Your Ears Are Small So No Diagnostics For You...

Summary: There seems to be a broad consensus that you can’t identify or screen for Fragile X (a leading cause of intellectual disability) on the basis of physical features without a reasonably high false negative rate. However many clinicians will not perform fragile X testing on intellectually disabled children in the absence of facial features indicating fragile X. This is despite these tests being cheap and accurate and non-invasive.

In this short series of posts about conversations with clinicians. I’m going to continue to look at why some doctors don’t seem to be particularly fond of diagnostic tests.

Here’s another fragment of a conversion I had with a Neurologist at Chiba University Hospital:

Me: Fragile X is not tested for in Japan, but it is common in other countries. please explain.

Doctor: Well, if the ear has a major abnormality, you can do it.

To give some background. My son has profound intellectual disability¹. Here in Japan he wasn’t offered Fragile X testing. Elsewhere this is a standard test, as the American Society of Pediatrics write “Fragile X genetic testing should be performed in all.” (cases of intellectual disability).

Fragile X often results in other symptoms along side intellectual disability such as a “long and narrow face and large ears”. Which is perhaps why this doctor is suggesting testing only when the child has abnormal ears.

Why then is the American Society of Pediatrics in favor of testing in all cases?

Informally the American Society of Pediatrics writes about this on their blog citing one case in particular:

“His parents came into my clinic when Brian’s developmental pediatrician referred him for a genetic evaluation. Part of the genetic work-up we did was a Fragile X DNA test. When those results came back positive, his parents were surprised to hear that Brian had Fragile X syndrome.  They thought that he was just a little slow with his language and that he might be autistic. They didn’t think he looked different enough to have a syndrome.

Not all children with Fragile X have distinctive features, which is why it’s important to test.”

Let’s try and put some numbers around this. One study showed that <50% of individuals have any one facial feature associated with fragile X:

Another study showed better results, in this case 72.2% of boys showed increased ear length, 83.3% an elongated face:

In both cases it’s relatively clear that if you look at physical features alone there will be a high false negative rate. Results from the Netherlands suggest that >50% of fragile X cases are undiagnosed². These and other results have led many to consider facial features unreliable in diagnosis:

“Physical features involving the craniofacies (long face, prominent forehead, large ears, and prominent jaw) not readily recognizable in the preschool-age child become more obvious with age. Only a subset of affected individuals have typical physical features of FXS and presence of these is not reliable for diagnosis.”

And is perhaps best summed but by these authors: “Despite many attempts to classify the facial features in fragile-X subjects, conflicting opinions remain on the nature of the anomalies and their degree of severity.”.

So Why Don’t They Test?

I don’t know. So I can only speculate. I assume if you pre-screen based on physical features a much higher percentage of tests come back positive. The literature appears to back this up³.

If you don’t pre-screen a much lower fraction of tests are going to come back positive. This is expected. The statistics just work this way and you’re either going to pay with a false negative rate or by running a large number of additional tests. The tests being accurate, low cost and relatively non-invasive, many would consider it worth while to test in the case of intellectual disability.

I suspect, as previously mentioned, many clinicians don’t like running tests which have a high probability of a negative result. And in any case don’t see an accurate diagnosis as valuable if there are no clear therapeutic opportunities⁴.

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1. While I’m still waiting on a diagnosis under the DSM5 he’s been diagnosed as intellectual disability with autism at the highest level of disability under the Japanese classification system.

2. Though it should be mentioned that in these research hands physical examination appeared to be highly sensitive. At least part of the issue may be that physical examinations lack the uniformity of other diagnostic approaches.

3. I believe I’ve seen this explicitly stated somewhere, but the numbers in the tables above also indicate that this would be true.

4. Which again I disagree with as there are clear benefits to an accurate diagnosis in terms of family planning, siblings understanding disease course etc. etc.