Hi, did it turn our to be NRAS-associated RALD (NRAS-associated autoimmune leukoproliferative disorder)?
Yep, but every doc knows about macrocytic ('large cell' anemia, so don't muddy the waters with that. Likewise that B12 deficiency can also cause neuropathy.
Make sure you do mention that our ALPS->B12 source is NIH (but never mention a non-authoritative site like walkinlabs).
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Speaking of NIH:
https://rarediseases.info.nih.gov/diseases/8686/autoimmune-lymphoproliferative-syndrome
"Some of the autoimmune disorders associated with ALPS can also damage the kidneys, liver, eyes, ***NERVES****, or connective tissues."
So there we have it stated about neuropathy. You can and should also show that to any doc that you visit.
That's something that you can accomplish yourself immediately (and feel less helpless): phone to get a doc of his to order the B12 test. If it comes back way above normal then that will strongly prompt everybody to pursue ALPS testing. What I cited is from the National Institute of Health, which is very much an authoritative source.
Or you can even get it yourself for ~ $30, no script needed:
https://www.walkinlab.com/catalogsearch/result/?q=b12
Has he had B12 tested? Because: "People with ALPS-FAS tend to have much higher B12 levels than do healthy people..."
https://www.niaid.nih.gov/diseases-conditions/alps-symptoms-diagnosis
Regarding neuropathy: I see nothing directly for ALPS or NRALD. But there certainly are well known autoimmune neuropathies (such as lupus) that are unrelated to ALPS/NRALD. The neuropathy comes about because the immune system attacks nerves directly.
We know that the A in ALPS and NRALD stands for autoimmune. Attacking red blood cells is a known result. So it's entirely possible that ALPS/NRALD can cause also neuropathy.
The cited paper by Oliveira on "How I treat ALPS..." says that steroids are ineffective in reducing the nodes in ALPS, because steroids don't reduce the huge numbers of runaway T-cells that are filling up the nodes. However, steroids are also used to suppress autoimmunity, which is a different matter altogether. That would be something to eventually discuss with doctors, even though there are some bad downsides to taking high dose steroids for long periods.
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As for the CD4 and CD8 numbers... I was hoping for something telling the measured number of DNT cells. Like exactly this test: http://ltd.aruplab.com/Tests/Pub/2014513 That's probably the test he needs, wherever you can find it.
Let's get back to the DNT cells for a bit. In the flow cytometry results, do you see anything that talks about CD4 or CD8?
T-cells would normally have one or the other. When a T-cell has neither, that's a DNT (Double Negative T-cell). Having lots of DNTs is a strong sign of ALPS. But having symptoms like ALPS with few or no DNTs points to NRALD instead.
You posted earlier today about "T Cell Markers are high - up to 88% positive". I don't know if they were counting CD4 and CD8 or not. (Maybe only CD3. That is the main "marker" for T-cells.)
Btw, I hope that when you finally get a diagnosis that you do post that here.
Nope, I looked and haven't seen anything about neuropathy with ALPS. But neuropathy is found in another lymphoproliferative disorder called Multicentric Castleman's Disease (MCD), though that's usually found in much older people. It's found in POEMS Syndrome, but that has skin darkening.
This gets back to what I'd said way before, that rare immune conditions can take a long time to diagnose because there is a lot of mystery to them.
It might be that your son doesn't fit an any established category. After the trial with colchecine is over and presumably has no benefit, they might want to try immune suppression with steroids, just to see if that helps with symptoms.
Some of the ALPS like conditions eventually get better by themselves, so that's something to hope for.
It's good to ask questions now while things are fresh in my mind. Otherwise, after a week or so, some things will be forgotten and I won't have time to read back.
Also, an observation: I think that the lack of splenomegaly is a very good thing because it probably means a milder case or a less advanced case. The lack probably should not rule out NRALD.
If any doc wants a BMB for any reason other than DDx'ing ALPS vs NRALD, I'd resist that because that's just sidetracking. But if later on, if ALPS and NRALD happened to be ruled out (unlikely), I'd press very much for the BMB in order to gather more clues.
That's the % of the cells that lit up (fluoresced from being tagged). What stands out is that the quantity of T-cells is high but not the B-cells. That's probably consistent with both ALPS and NRALD. The 'A' in those names is for autoimmune. T-cells can be killer cells, possibly they are destroying red blood cells which accounts for the 'debris' noted in the flow cytometry (and the anemia). (That also relates to there being no good reason to suspect that RBCs are low because of some problem in the marrow, and hence why no BMB should be done at this time.)
They can rule out cancer by testing that the T-cells are not all alike (not 'clonal'). Cancer cells would all come from one starter cell, so they are clonal. Your son's T-cells very likely are not clonal.
"Is this why his doctors are thinking it's ALPS?" Yes. The 'L' in ALPS stands for lymphoproliferative and the L in NRALD is similar, standing for leukoproliferative (lymphocytes plus all other white cells, such as were mysteriously high in his CBCs.)
"I'm going to do a ton of research to bring to the attention of his doctors!"
That is a terrific attitude on your part. Bravo. When you've been studying so much that it feels like your head might explode, you know you are doing this right :)
"Tissue Immunohistochemistry" means that in a lab they use antibodies (part of the immune system) which are engineered to attach to only particular molecules. If those molecules are not present, the antibodies just wash away. It's kind of like staining.
"Sinus Expansion" Sinus refers to an area inside a node, expansion refers to the cells having multiplied. Does that help differentiate? I dunno, that would take researching. Things are further complicated because there are always "atypical cases" of medical conditions.
For the rest, BCL2 stands out. Don't get alarmed because you will see that as being part of lymphoma - because the ped onc didn't get alarmed. BCL2 is involved in inhibiting apoptosis, which we are looking at as also being the reason for *benign* proliferation of the B-cells.
"Would the NRAS gene be included on a full genome panel when dealing with neuroblastoma? "
You're right, that's exactly the most important question. For starters, look for the workup procedure on sites like Medscape etc. My guess is that it is not a part of normal testing,
You're welcome and good luck. You can print those 2 papers that I posted and highlight the appropriate parts. They are "authoritative sources" that any doc should take seriously. Most other sources (like blogs or wikipedia) would be scoffed at.
I would call those 2 docs offices (that I'd named) and see if they are interested in receiving your son's records to aid in their research. Since this is quite rare, and your son possibly has an even rarer version, they might be interested in another "data point".
This condition is all about apoptosis (normal and benign programmed cell death) failing to occur, because the chemical signals aren't working. So the cells pile up.
Here is another important paper from Oliveira. It even discusses how your son's condition can almost mimic a T-cell lymphoma, which is what the path report wanted ruled out.
"How I treat autoimmune lymphoproliferative syndrome"
http://www.bloodjournal.org/content/118/22/5741?sso-checked=true
"The diagnostic workup for ALPS after a lymph node biopsy should include flow cytometry, immunohistochemical evaluations, or molecular studies that rule out clonal B- and T-cell population."
Rough overview:
Good, that brings things right back to my first reply to you, "His CBC seems very unusual, enough to point to something besides cancer." The unusual aspect was monocytosis and granulocytosis (the eosinophils and basophils).
But when the rheumy says "...Autoimmune Lymphoproliferative Disorder. She states, the histological findings (follicular hyperplasia), anemia, chronic lymphadenopathy not decreasing, with excessive amounts of lymphocytes may confirm the diagnosis", that doesn't mention the monocytosis etc.
Still, the type of ALPS called ALPS-FAS does have that. But the biopsy would not only have the enlarged node follicles but also enlarged paracortex -- which latter your son didn't have.
So ALPS is close but what you probably really want them to look at is NRAS-associated RALD (NRAS-associated autoimmune leukoproliferative disorder), which is similar but has a somewhat different cause and treatment.
Now listen to this: an NRAS defect is also a cause of neuroblastoma! So there's a strong genetic clue. Didn't the rheumy or the consultants know about the neuroblastoma Fx? (This is not the same gene as what you mention above.)
Fx = Family History
But NRAS-RALD usually has an enlarged spleen. So tends against, a bit.
Hopefully your rheumy can talk to Drs. João Oliveira and/or Michael Lenardo at NIH.
http://www.pnas.org/content/104/21/8953
"NRAS mutation causes a human autoimmune lymphoproliferative syndrome"
I have an idea that looks like it very well could be the Dx, and it relates to the Fx of neuroblastoma, but first: hasn't he ever had enlarged spleen?
Also, is there any Fx of melanoma?
So then, as predicted you've gotten the good news that it's not lymphoma. What remains is that it's likely to be some unusual immune condition. Those unfortunately can often take a long time to diagnose.
The rheumy can be more aggressive in looking for something rare like that since cancer is effectively ruled out.
In the meantime, you can try to be sure that there's not some environmental trigger, even a food.
I'm glad to be of help.
I hadn't heard that before about the autolysis/formalin, and I'd bet that happens rarely. Your guess that it was a foulup seems very reasonable.
I don't know if that would affect the further lab analysis of the biopsy tissue. My speculation is that it won't if it's diffuse... and that there isn't some focal area that all died where the T-cells are expected to be. the T-cells should be expected to usually be mainly in a certain area of a node. Just as the B-cells would probably mainly be in another area of a node.
I'd also want the onc, after eliminating cancer, to say what the real cause might be of all the symptoms. Or even get the onc to say so tomorrow, to set your mind at ease while waiting for any more testing to be done. You could ask for guesses.
Congratulations, that seems to rule out non-Hodgkins Lymphoma (the B-cells are normal, there are just lots of them) and also rules out Hodgkins Lymphoma (no Reed Sternberg cells found).
B-cells are the most numerous type of lymphocytes. The other, less common type, are the T-cells. The T-cells do a lot of signalling which tells other immune cells what to do, such as to proliferate.
So the report suggests that very advanced laboratory tests be done on the T-cells to see if they give a clue as to what is happening. That can include looking at the genes in the T-cells. I imagine that's being done, but can take time.
Kudos to you for getting the detailed path report done. That seems to rule out a lot and is a good result for that reason. There are no clues gotten from the biopsy, which is good; but the mystery still remains. There's no particular reason at this point to think that something very bad will be discovered. Let me know what happens next.
("immunophenotypic" means they examined the surface of the B-cells and found nothing that points to cancer)
Okay, it seems very good they will look for pathogens. But why not also for granulomas? There are mystery types with no known pathogen.
As to why the CT didn't see enlarged nodes, I don't have a guess. But it seems moot at least for now with the biopsy being done. I'd also be very wary of any more radiation, and question why the CT was even done in a 4 yr old seeing as how the biopsy will be done.
Was the CT done in the same place that you can feel the enlarged nodes?
I would think that the biopsy is a good idea *if* they also look for immune cells and whatever else might be causing his condition. If they only look for cancer and find none then that is a wasted opportunity. E.g, are there a lot of eosinophils in the node? Are there any detectable pathogens in the node? Giant cells or lots of fibrosis?
My sheer guess is that the anemia is not an important clue -- it's just a minor side effect. It might simply be because he's got gut inflammation and is not absorbing iron.
Regardless, in theory it would be because (1) RBCs are not being manufactured enough or (2) that they are somehow being destroyed by the immune system - or by a virus. Or (3) lost via bleeding. The docs would probably have picked up on anything dangerous if it existed.
But if he's not badly out of breath then it's maybe not significant.
"...in the past - he was dealing with frequent fever/infections"
So there it is, no particular reason to fear lymphoma then since at this time there is a better alternate diagnosis..
I suppose they've also looked into immunodeficiency disorders and everything else that might possibly apply. But the immune system is mysterious and nobody on the planet understands it all.
"an infectious disease specialist who has ruled out anything infectious."
Well, we don't know all infectious agents so they can't all be ruled out. Especially viruses. Also, there are parasites in the U.S.
https://www.cdc.gov/media/releases/2014/p0508-npi.html
You can look up a little about Eosinophilic Disorders, just as a way to see how strange things can be with immune signalling gone awry.
I would think very hard about anything that happened before he got sick. Be a Sherlock. A doc can't spend the time thinking it out like you can.
I'd also really lobby for the biopsy pathology to not be limited only to excluding lymphoma.
It's a shame when they do a sono only for size and don't look at the internal architecture. That's if a large node was available near the surface in neck e.g., and they didn't only sono the abdomen.
So then there are only tendencies this way or that. The size of the largest node is concerning but is still within range to be not-cancer -- esp if not growing more. The shape does tend toward not-cancer... oval and flat, not round.
Enlarged nodes in the abdomen together with elevated basophils and eosinophils maybe point to a food allergy. Or maybe there's some autoimmunity or granulomas. These three are more likely if there's a family history of immune conditions, especially overactive immune reactions.
Basophils and eosinophils can each multiply because of very rare cancers but they likely wouldn't *both* do that because of a cancer.
Any chance of unusual parasites?
I'd ask why they don't sono the neck node esp if that's the largest. If they see a fatty hilum then that is a very strong indication of not-cancer. Why just keep looking for extent of enlarged nodes?
My guess is that they'll rule out lymphoma and then have to look for the real cause.
Hi, can you post the ultrasound report? There might be a key word in there which makes all the difference and relegates everything else to being of secondary importance.
His CBC seems very unusual, enough to point to something besides cancer.