New to the forum- Son diagnosed with Major and then downgraded to Intermedia

Hello all. I am new to this forum. I am a mother of a 2 year old son. He was originally diagnosed with Major, but recently has been downgraded to Intermedia. This was because he did not fall under the classic symptoms of Major, even though genetic testing shows otherwise. He has not been having many symptoms. At his last check up in March his hemoglobin level was a 9.4, his spleen was slightly enlarged, and his eyes a bit yellow. He also sleeps more than the normal toddler. This past week he has not been feeling well. He has been having fevers for about 6 days and the pediatrician believes this is due to a virus of some sort. But we did have a CBC and his levels have dropped to 8.3. Could this be due to him not feeling well? He is also very pale, not eating well, and not playing as much as normal. I know that these are all of the things we are suppossed to watch for. His fever seems to have subsided now but his other symptoms have not. Is there anyone else who was diagnosed with Major and then changed in Intermedia? Has anyone else started transfusions as old as 2 years? Does anyone have any advice or guidance in general? THANKS FOR ANY ADVICE!! 

Elizabeth

Hello Elizabeth,

Welcome to thalpal. Please view the posts in thal(Intermedia) section and you will be able to read a lot of how to manage his thalassemia.

This past week he has not been feeling well. He has been having fevers for about 6 days and the pediatrician believes this is due to a virus of some sort. But we did have a CBC and his levels have dropped to 8.3. Could this be due to him not feeling well?

Yes, the HB levels drop when a viral infection enters the body.

Has anyone else started transfusions as old as 2 years?

Most of the thal (Major) are transfused when they are in their 1st year.

Hi Elizabeth,

Do you have the results of a hemoglobin electrophoresis for your son? And the results of the CBC. The Hb over 9 is uncharacteristic of thal intermedia, and transfusions are usually not considered for intermedias unless the Hb drops to the 6-8 range, depending on the health of the patient. The test results could be helpful in understanding his particular situation.

Thanks for the reply Narendra.

Hi Andy. The electrophoresis showed 100% hemoglobin F and no hemoglobin A. It was then determined that I have trait with a hemoglobin A2 of 6% and my husband also has trait with a hemoglobin A2 of 5.2%. Further DNA analysis was performed to confirm that Sean (my now 2 year old son) has beta thalassemia major caused by a homozygous beta zero mutation. Sean's father is heterozygous (carrier) for codon 39 CAG>TAG beta zero mutation. And I have a very unusual Dutch beta zero thalassemia mutation. These tests all predicted that Sean would become transfusion dependent. They thought it would happen during the first year of life. Since it has not, they have downgraded him from major to intermedia. Is this normal to be downgraded? In anyone else's experience, could he possible never become transfusion dependent? His current Hb is 8.3 but he has not been feeling well this week. A few months ago it was 9.4. Is it likely that his Hb will go back up or could this be the beginning of it gradual decent and eventual transfusions? Thank you all for any answers or experiences they could share!

Elizabeth

Elizabeth,

Has hereditary persistence of fetal hemoglobin (HPFH) been investigated? If his hemoglobin is 100% HbF and he is maintaining at a level that high, it may be the reason. If HPFH is present, consider it a blessing. I know of no other explanation for his Hb to remain this high when the hemoglobin is all HbF.

Andy,
  Yes, HPFH was investigated and found to be not the case. The doctors are also quite confused, but feel that they do not know enough about Sean's type of mutation to really speculate. I guess that I should just be grateful that he has not become transfusion dependent at this point. I just really want to know if it will ever happen. I feel like we are/have been playing this giant waiting game since the letter came in the mail when Sean was 4 days old saying that his newborn screen had come back positive. I wish there were more answers. It seems that thalassemia is so different in every person. It seems that it is a very difficult disease to predict. Thank you for your response. 

This may explain it.

The father's gene, http://globin.cse.psu.edu/html/huisman/thals/beta/Codon.39.(C-@T)..CAG(Gln)-@TAG(stop.codo.html

MUTATION      Codon 39 (C->T); CAG(Gln)->TAG(stop codon)   
 
AMINO ACID REPLACEMENT      None   
TYPE OF BETA-THAL      beta°   
MECHANISM      This mutation changes codon 39 into a stop codon terminating translation   
IDENTIFICATION      Cloning of the beta-globin gene; amplification of the beta-globin gene and sequencing; dot-blot analysis; ARMS; gene mapping with MaeI   
HEMATOLOGY IN HETEROZYGOTE(S)      Typical for beta°-thal with low MCV and MCH values; microcytosis; hypochromia (n=10): Hb 11.1±1.35 g/dl; MCV 72.6±8.5 fl; MCH 20.2±1.1 pg; Hb A2 4.85±0.5%; Hb F 1.25±1.0% (Ref. 4)   
HEMATOLOGY IN HOMOZYGOTE(S)      Severe transfusion-dependent beta-thal

Your gene  http://globin.cse.psu.edu/html/huisman/thals/beta/12.620.bp.deletion..the.Dutch.deletion.html

MUTATION      12,620 bp deletion (see Fig. 4); the Dutch deletion   
 
AMINO ACID REPLACEMENT      None   
TYPE OF BETA-THAL      beta°   
MECHANISM      No beta chain production; considerable increase in gamma chain formation   
IDENTIFICATION      Gene mapping; cloning; amplification; DNA sequencing   
HEMATOLOGY IN HETEROZYGOTE(S)      Hb 12.4-13.0 g/dl; MCV 65-70 fl; MCH 18-24 pg;   
Hb A2   6.8, 5.9, 6.3, 6.0, 6.4, 8.6, 5.1, 6.5, 5.9, 5.5, 6.1%;   
Hb F   8.0, 10.7, 6.7, 10.4, 4.6, 4.1, 9.4, 5.9, 5.5, 7.7, 10.9%   
HEMATOLOGY IN HOMOZYGOTE(S)      Two homozygotes: Hb 10.9, 13.1 g/dl; MCV ~73 fl; MCH 20-25 pg; Hb A2 2.0, 2.4%; Hb A 0%; Hb F 98.0, 97.6%

The Dutch beta zero deletion allows for a compensation by the gamma gene, resulting in a high production of HbF. This is a characteristic of some of the beta zero thalassemias. It seems the Dutch deletion results in high expression from the gamma gene. This is explained in this article excerpt http://www.mendeley.com/research/filipino-beta-zero-thalassaemia-high-hb-a2-beta-zero-thalassaemia-resulting-large-deletion-5-beta-globin-gene-region/

A large novel deletional beta zero thalassaemia mutation associated with unusually high levels of haemoglobin (Hb) A2 in heterozygotes is described in two unrelated subjects of Filipino background. The deletion was characterised by DNA mapping including pulsed field gel electrophoresis. Filipino beta zero thalassaemia extends for approximately 45 kb beginning approximately 1.5 kb 3' to the delta globin gene. It is the largest deletion to date which gives rise to the beta zero thalassaemia phenotype. This mutation, similar to previously described deletional beta zero thalassaemias associated with high Hb A2, removes sequences 5' to the beta globin gene promoter and emphasises the functional importance of the 5' beta globin region in eliciting the unusually high level of Hb A2. This example also suggests that it is the 3' sequences which are transposed rather than the actual deletion size which are significant in the raised fetal haemoglobin (Hb F) found with some of the thalassaemias.

The full article can be read at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1016308/

Because the other gene deletion offers no compensation it may be too early to predict the long term outcome. I tend to think this will manifest as intermedia and transfusion might be avoided if fetal hemoglobin production stays at such a high rate. Because of his relatively young age, it is not yet predictable, but being that he is 2 years old and carries a hemoglobin level more associated with thal minor, it is a good sign. Intermedia is simply a classification and basically means the genes say major, but either the genes are + and do produce enough adult hemoglobin to survive without transfusion, or are zero and some other factor compensates in some way, such as in the described cases where a large deletion actually allows for higher activity of the gamma gene, allowing gamma globin to combine with alpha globin, producing unusually high fetal hemoglobin. Because there is a better balance of globins, this also greatly reduces the amount of unmatched alpha globin. This is far more important than one may realize, as the damage these unmatched alpha chains cause in beta thal is great.

So, it appears that the same effect is realized as with HPFH, even though that is not the reason. It is amazing but two of the Dutch deletion can result in a normal hemoglobin level. "HEMATOLOGY IN HOMOZYGOTE(S)   Two homozygotes: Hb 10.9, 13.1 g/d" Even with no beta globin produced, a hemoglobin range as high as 13 is observed.

I don't know if it can help even more because the HbF level is already so high, but he may be helped by natural methods like wheatgrass extract and resveratrol supplements. Both show some ability to raise HbF levels in people with active gamma genes. Both also have positive properties than can be of benefit in thalassemia. I don't know if I would go the hydroxyurea route for raising HbF unless his total Hb drops into a range where transfusions might be considered. Because he has shown a good ability to produce HbF, he would be a good candidate for hydroxyurea therapy if his Hb drops to the 6-7 range. Folic acid, B complex and vitamin E are all recommended.

Do you also have a high HbF level?

Hello Elizabeth,

Welcome,

My name is Bobby. I was diagnosed as Beta Thal Major as a child, but am now classified as Intermedia. I recieved transfusions from the ages of around 11-14 maybe. Not really sure. Probably had a total of 8-10 total, but I don't know how necessary they were at the time. I started playing sports and being more active in high school and the transfusions stopped. My eyes have always been jaundiced and sometimes I battle severe fatigue, but i bounce back and do ok. My HGB is normally ranges from 8.2 to 9.1. My sleep is about the size of a grapefruit, but it works ok, so I'm keeping it for now. A year ago I had 5 months of Exjade because my ferriten levels were high, but I was able to get them down and haven't had any trouble since. If you have any questions feel free to ask.

Dear Bobby,

Its really good to hear from you that you are doing fine. May god bless you all the time.

As somebody says in this forum, thalassemia is different from person to person.

I too have lot of consufion with regards to my son case still I could not able to diagnose him since last 4 months.

I have some query regards to your post...as you know Thalassemia Major will be diagnosed at the beginning of the first year of life...but in your case when it has been detected and how ?

Would you like to share the HPLC report of yours ? Do reply please.

Warm regards,
Sys

Hi Sys,

Thank you for the well wishes. I will try to answer these as best as my memory will allow. My Thal wasn't diagnosed in my first year. I wasn't diagnosed until I was around 7 or 8 years of age began to continually get sick when I participated in outside activities. I was always a small child and I seemed to alway overexhert myself and fall ill. At first Dr.'s diagnosed me with anemia and put me on iron pills for years, but my condition never improved and the iron build up started to caused changes in my facial structure. My uncle is a General Practioner here and my mom took me to him for better tests and he sent me to a the Childrens hospital here where they found Thal. Both parents have the beta thal minor trait and I had Beta Thal major and was told to not play sports and be careful about injuring my spleen. From that point I got better treatment and taken off iron and started transfusions on an as needed basis. My parents still allowed me to play sports (light contact) and be active which increased my appetite and I feel it's part of the reason I did so well as i got older.

i don't have any results or reports from childhood, but the results from my most recent blood work are posted in another thread. I'll try and add a link here.

Hello Sys,

I'd just like to add onto what everyone else said. My husband's is very similar to everyone's. He was diagnosed at birth with Thal Major. Over the years he received transfusions regularly. It wasn't until he was 17 or 18, he removed his spleen and after that, the doctors saw that he did not need transfusions anymore. I believe it was then that they re-classified him as Intermedia. They now put him on Folic Acid and penicillin regularly. He's a lot better now, and is no longer dependent on transfusions. We just work on visiting his specialist at the children's hospital quarterly. Take care and I hope this helps.