RB genetics ... What would happen in Ethiopia?

Retinoblastoma is a complicated business. It’s not uncommon for us to ask a question of a doctor, only to be told, "Ah, that's a question for Dr X."

The team that manages Asa’s treatment includes ophthalmologists, oncologists, and geneticists – each of whom contributes a piece of the puzzle.

As it turns out, some of our questions about the causes of Rb and its long-term implications are questions for geneticists.

Genetics is relevant here because, given that both Asa's eyes are affected, there's a very high likelihood that it’s due to a mutation in a gene known as RB1. 

Dr Rosser, a geneticist at Great Ormond Street Hospital, helped us understand how this mutation might have arisen, and what its implications are.

Since neither Selam nor I have relatives with Rb, the most likely way Asa got the mutation is through a random change in the sperm or egg that made him.

As Dr Rosser explained: "Every time a cell divides, 40,000 genes get copied.”

“All of us have 20-50 mistakes in every gene, but most don’t matter.

“His matters."

It’s kind of a relief to know that genetic mutations are common – that we all have them.  And that they’re not always bad news.

But obviously some are more important than others.

How does Asa’s matter? 

How (not) to build a retina

One of the major jobs genes do is to give instructions on how to build a body.  Genes have relatively specialised tasks, and the job of the RB gene is to issue the command, "Stop growing, retina." When there's a mutation in this gene, the "stop" command doesn’t register, and cells keep dividing in the retina area, more than are needed. (Retinoblastoma literally means growth on the retina – blastos being Greek for bud or growth.)

Eye anatomy, showing the retina (from visionandeyecare.wordpress.com)

Since the retina does most of its developing by age 5 – and most of that during the first two and a half years – Asa will be at greatest risk from Rb during the first 5 years of his life.  After that, according to Dr Rosser, he will have about a 6% chance of other tumours, e.g. in bones, muscle or skin, with the risk peaking in his teens or early 20s, and declining thereafter.

There are two other corollaries of RB mutation: it may be accompanied by other mutations, and it can be passed on to children.

 

Sometimes when the RB gene isn’t working, it’s the first sign that there are other abnormalities: neighbouring genes could also be faulty, and these could lead to other problems in development.  We will have to keep an eye out for developmental oddities in Asa.  The fact that he’s developing normally so far (he started walking independently this week!) bodes well.

There’s a 50:50 chance that Asa’s children might inherit the RB mutation.  Knowing this, however, means that any child he might have could receive prompt evaluation and, if necessary, treatment to nip tumours in the bud.

How common is Rb?

For some reason, the copying mistake that leads to the RB mutation happens at a fairly predictable rate across human populations.  The figure that's often cited is 1 in 20,000 (50 in a million). 

The universality of this phenomenon can be difficult to believe, because almost everything you see on the internet (and we’ve spent some months searching) is related to Rb in Europe and North America.

In Europe, we learned recently, there’s some variation, with slightly higher incidence rates in the north than the south (MacCarthy et al. 2006).

But if it occurs at roughly the same rate all over the world, how come we don’t hear more about Rb in Asia, Africa, and South America?  

Some possible answers are that high child mortality from infectious diseases in the developing world makes cancer a marginal concern; there are a lot more resources available for cancer treatment in the West; and the internet is Eurocentric.

Still, we wonder.  Are there really thousands of children born with Rb in the developing world?  What happens to them?

What would Asa’s chances of survival have been if he was in Ethiopia?

Rb worldwide

This month, a review was published in the Lancet by a team of physicians in Canada and Kenya (Dimaras et al. 2012).

Their review doesn’t confirm the 1 in 20,000 incidence rate, but it does show that there’s a lot of Rb in other parts of the world.

In Kenya (one of the few countries in Africa where there is a dedicated treatment centre for Rb) more than 70% of children with Rb die from it. The mortality rate from Rb is surely higher in places where there are no treatment centres.

What happens when Rb goes untreated is quite horrific.  The Lancet article includes a photograph of a child with a very large tumour that has burst out of the eye socket.

Ethiopia is one of the places that lacks a treatment centre.  While we don’t know how many children in Ethiopia have Rb, the ophthalmologist in Addis Ababa who first diagnosed Asa, had referred patients to Kenya. 

And as the second most populous country in Africa, Ethiopia usually comes close to the top of the list when cases of disease are tallied up.

So given what we know about the genetic basis of Rb, and its regular incidence rate, it seems likely that there are scores of children being born with Rb in Ethiopia, most of whom will die of it.

Selam and I would like to help families there whose children have Rb get treatment. Next week I’m going to Ethiopia, and I’ll try to find out more about how we might do this. 

Sources:

A recent article documents the commonness of genetic mutations, and suggests that most do not have any major consequences for health (MacArthur et al. 2012, Science 335, 6070:823-8; news item here). 

 

Incidence of retinoblastoma higher in northern than southern Europe (MacCarthy et al.2006, European Journal of Cancer 42, 13: 2092–2102)

Lancet review of retinoblastoma (Dimaras et al. 2012, Lancet 2012, doi:10.1016/S0140-6736(11)61137-9)

Thanks to Charlotte Kvasnovsky for letting us know about the Lancet review.

"What's the prognosis?"

The examination under anaesthetic last week revealed that the tumours in Asa’s eyes have halved in size in the left eye and more than halved in the right eye since he began chemo.

Retina scans showing tumours before and after the first two cycles of systemic chemotherapy.

The retcam images show how the tumours have shrunk, and also changes in texture from diffuse blobs to gnarly, calcified masses.

 

This is encouraging, but there’s still a lot of cause for concern.

For one thing, systemic chemo has its greatest effects in the first cycles.  So unfortunately we can’t expect this rate of shrinkage to continue through the remaining 4 cycles of chemo. As the ophthalmologist told us, the remaining chemotherapy is to prevent relapse.

The other cause for concern is seeding. 

In the images, the constellations of little spots around the tumours are “seeds”: tumours-in-the-making that, if they’re not attacked, will grow bigger.  These are a worry because (a) they’re so many of them and (b) they’re not well supplied by blood vessels, the way the big tumours were, so they won’t respond as well to systemic chemo, which relies on the circulatory system to deliver the drugs.

The seeds can be attacked in a variety of ways, including laser and cyrotherapy.

But there’s a delicate balance to be struck between the benefits these treatments can bring in terms of destroying the seeds, and the collateral damage they can cause in the process.  Aggressive use of laser, for instance, might inactivate the seeds, but could also further detach the retina, which would cause problems of its own.

This is part of the reason why, after this first course of chemotherapy ends, Asa’s going to need to be examined under anaesthetic every month or 2 months for the next few years.  The doctors will be trying to keep these seeds under control, using an appropriate level of focused therapy.

Where we are now

The day after the examination under anaesthetic, Asa received his third dose of chemo.  

Now we have three down; three more to go.

Asa and parents at the new Royal London Hospital, in Whitechapel

Last week Asa's blood counts -- specifically, his neutrophil count -- didn't return to normal in time for him to undergo his eye exam and begin the 3rd round of chemo. Our medical appointments were pushed back a week, and in the meantime we've enjoyed a lull, waiting things out, and hoping the neutrophils are climbing, but also getting more time and space to reflect on life than we've had for the last couple of months.

The first time Asa’s neutrophils fell below 1.0, during the first cycle of chemo, we were thrown into a panic, and half expected him to break out in spots or immediately develop a fever.  Since then we’ve learned that the danger is manageable.

Neutrophils are one component of white blood cells, which indicate your body's ability to withstand infections.  The chemo drugs Asa is taking inhibit his ability to produce white blood cells, and consequently his immune system is seriously depressed for a while after each dose.  During the first cycle they plunged after 9 days, and then returned to normal by day 20 or so. This time they fell more rapidly and stayed down for longer. 

The implications for our day to day life aren't all that great: We've been taking precautions to protect him from infections, and we don't get out much: an excursion to the shops every now and then or a walk in the countryside when the weather's fine is about as adventurous as we get.

One of the precautions we take – keeping Asa (and sometimes Selam) penned in

This has become our normal routine now, so we're used to it.  And so far we've been lucky this time around -- no fevers, no scary coughs, no inflammation around the Hickman line.…

The downside of up

At first, the absence of crisis was a bit difficult to deal with.  When you've been putting out fires for weeks on end, it feels weird not to have an emergency on your hands.  And the first week or so after Asa's appetite returned, when he seemed to be pulling back and was acting (as he still is now) pretty much like any other toddler, saw us struggling much more than we'd expected, with worries bubbling up.  Your mind goes strange places under these circumstances -- you start wondering how long all this treatment is going to last.  How you’ll get your own career back on track.  How nice it would be to return to Ethiopia.  And what it would be like if Asa were really to lose his sight….

We started searching for more information from other families who had children with Rb, and how things had worked out for them. 

This has been a sobering exercise, and the stories make difficult reading.  The first 6 months of chemo are never the end of the road, at least in the cases we've heard about.  There are long periods when children are getting regular eye exams under anaesthetic, doctors are spotting new tumours, and children are receiving focused therapies like cryo, laser, and radioactive plaque… 

And sometimes, after all this, removal of one or both eyes is necessary.

The blog that we've learned most from is Fintan Tadgh's.  Maintained by his parents James and Fiona, it tells the story of their journey from Fintan’s diagnosis in 2007, when he was 6 months old, through an EUA last week, at the age of 4.

Fintan and his family have been through a lot, and learned a lot, over the years.  Following them through this, reading a year's worth of posts each evening last week, we empathised as they took a roller coaster ride through periods when it looked like Fintan’s cancer was on the ebb, through times when it was resurgent, and through many and various treatments, all of which they suffered with great strength and dignity.

At the moment, we can’t tell how closely Asa’s story will resemble Fintan’s.  We expect we’ll get more information when we see Mr Reddy, the consultant ophthalogist at the Royal London Hospital on Wednesday.  And while we’re hoping for good news on how the chemo’s working, we know that this won’t be the final judgment, and there are likely to be more surprises ahead.

For the time being, we’ve attained a certain amount of equanimity, and the past few days have been as good as any I can remember of late. 

Asa's been developing in new and surprising ways: imitating sounds, walking more confidently each day, fussing for our attention (are we spoiling him??), and kissing us (wetly and smack on the mouth).   

And we've felt more lighthearted than we have for a long time, one sign of which is our ability to laugh at things that would have caused us to freak out just a week or two ago -- for example, me tracking dog shit into the house one day… Not a great move at the best of times, but especially not when you've got a severely immune compromised toddler in the house.