Fine tuning medical diagnoses to rare genetic disorders

9 March 2013 by

298x232-dna_genetic_test-298x232_dna_genetic_testMeiklejohn v St George’s Healthcare Trust [2013] EWHC 469 (QB) – read judgment

Richard Booth of 1 Crown Office Row acted for the claimant in this case. He is not the author of this post.

There is no doubt that medical diagnosis and therapy are struggling to keep pace with the genetic information pouring out of the laboratories and sequencing centres. And the issue of medical liability is being stretched on the rack between conventional treatment and the potential for personalised therapy. Treatment of disease often turns out to be different, depending on which gene mutation has triggered the disorder. However fine tuned the diagnosis, it may turn out to be profoundly wrong in the light of  subsequent discoveries.

This is perhaps an oversimplified characterisation of what happened in this case, but it exemplifies the difficulties facing clinicians and the courts where things go wrong, against the backdrop of this fast-moving field of scientific endeavour.


The claimant had been diagnosed at the age of 21 with thrombocytopenia, macrocytic anaemia and hypocellular bone marrow. In sum, a failure of his body to make up the necessary components for blood cells.  At the time (1993), a “wait and see” approach was adopted. However  by 2003 new learning about the genetic basis of this aplastic anaemia (“AA”) had arrived, and the claimant argued that he was the victim of clinical negligence in the diagnosis and treatment at the time.

AA is a rare, potentially life-threatening failure of the body’s ability to manufacture blood cellular components. It is generally understood to be an acquired disease. (ie developing post-foetally) and environmental factors are sometimes the cause of this condition. This case was concerned with a form  of AA known as Dyskeratosis Congenita (“DC”) which is caused by mutations in the “TERC”  gene. TERC encodes the RNA component of telomerase, the enzyme responsible for the production of telomeres, or stretches of DNA that “cap” the ends of our chromosomes and prevents them from shortening too fast as cells replicate. Telomere shortening is the root of the ageing process. One of the telling symptoms of the syndrome is premature greying of the hair.

DC is a germline mutation, in other words a mutation in the cells given to offspring, which means the mistake in DNA sequencing is present in virtually every cell of the body. The confusing thing is not all of these passed on germ-line mutations are inherited, as such. Sometimes the mutation, in the sex chromosome from the mother or father,  only develops after fertilisation of the gamete sperm and egg cells. This so-called “constitutional” mutation can occur very soon after fertilisation, and therefore may not be present in the parent. As it happened, tests performed upon the claimant’s parents were negative, leading to the conclusion that the claimant’s  mutation had arisen de novo.  The treatment for “constitutional” DC is now known to be different from that appropriate for acquired AA.

At the time the claimant was diagnosed, the treatment for acquired AA was the steroid Anti Lymphocyte Globulin, which brought with it the rare side effect of avascular necrosis . The claimant developed the symptom after commencing treatment and  had to have bilateral hip replacements. Thereafter the claimant was switched to an alternative treatment for AA, via the synthetic hormone Oxymetholone.

The crux of the claimant’s case was that the defendant’s consultant had performed an inadequate examination of him in 2005,  that she should have spotted that he had constitutional DC and that he should not therefore have been treated with ALG, which is more appropriate for acquired AA.

HHJ Robinson (sitting as a High Court judge) dismissed the claim.

Reasons behind the judgment

The claimant’s expert considered that the diagnosis should have raised a suspicion of DC, or at least that it should not have been excluded.

 That being so, there should, in her opinion, have been what she described as a “nuanced” discussion concerning treatment options. The basic premise appears to be that both ALG and Oxymetholone would be considered as treatment options since both AA and DC were potential diagnoses.

But this, observed the judge, was a view taken with the benefit of hindsight. At the time of this litigation, it was known that the claimant had constitutional DC. Naturally, in retrospect it could be seen that some features exhibited by the claimant were consistent with that diagnosis. But that was not the question to be asked. What the court had to consider was, what conclusions should have been drawn by a clinician who did not have the luxury of knowing that the claimant had DC? Even by reference to guidelines on the diagnosis of AA published six years after the claimant’s diagnosis, he would not have been diagnosed with DC. And even if the consultant had been aware that the claimant was suffering from DC, what would she have done with that information?  Was treatment with Oxymetholone beyond question in these circumstances?

The evidence before the court on this issue demonstrates just how fast this target is moving.  In 2003 – at the time of the diagnosis at the centre of this litigation – there was no truly recognised treatment for DC arising out of a mutation of the TERC gene. All that was known then was that one form of DC, caused by another gene mutation affecting telemorase, responded to Oxymetholone. This of itself did not mean that DC caused by the TERC mutation would similarly respond. It was not until 2006 that there was a “feeling” that TERC mutation patients might be better off being treated by Oxymetholone rather than ALG.

HHJ Robinson therefore found that it had not been negligent for the consultant to recommend ALG, which is the standard treatment for AA. Moreover, it had not been negligent to commence treatment more or less immediately. The claimant’s complaint that he had not been warned about the possible complication of vascular necrosis as a side effect of this steroid was dismissed.:

it does not seem to me that the decision at the material time not to warn about the development of an extremely rare side effect which had hitherto never manifested itself in patients given the low dose administered at St George’s Hospital can be said to be logically indefensible.

And even if the risk had been disclosed, the judge had no doubt that the claimant would have accepted the advice to undergo  the ALG treatment, not least because he would have been told that there had hitherto been no case of anyone treated with the low dose regimen at St George’s ever going on to develop the vascular complications he suffered.

There were two side issues concerning the taking of the sample of the claimant’s blood which was sent off for research purposes. The first was that of informed consent, which the claimant said he didn’t give. The second was the purpose for which the sample was taken. The process involved no additional invasive procedure since blood was drawn (by consent) for various tests in any event.

The judge found that in the circumstances, there had been no requirement for written consent, and there was sufficient evidence that the claimant had given sufficient verbal consent for the testing of his blood for research purposes.

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1 comment;

  1. Janet Bloor says:

    As a Mother of a son with a rare Muscular wasting disease, Duchenne’s Muscular Dystrophy I can sympathise entirely with this case. When my son was diagnosed at 9 – that in itself a mistake – not picked up at birth – we were told no hope no cure dead by 20. He is now 19 in a wheelchair but relatively strong. Science has moved on a pace to genetic fixing of the dystrophin gene and up regulation of utrophin a similar gene to stem cell repair. There is never an excuse for complacency and settling for only what’s available at the time. You have to future proof and put the patient in the best position to take advantage of new treatments and cures while doing no harm.

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