PCD Terminology

History

PCD is actually an umbrella term for genetic defects of the structure and function of motile cilia. There are now 37 known genes associated with PCD and disorders of motile cilia. This means that genetic mutations on any of these genes can potentially result in PCD (look for a post on PCD genetics soon). In comparison, cystic fibrosis is caused by mutations on a single gene called CFTR. On that one gene, there are close to 2,000 individual mutations that cause CF. Some result in more severe disease, some in less severe. And this is on only one gene. We have 37 genes and an unknown number of mutations per gene that can lead to PCD.

A syndrome is a set of symptoms seen in a recurring pattern. This pattern may be recognized prior to understanding why it occurs–the underlying reason for the symptom pattern. Often, once the actual cause is understood, the symptom name will change to reflect that. An example is Down syndrome, named for Dr. John Down, who described this syndrome back in the 1860s. When it was discovered that the symptom pattern seen in Down syndrome was caused by an extra copy of chromosome 21, the name was changed to ‘trisomy 21’ to reflect this. Both terms are still used, but the preference for accuracy is trisomy 21. Naming disorders after the physician (called ‘eponymous’ naming) who described them is problematic for a number of reasons and is no longer encouraged. However, many of these disease names from eons ago are still firmly entrenched and likely will remain so. This is one explanation for the continued use of ‘Kartagener syndrome’ to describe a subset of PCD.

In the 1930s, before the genetic nature of PCD was understood, a syndrome consisting of nasal symptoms, situs inversus totalis and bronchiectasis was described by Dr. Manes Kartagener, a Swiss pediatrician. He published his findings, which came to be known as the ‘Kartagener triad,’ or ‘Kartagener syndrome. Because he was seeing children, problems with infertility in this population were not known to him. What Dr. Kartagener did, which was common in his day, was bring attention through publication in medical journals to an observation he made that these three symptoms appear to occur together in a pattern that suggested a single underlying disorder was responsible.

In the 1970’s, a Swedish electron microscopist named Bjorn Afzelius was analyzing sperm of infertile men and notice that a subset of them also had bronchiectasis and sinus issues and that about 50% of this subset also had situs inversus–the so-called Kartagener syndrome. He was intrigued that only about half of these patients, actually had the hallmark symptom of Kartager triad–situs inversus–though.

These patients looked identical in all respects, except the situs issue. Because he had noted distinct changes in the internal ultrastructure of the cilia of these patients, he theorized (and turned out to be correct) that all their symptoms–infertility, respiratory disease and situs inversus–were caused by a single factor–underlying ciliary defects–and that situs inversus was, in fact, just a random manifestation of this dysfunction (correct again). Because microscopes of that time were not particularly sensitive, ciliated samples from these patients appeared to be completely immotile, so he called this ‘immotile cilia syndrome,’ a name that stuck for decades. This was progress and we were getting closer to the underlying cause, but it was still a syndromic diagnosis based on observation.

Fast forward to the mid-1980s. Scientists have been able to take the findings of Dr.’s Kartagener and Afzelius and, with improving technology, take a closer look at ciliary function in these patients (not genetics yet, though–while they knew this was most likely a genetic disorder by that point, the first gene was not discovered until the late 90s). Rather than truly immotile cilia, what they discovered is a wide variety of ineffective or aberrant ciliary motility ranging from complete immotility (not common, btw) to stiff, disorganized or otherwise faulty movement or beat patterns. In 1983, (33 years ago) a paper recommended retiring other terms for this disorder and calling these changes collectively ‘primary ciliary dyskinesia,’ the term still in use today. It is useful to point out that the change to PCD is now over three decades old and is consistent around the globe. Use of the older term ‘immotile cilia syndrome’ may indicate lack of familiarity with the major advances that have occurred in PCD recently.

When certain genetic defects of motile cilia are present, organ placement becomes a random event. This means if you have PCD, there are three possible ways your organs can present–completely normal left-right patterning (situs solitus), completely reversed in a mirror-image fashion (situs inversus totalis or ‘situs inversus’) or something in-between (situs ambiguus or heterotaxy). This is because organ placement is partially determined by the activity of special motile cilia during embryonic development. When these cilia don’t move, the process that tells the body how to differentiate right from left can be disrupted. This happens randomly with each pregnancy. In the same family, it is possible to have one child with normal situs, one with situs inversus and one with heterotaxy–all with the same genetic defect that causes PCD.

This is one reason that terms like Kartagener syndrome, which admittedly is useful shorthand for PCD with situs inversus, can actually cause confusion. In fact, all it describes is one of three possible organ placement issues seen in PCD. Technically, the Kartagener triad, as described by Dr. Kartagener, includes bronchiectasis, sinus symptoms and SITUS INVERSUS TOTALIS. It does not include PCD with either normal organ placement or situs ambiguus (‘ambiguous’ aka ‘heterotaxy’), even though it is often misused this way. Singling out and giving a different name to one of the three possible random organ placements seen in PCD gives the erroneous impression it is a separate disorder. It is not. It is simply PCD with situs inversus vs. PCD with normal situs or PCD with situs ambiguus.

It is also important to note that the specific motility of cilia and situs arrangement are not–as far as we know now–indicators of worse disease. The exception is heterotaxy with complex organ issues like cardiac defects. These PCDr’s may be sicker as the result of their other organ issues. So having completely ‘immotile’ cilia does not mean you will be sicker. There are, in fact, some PCD mutations that result in hyperactive cilia (DNAH11) and these patients have exactly the same symptoms as people with PCD mutations that cause complete immotility. From this standpoint, specifying ‘immotile’ really is not helpful in describing the disease.

So while older terminology may still be in wide use, it actually can affect understanding of PCD (most PCD cilia are not actually ‘immotile’ and Kartagener syndrome is not separate from PCD, for instance) and makes raising awareness challenging for us, as well.

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