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Author: Adam Md Kamal
Editor: Dr. Suneet Sood
Narrator(s): Adam Md Kamal

Transcript

Imagine this:  you are a houseman in your obstetrics and gynecology posting currently seeing a couple complaining of fertility problems. You ask them fairly standard questions about their family history and discover that the 32-y/o wife, Cynthia, has had 3 children from a previous marriage, and the husband, 38 y/o Jake, does not have any children from his first marriage.  After more extensive questioning, you find no obvious causes from the couple: neither of them smokes, drinks excessively nor has abnormal BMI. They don’t have any medical illnesses of note and are fairly active physically, except that Jake complains of chronic coughing and having a flu very often.

And being the outstanding houseman you know yourself to be, you proceed to physical examination of the wife. The results are fairly standard: she’s a healthy 32 y/o woman with a Pfannenstiel scar, further dissuading you from suspicions towards her fertility.

Then you examine the husband. As with Cynthia, you don’t expect any problems. All is fine until you start feeling for his apex beat: it isn’t there. Not that it’s displaced anywhere, you can’t palpate for an apex beat, nor any beats for that matter on his left chest.  So you try auscultating, the left chest is strangely quiet. As you proceed to auscultating the right chest, you hear it: the unmistakable, distinct thumping of a beating heart, Jake’s heart, but it’s on the right side? You palpate the right chest for his elusive apex beat and there it is, 5^th intercostal space, midclavicular line, on the right. “This could only mean one thing.” you say to yourself, trembling as you remove the stethoscope. “What’s that, doctor?” Jake asks you as you realize you were thinking aloud. You reply, “Situs inversus”.

But let’s take a step back for just a minute and recap.

A couple comes in to discuss fertility issues and you rightly suspect that issues may lie with the husband since the wife has 3 kids but he doesn’t. Jake also complains of frequent infections and chronic coughing and on examination you find the not-so-common situs inversus. The question is: could they all be related to each other and to the fertility problems? You ponder for a minute and relay your question to your O&G consultant who’s looking quite relaxed in the pantry and who you know is fond of teaching.

After a lengthy talk with him, a look of confidence flashes on his face. “Aha!”, he exclaims, “you, my friend, may have found a man with Kartagener’s Syndrome”. “Kartagener’s Syndrome?, ehm…what’s that, doctor?” you ask, puzzled. “Well, here’s the thing young man”, he says,  with proud tone liken to that of a professor “Kartegener’s Syndrome, apart from being one of the more difficult conditions to pronounce correctly, is also one of the rarer conditions. Frankly, I quite like its other name which is a bit easier to pronounce`: primary ciliary dyskinesia” (1)., “So something is wrong with the cilia”. (1) you say.

“Correct! So can you connect the dots now?” he asks. You take your time thinking about it and reply, carefully choosing your words. “So he has problems with his cilia and that affects his respiratory system’s ability to clean itself. Hmmm….I can see how that causes the frequent URTIs and chronic coughing (1)…but what about the infertility and situs inversus?”.

“Well, fairly good try but not accurate enough, young man” he says. “All this man’s problems are related to a single enzyme, an enzyme called dynein (1). So dynein is found in within all the cilia in a person’s body and is a type of ATPase*(1). Hopefully, you will remember that an ATPase breaks down ATP for energy. In normal people, dynein generates this energy to allow for proper ciliary movement, specifically bending. However, in Kartagener’s this enzyme is defective. So the person’s cilia can’t convert this energy to proper bending movements of the cilia. So, yes, you correctly mention why his respiratory to tract fails to perform mucociliary clearance well, it could even lead to bronchiectasis in severe cases (1).

But cilia in other places are also affected. In the reproductive system, cilia in the sperm and cilia in the fallopian tubes causes infertility for both men and women respectively (2).”

“And even before birth, during embryogenesis, there are crucial roles played by the cilia. In a normal person, the cilia in the primitive knot at the anterior end of the primitive streak in the embryo can beat regularly. This sweeps the organs into their normal orientation (3)(4). However, in people with Kartagener’s the cilia cannot beat and can only rotate clockwise. So the organs aren’t able to move into their correct position because of the defective cilia, leading to a mirror image of normal organ orientation, in other words, situs inversus” (2).

And with that brilliant answer, everything suddenly makes sense to you now. “So all this patient’s problems are caused by a defect in a single enzyme in the cilia! That’s amazing!” you exclaim with much enthusiasm. “Well, yes it is quite amazing for a young houseman like you. Kartagener’s is a rare occurrence so you’re quite lucky to have the opportunity to come across and manage one. But your patient would probably not consider himself quite so lucky, you see” the consultant replies.

Your enthusiasm now becomes concern, and empathetically you ask, “So how can we help this man?”. “Well first thing’s first” he replies, “we must confirm the diagnosis. We can do a screening test measuring nasal nitric oxide levels.(5) We could further do light microscopy to look at the ciliary beat patterns but that might be a bit expensive. Either way, we have to manage him symptomatically. We can refer the husband and wife for assisted reproductive therapies (ARTs) to help them with fertility (6). Artificial insemination might be useful for them (6). Also, you need to tell them that since the condition is autosomal recessive there’s a good chance their children may be carriers as well, and that the man may have inherited it from his parents who were also carriers” (1).

“Can you remember all that?” your consultants barks, breaking you out of your stuporous posture. “Ehmm yes…..kind of. So Kartegener’s Syndrome aka primary ciliary dyskinesia, is an autosomal recessive medical condition that arises from defective dynein, an ATPase found in cilia. Because of this the cilia are defective, leading to classical symptoms of chronic respiratory tract infections, lung problems like bronchiectasis, situs inversus and infertility.

“Very good!”, the consultant replies, with an empathetic expression. He stares into space for a moment. Then suddenly his expression changes “Well, that’s enough lecturing for me today, off you go! I’ve got a Caesar to do in an hour.”

REFERENCES

• “Primary Ciliary Dyskinesia: Background, Pathophysiology, Epidemiology,” November 8, 2019. https://emedicine.medscape.com/article/1002319-overview.
• Stern, Brittany M., and Girish Sharma. “Ciliary Dysfunction (Kartagener Syndrome, Primary Ciliary Dyskinesia).” In StatPearls. Treasure Island (FL): StatPearls Publishing, 2020. http://www.ncbi.nlm.nih.gov/books/NBK448201/.
• Cartwright, Julyan H. E., Oreste Piro, and Idan Tuval. “Fluid-Dynamical Basis of the Embryonic Development of Left-Right Asymmetry in Vertebrates.” Proceedings of the National Academy of Sciences of the United States of America 101, no. 19 (May 11, 2004): 7234–39. https://doi.org/10.1073/pnas.0402001101.
• Nonaka, Shigenori, Satoko Yoshiba, Daisuke Watanabe, Shingo Ikeuchi, Tomonobu Goto, Wallace F Marshall, and Hiroshi Hamada. “De Novo Formation of Left–Right Asymmetry by Posterior Tilt of Nodal Cilia.” PLoS Biology 3, no. 8 (August 2005). https://doi.org/10.1371/journal.pbio.0030268.
• “Nitric Oxide in Primary Ciliary Dyskinesia | European Respiratory Society.” Accessed January 30, 2020. https://erj.ersjournals.com/content/40/4/1024.
• Sha, Yan-Wei, Lu Ding, and Ping Li. “Management of Primary Ciliary Dyskinesia/Kartagener’s Syndrome in Infertile Male Patients and Current Progress in Defining the Underlying Genetic Mechanism.” Asian Journal of Andrology 16, no. 1 (2014): 101–6. https://doi.org/10.4103/1008-682X.122192.