex and the Von Hippel–Lindau (VHL) tumor suppressor. Also, there can be mutations in the alpha or beta globin genes that make up the hemoglobin protein which result in hemoglobin with a high affinity for oxygen. These high-affinity hemoglobin proteins bind oxygen more tightly in the bloodstream and don’t release it properly to the tissues. As a result, the tissues are in oxygen deficit, which stimulates the production of more red blood cells, and hence raising the red cell count. There are also fairly newly described mutations in the EPO gene itself. These are very interesting types of gain-of-function mutations that result in a hyperactive truncated form of the protein that overstimulates that pathway. Additionally, there are some other, much more rare mutations in the BPGM gene, which encodes bisphosphate glycerate mutase, resulting in an enzymopathy that causes raised hemoglobin.

Why is diagnosis necessary and how is the disease managed?

It is crucial to get a correct diagnosis of the cause of the patient’s erythrocytosis because the different classifications of erythrocytosis have different treatments and different follow-up requirements.

Also, for example, diagnosis of the acquired polycythemia vera, which involves the JAK2 V617F somatic mutations, is important as this mutation is characteristic of myeloproliferative neoplasms. Those patients, therefore, will be monitored for any sign of transformation into myeloid malignancies. Monitoring is key for early detection and treatment of those conditions should they occur in those patients.

The other reason for wanting a correct diagnosis is managing the risk of cardiovascular events in these patients. They have increased risk of clotting events, strokes and heart disease. There are treatments available to mitigate those risks – and information and advice can be given about lifestyle factors if the primary cause for the erythrocytosis is known.

In terms of congenital erythrocytosis, there is very little clinical guidance around treatment and monitoring of these conditions, mainly because they are so very rare. Because of that, there’s not a huge amount of evidence-based literature around the impact of different treatments, but the sort of the things that are reported in the literature are venesection and low-dose aspirin. Venesection (also known as therapeutic phlebotomy) is essentially the careful removal of blood from the patient to reduce the hematocrit. However, this needs to be done with very careful monitoring of the patient’s response as the impact of that treatment depends on the particular subtype of disease and the precise genetic mutation that the patient has.

Also, for congenital erythrocytosis, correct diagnosis is important for testing other family members. If a pathogenic variant in a particular gene is identified in a patient with erythrocytosis, cascade screening can be offered to identify other family members with the inherited pathogenic variant and their disease risk can be assessed they can be monitored for the associated adverse clinical events.

I think the main thing that we need to improve is the knowledge and literature and funding into research around these conditions and look at bigger cohort studies around diagnosis, treatment and management of patients. We’ve come a long way terms of understanding the disease mechanisms and what causes it, but very little has been done on the treatment and management.

How is diagnosis normally achieved?

The first test would be a full blood count and a blood film to look at what’s going on in the general picture. A thorough examination is done to check for other causes of erythrocytosis. For example, renal and liver function tests would also be done as EPO is produced in the kidneys and there are some types of kidney tumours that upregulate the expression of EPO.

Additionally, there are a lot of very common environmental causes for erythrocytosis. For instance, smoking, living at high altitudes and sleep apnea – anything that can impact oxygen uptake can contribute to a raised red cell mass. Following on from that, a family history will be taken, usually to identify whether there might be a potential inherited cause.

A red cell mass study might be undertaken, but that is actually becoming quite difficult to do – it’s technically quite a difficult assay and not many labs are actually offering it anymore. Hence, usually it’s just the hemoglobin and the hematocrit levels which are which are assayed regularly. The EPO concentration can be tested to distinguish between these primary and secondary causes of erythrocytosis: the primary causes have low EPO, secondary causes have either normal or high EPO levels.

Next would be a JAK2 somatic test, to initially look for the JAK2 V617F mutation, and then there are some other mutations within the same region of the JAK2 gene which also cause somatic polycythemia vera that could be tested for to rule those out. Then a bone marrow biopsy could be done, but that’s quite an invasive procedure for a patient. However, it would allow testing for the changes in other blood cell lines that are seen with polycythemia vera, such as increased white cells and plasma cells.

Finally, if you’ve excluded all the common environmental causes as much as you can do (given that they’re highly complex and many), you’ve excluded your potential malignancies and you’ve excluded your somatic causes with JAK2 gene mutations, you then go on to do the test that we do in my lab, which is the congenital erythrocytosis gene panel. This gene panel includes ten of the genes that are known to be associated with these congenital causes and the genes are, as I was describing before, covering those primary and secondary causes. These ten genes are: BPGM, EGLN1, EPAS1, EPO, EPOR, HBA1, HBA2, HBB, SLC30A10, and VHL. We use a next-generation sequencing approach where we target just genes that know are associated with congenital erythrocytosis. The data then goes through bioinformatics analysis and then we, as clinical scientists, would look at the genetic variations that have been identified in that test and then make an assessment around the pathogenicity of those variants. So we need to collect all of the evidence that is available for those variants that have been found and then we apply a Bayesian statistical framework on all of those pieces of evidence that we’ve managed to gather about a particular variant to determine whether it is either pathogenic (so causative of the patient’s presenting phenotype) or benign (which is not causative of the patient’s presenting phenotype). To put this into context, the vast majority of genetic variants that are found in people’s genomes are not pathogenic, they’re just genetic variation, which leads to the different characteristics that we all have as human beings. Then we write a report with those results and that goes back to the clinician.

What are the limitations of the current diagnosis pathway?

In terms of the congenital erythrocytosis diagnostic pathway, a lot of work needs to be done, and this is what we’re planning to do as a follow-on to the work that we have just presented at the European Hematology Association 2026 Congress EHA, which is to look at the correlation between clinical phenotype of the patients. Currently, when a patient is referred to us for genetic testing within the NHS England funded Genomic Medicine Service (https://www.england.nhs.uk/genomics/), the patients have to fulfil certain eligibility criteria before they can have a funded test. Unfortunately, the adherence with the eligibility criteria for these tests have been historically fairly poor. For example, we sometimes receive referrals with very scant clinical information, which makes it very difficult for us to determine if the patient has met those eligibility criteria. In the current financial climate, ensuring that the eligibility criteria are met is becoming much more tightly controlled, so that’s one area that could be improved.

The other thing is the very complex interplay between genetic variation and environmental factors. One of the hallmarks of a congenital erythrocytosis is often a family history of the same condition; quite often, though, we don’t find a mutation – a pathogenic variant – in those families. Now, you could take that to mean there are ‘missing’ heritable factors that we are not yet aware of. So again, that needs some further investigation into the rest of the genetic variation in the rest of the genome. However, it could mean that there’s just been a shared environment between family members. So pulling those things apart is very difficult but it’s something that we at least need to start to do to be able to try to understand this complex interplay.

The other thing just to touch on is that when we find a genetic variation, it’s not always easy to tell whether it’s going to be pathogenic or whether it’s benign. We get what we call ‘variants of uncertain clinical significance’. It could be that we’ve got no evidence whatsoever about a particular variant or it might be a rare variant in a gene which is implicated in the condition, but that doesn’t necessarily mean that it’s causing that phenotype – it might just be a very rare benign variant. So determining whether those variants are actually causative is again an area that needs some work. And having functional systems that we can use to plug a variant in and say, does this actually affect either the oxygen-sensing pathway or the EPO receptor or whatever part of the system that that we’re looking at, it would be hugely beneficial. Again, that needs lots of research – and therefore lots of funding that currently just isn’t available.

The PIEZO1 gene is very interesting. It’s a gene that we actually test on a different panel for a completely different disease subtype. In the dominant form, PIEZO1 mutations cause a red blood cell membranopathy – a hemolytic anemia. The recessive form causes lymphedema. So if you have one mutation, you get this red blood cell phenotype, but if you have the recessive form, 2 mutations, you get this lymphedema phenotype. However, some evidence has been presented in the literature that suggests that there might be an association with PIEZO1 mutations and erythrocytosis. So far this does not involve huge numbers of papers or patients, so it’s not a robust link at the moment. However, because of the size of the cohort of patients that we’ve tested, we’ve been able to go back and see whether or not the PIEZO1 mutations are enriched in our cohort. And we’ve actually found several patients who do have genetic variations that might be linked to their erythrocytosis. Again, we need to do more work on the mechanism of how that’s actually happening.

Another thing that’s been published fairly recently was a potential link between carrier status for hemochromatosis and erythrocytosis. Type 1 hemochromatosis is very common genetic disorder caused by mutations in the HFE (high Fe) gene, which result in iron overload. There’s a high carrier frequency of the HFE gene in the Northern European general population and some centres had reported an enrichment of HFE carrier status in their patients with erythrocytosis. We have had a look at our patients and haven’t found any enrichment. Currently this looks like just background levels within our cohort, although we do need to refine the data slightly according to family origin of the patient cohorts as the HFE frequency varies very highly in the different areas of the world. So although some more work needs to be done, it doesn’t jump out as an association in our cohort.

How can diagnosis be improved?

The main thing to improve diagnosis is, as mentioned above, very strict adherence to the eligibility criteria for genetic testing so that we can ensure that the resources are being directed to the patients most likely to benefit.

One approach that we would like to try to develop – moving on from our initial study of the different mutation types that we found – is to look more deeply into the phenotypic information of the patient and compare that to the pathogenic variants and to see if we can come up with a phenotypic score that would indicate the likelihood of having pathogenic variations for congenital erythrocytosis and so direct screening to patients with the risk of the disease. This has been done in other genetic, inherited diseases to really streamline the testing and target that testing to the most appropriate patients as genetic testing is still pretty expensive relatively compared to other pathology tests. However, for inherited diseases it is usually a once-in-a-lifetime test, because a person’s germline genome doesn’t change throughout life, unlike the somatic genome. I think the other area to address for potential improvements to the current pathway is better access to gene agnostic approaches of genetic testing. Currently, our genetic testing is targeted at genes that are known to be involved in causing the disease. However, what we don’t see are the genes that are not yet associated with the condition. So even though we might think we know all of the different players in this very complex pathway, there will undoubtedly be more. If we could collect together a cohort of patients with a strong phenotype, potential strong family history, and then look in a whole exome or a whole genome level to ask: Are there any genes in here which we’re finding enriched for variants within these patients? This would be a powerful approach to find out if there are any other genes involved that we’re not currently testing. This approach would also ultimately open the door to personalized treatment, which is a goal for a lot of areas of medicine is to specifically target that region. There is a lot of exciting progress happening in the area of genome editing, for example for sickle cell anemia and thalassemia and ultimately this could be a goal for treating congenital erythrocytosis also.

The interviewee

Dr Frances Smith FRCPath, DClinSci,
Head of Laboratory and Consultant
Clinical Scientist

Synnovis Molecular Pathology Laboratory, King’s College Hospital, London, UK

Email address: frances.smith@synnovis.co.uk

Bibliography
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