Now that I’ve attempted to lay out some basic information for understanding HLH, I’d like to take a look at the real issue: the difference between FHL and HLH.
When I began reading up on this disease it took quite some time to understand where FHL, or Familial HLH, fit in to the picture. When literature or doctors talk about the disease, they tend to refer to it simply as HLH. Over time I’ve come to realize there are a variety of reasons for this, not least of which is the difficulty in diagnosing which of the forms of HLH a patient has. So, let’s take a look at the two forms side by side.
HLH, or Hemophagocytic Lymphohistiocytosis, is the name for the immune disorder. It can come in one of two forms: Familial HLH, also called FHL, and Acquired HLH, usually referred to simply as HLH.
FHL:
- Is the primary, or most common, form of HLH
- Is also known as Familial HLH
- Is caused by a genetic defect passed to the child by parents who are carriers; children of parents who each are carriers (as they must be for the child to have the disease) have a 1 in 4, or 25%, chance of getting FHL.
- Is rare for two reasons primarily: because it requires two parents who both carry the recessive genetic defect to mate and pass on the gene (only a 25% chance); and because it goes undiagnosed often enough with 100% fatality, so as to seem more rare than it likely is.
- Is generally found in very young children; this is because it manifests itself when the child has an immune response (such as to a cold) and once it manifests is fatal if untreated. Kids who have FHL get sick as kids always do at some point, and they don’t survive unless treated. So, it’s not usually found in older kids — it’s either treated successfully or it is fatal.
- Is fatal if uncured. This means that the disease can be put in remission temporarily through the HLH-2004 protocol, but will return worse and likely with fatal results if uncured.
- Can only be cured with a Bone Marrow Transplant, or a Stem Cell Transplant.
- Requires genetic testing to positively confirm
HLH:
- Is the secondary, or less common, form of HLH
- Is also known as Acquired HLH
- Is caused by an immune disorder resulting from another condition putting the immune system under severe strain
- Patients who have HLH are usually slightly older children (>1yr), though it has been seen in infants as well
- Is able to be treated successfully with HLH-2004, and often resolves itself permanently once it and the underlying condition are treated
- Cannot be positively confirmed through genetic testing
The Diagnosis Problem
HLH, in either form, is rapidly fatal. Within two months of the disease manifestation, an untreated (undiagnosed) child will die 100% of the time.
Therefore, diagnosis of the particular form of the disease is not the most pressing issue, but instead the focus is on treating the patient as soon as possible to control the immune response before it destroys the body.
Once the disease is under control, a determination has to be made as to whether a Bone Marrow Transplant (BMT) or Stem Cell Transplant (SCT) will be needed. This is where it really gets tricky, and why distinguishing between the two forms is so vital. FHL requires a BMT/SCT to be cured, whereas Acquired HLH does not.
Both BMT and SCT are highly dangerous procedures, not due to the transplant itself but to the difficulty the patient has with accepting the new cells and surviving the side effects. Survival rates for children appear to be in the neighborhood of 70%, with some variation depending on the type of transplant cells used. The numbers never look “good” though, for these procedures — the risk is always too high.
Therefore deciding to get a BMT or SCT is a tough decision, and unfortunately diagnosis of FHL is not always able to be positively confirmed. What has to happen is the tests must be done, and the overall picture must be looked at.
Factors that are considered:
- Results of genetic testing: Sometimes will positively confirm the disease, however because we do not yet know all of the genes to test it does not always confirm it
- Results of Soluble IL-2 test: Over 10,000 tends to be a marker for FHL
- Results of NK cell count test: Low or absent counts are a marker for HLH in general, but not specifically FHL or HLH
- Age of the patient: due to the manner in which Acquired HLH manifests, very young patients without an underlying condition tend to be assumed to have FHL
It is unfortunately not possible to positively confirm Acquired HLH, only FHL. Therefore, to make a decision the doctor and parents will need to look at all of the information and test results before deciding on the need for the transplant.
Click to enlarge
Here is a chart sometimes used to understand the process for diagnosing FHL. Please note: HCT is the acronym for the medical term for Bone Marrow or Stem Cell Transplant
HLH Journal 
Hello Evan, so glad to see Zoe walking and celebrating her 1 year anniversary! What a year it has been. I am the other grandma of Liam Smith and have emailed you in the past. I am curious what gene did Zoe have. Liam has the STXBP2 (FHL-5. Liam has 3 older brothers and I have read some interesting information on the STXBP2. his two older brothers are matches for the BMT per the HLA typing and have normal NK function. his 3 year old brother has decreased NK function but not as bad as Liam’s. we have a long wait now for the genetic tests to come back. 3 more weeks.His BMT will be at the Seattle’s Childrens Hospital. We have a long road ahead of us-Thanks for all the great information for all of us
My son was diagnosed with aquired HLH. The Drs think it was triggered by a tick bite. All of his Drs tell me he is doing very well and that he will recover. They also tell me the reason he is doing so well is because I got him to the Dr as quick as I did. For aquired HLH time is essential for any type of recovery. I’m greatful he is doing so well, but I don’t think there is enough information out there about this disease. Never heard of it till now, or that a tick bite could be so deadly. He’s had two treatments of chemotherapy and looking at a couple of weeks more for a full recovery. The outlook is good.
hello doctor.
my brother(21yrs) has been diagnosed with HLH. initially he had stills with MAS negative and after 1month MAS came positive in bone marrow test
his NK cells count being 7% doctors have diagnosed it to be familial hlh. he is on hlh 2004 protocol and has received 3rd weeks dose of etoposide. his counts don’t fluctuate much now but still on the lower range. 7days after getting etoposide his WBC starts shooting up and has even touched 32000 after first weeks dose.
my biggest confusion is how do i conclude that it is familial HLH. their was a break in the protocol after 1st weeks (2doses) of etoposide because his WBC count has touched 600, platelets 25000. last week his counts were better than before after getting etoposide. now it does not fluctuate much.
doctors have advised BMT. and unfortunately i am the only sibling and it matches partly (haplo) and hence we have no option. here in India it is very difficult to get donors. and getting it from abroad is very expensive which we are unable to bear the cost. please guide me about the same.
thanking u in anticipation.
pragya
hello doctor.
my brother(21yrs) has been diagnosed with HLH. initially he had stills with MAS negative and after 1month MAS came positive in bone marrow test
his NK cells count being 7% doctors have diagnosed it to be familial hlh. he is on hlh 2004 protocol and has received 3rd weeks dose of etoposide. his counts don’t fluctuate much now but still on the lower range. 7days after getting etoposide his WBC starts shooting up and has even touched 32000 after first weeks dose.
my biggest confusion is how do i conclude that it is familial HLH. their was a break in the protocol after 1st weeks (2doses) of etoposide because his WBC count has touched 600, platelets 25000. last week his counts were better than before after getting etoposide. now it does not fluctuate much.
doctors have advised BMT. and unfortunately i am the only sibling and it matches partly (haplo) and hence we have no option. here in India it is very difficult to get donors. and getting it from abroad is very expensive which we are unable to bear the cost. please guide me about the same.please tell me how do we know that 2004 protocol is not working for him and he needs transplant?
his all the vital organs are working fine. no abnormalities seen.
thanking u in anticipation.
pragya
MY GRAND MOTHER WILL SUFFER FROM HEMOPHAGOCYTOSIS DISEASE SO PLEASE HELP ME AND INFORM ME THE BEST HOSPITALS REGARDING THIS DISEASE AND DOUCTORS
Hello, my friend found out 2 days ago that her daughter (who is 4 1/2) has the familial variety of HLH and needs a bone marrow transplant. (Her 6-year-old son is getting tested tomorrow.) I want to help somehow. Aside from love and support, do you know of a bone marrow transplant donation organization that helps kids with HLH? I don’t know if I’m a match, but I’d like to try. Thank you.
Hi Wendy, I would start with bonemarrow.org and see if that organization is what you’re seeking. We wish your friend’s family the best. Evan
My son passed away in 2004 from the familial form of HLH. What are the chances of me having another child with the same illness if it would be by a different father?
Hello,
my cousin’s 6 month old so is ill and hospitalized for a month.. Dr. in India has advised us to get the following tests conducted – FHL 1 (HPLH1), FHL2 (PRF1), FHL3 (UNC13D (MUNC13-4), FHL 4 (STX11), FHL5 (STXBP2) / UNC18-2.
We are unable to identify where these tests will be conducted.
Pls. let me know the following
What and How much sample is needed (blood / urine or any other)
How long does it take for the results to come?
Any special precaution to be taken while sending the sample?
Complete postal Address and contact information where this sample needs to be sent
if possible approximate costs for the same.
Please note that the sample will be sent from India.
regards,
-Srini
Hi Srini,
I can’t give you specific medical advice or tell you what exactly to send for testing. What I’d suggest is that you follow up with Cincinnati Children’s Hospital, one of the bigger testing hospitals, and see what they advise: http://www.cincinnatichildrens.org/service/i/immune-deficiency/default/
I wish you and your cousin’s child the best!
Evan
Thank you for your quick response Evan. I will reach out to this Hospital and revert to you if any further info. is needed.