Diagnosed with Thal Minor, HB levels closer to Intermedia

This is my first post so hello everyone, my name is Navneet, I am 23 and have recently graduated from university, got a bachelor's degree in psychology. In infancy, I was diagnosed with a congenital overgrowth disorder called Beckwith Weidemann Syndrome and beta thalassemia minor, I have received two blood transfusions, but those were only for surgeries I had as a toddler to correct a hernia, and remove excess tissue from my tongue, both defects resulting from the BWS.

I have always had hemoglobin levels much lower than what is normal for a heterozygous carrier, mostly in the low 70s, once or twice it reached 80, it has gone as low as mid 60s with iron and b12 deficiency. I've been told over again, that this is bad for my heart, yet the only treatment I have received is correction of the iron and b12 deficiency, but my HB remains at 7-8g/dl even when I am nutritionally replete. My doctors have done many tests including a bone marrow aspiration to look for other causes of this anemia, but all have come up negative. I inherited the trait from my father and grandmother, both whom are only mildly anemic, manifesting it in the typical way.

I notice that I have less energy than others, but never tell doctors that I am tired, because for me it seems normal. In university especially, I was always exhausted, by the end of first year I had clinical depression, by third, I stopped working part-time.

What are the long term consequences of having this marginal HB level?
Is there anything I can do besides just trying to maintain a good diet?
Any advice would be appreciated
~Thanks
(cross-posted on Thalforum.ca, I apologize)

Hi Navneet ,
  to the forum , i dont know abt it but i m sure you will get a response to other member 7 you will get answers of your of the issues , you're concerning abt . other members will respond you realy soon , soo pleaese keep checking .. please keep in-touch and keep posting , dont hesitate to ask anything you want to know abt ... its your forum so feel free to ask anything and to share anything .... best of luck , i hope you will find this forum's members, very helping, friendly and caring .......

Best Regards
Take Care
Umair

Thanks for the warm welcome. I'll wait and would really appreciate some answers.

Genetic testing is amongst the battery of tests I have gone through repeatedly since infancy, so I doubt I could have intermedia instead of minor, unless I have a very rare form of it. Still with such low HB, I wonder if it is possible for my hemetologist to treat me as intermedia instead, and at least consider hydroxyurea and/or transfusion

Valkyria,

Welcome to the site.  You are right, your hg is closer to thal intermedia than thal trait.  I don't think that you should not be on iron supplements unless if it is known for sure that your iron levels are low. 

Perhaps you have an inherited a gene from your maternal side of the family which is causing your thalassemia to be a little more severe.  I do think that it would be a good idea for doctors to treat you more like an intermedia, you must feel very tired with such low hg.  It is also important to rule out that you may be losing blood in some other way (ie. milk intolerance can cause blood loss through the gut).    A protein electrophoresis will also give you more information.  If doctors determine that you are thal intermedia than they can try to increase your hg as they would for an intermedia.

There are many supplements such as wheat grass and carao that can help you with increasing your hemoglobin as well.

Once again, welcome to the site!!

Sharmin

Hi Valkyria,

Beta thalassemia and Beckwith Wiedemann Syndrome are both caused by defects in chromosome 11. Has this ever been brought up and if so, is there a possibility that the Beckwith Wiedemann Syndrome defect is causing a worse thal minor than would be expected?

can you tell me more about Beckwith Weidemann Syndrome?

I am sure the others can help you more than I can help you. (Is that a correct English sentence?)

Hello again, thank you for your responses.
Sharmin, my ferritin levels are regularly tested, and they have been quite low in the past, iron supplements have corrected this, but unfortunately do nothing to raise my hemoglobin. I have had many tests for possible blood loss through the GI tract (endoscopy, stool test for blood and parasites, celiac disease blood test, full abdominal CT scan), and all have come up negative.
Andy, my doctor said this was possible, but BWS is not a blood disorder, so the cause of my anemia remains unknown.
I also have Asperger Syndrome, and some learning disabilities; I think this explained my fatigue and depression during college more than thal trait.

A lot has happened over the past year and a half and I have new questions, in December 2009 I had my left ovary removed, it had huge cyst (looked 3mths pregnant) filled with old blood - got no transfusions for this operation, and went home after 3 days. I've become much more fatigued, and have stopped going to the gym because of worsening palpitations, shortness of breath, and even bouts of chest pain - when I told my hematologist about this in August, he put me on 5mg of folate and, referred me to a cardiologist. The folate has not helped, my hb was 67 when it was last checked two weeks ago. I had an echocardiogram, and EKG (does having normal results on these tests completely rule out pulmonary hypertension?); the cardiologist said my heart was in excellent condition, and my symptoms were probably all caused by the anemia. How could I suddenly have so many symptoms? I've been told before that young people can tolerate low hb, and until about a year ago, I had pretty good exercise tolerance. Does tolerance for anemia normally diminish around my age?

Hi Valkyria,

As I mentioned before, both Beckwith-Wiedemann syndrome and beta thalassemia find their causes on chromosome 11. In fact, both deal with genes in the same area, on the short end of the chromosome. BWS is caused by the abnormal regulation of genes in this area, so it does make me think that this is causing a much worse condition than should be expected with beta thal minor. Is the abnormal regulation affecting your ability to produce beta globin, resulting in a lifelong low Hb level? I believe a DNA analysis could show if there are abnormalities

http://wiki.medpedia.com/Chromosome_11

Beckwith-Wiedemann syndrome results from the abnormal regulation of genes on part of the short (p) arm of chromosome 11. The genes are located close together in a region designated 11p15.5 near one end of the chromosome.
The HBB [beta globin] gene is located on the short (p) arm of chromosome 11 at position 15.5.

http://www.news-medical.net/news/2008/10/26/42147.aspx

Beckwith-Wiedemann syndrome results from the abnormal regulation of genes on part of the short (p) arm of chromosome 11. The genes are located close together in a region designated 11p15.5 near one end of the chromosome.

People normally inherit one copy of chromosome 11 from each parent. For most genes on this chromosome, both copies of the gene are active, or "turned on," in cells. For some genes in the 11p15.5 region, however, only the copy inherited from a person's father (the paternal copy) is active. For other genes, only the copy inherited from a person's mother (the maternal copy) is active. These parent-specific differences in gene activation are caused by a phenomenon called genomic imprinting. Researchers have determined that changes in genomic imprinting disrupt the regulation of several genes located at 11p15.5, including CDKN1C, H19, IGF2, and KCNQ1OT1. Because these genes are involved in directing normal growth, problems with their regulation lead to overgrowth and the other characteristic features of Beckwith-Wiedemann syndrome.

Ten percent to twenty percent of cases of Beckwith-Wiedemann syndrome are caused by a genetic change known as paternal uniparental disomy (UPD). Paternal UPD causes people to have extra copies of genes that are active only on the paternal copy of the chromosome. People with paternal UPD are also missing genes that are active only on the maternal copy of the chromosome. In Beckwith-Wiedemann syndrome, paternal UPD usually occurs early in embryonic development and affects only some of the body's cells. This phenomenon is called mosaicism. Mosaic paternal UPD leads to an imbalance in active paternal and maternal genes on chromosome 11, which underlies the signs and symptoms of the disorder.

About 1 percent of all people with Beckwith-Wiedemann syndrome have a chromosomal abnormality such as a rearrangement (translocation) involving 11p15.5 or abnormal copying (duplication) of genetic material in this region. Like the other genetic changes responsible for Beckwith-Wiedemann syndrome, these changes disrupt the normal regulation of genes in this part of chromosome 11.

I would like to know if the beta globin gene is one that can also be affected in BWS. It would shed some light on why, but I don't know if that would be any practical help to you. Knowing why doesn't necessarily lead to a remedy. So, I continue to delve and,

http://www.epidna.com/showabstract.php?pmid=18413893

beta-thalassemia major can be caused by homozygosity or compound heterozygosity for beta-globin gene mutations (HBB gene). Most cases are inherited from parents who both have diseased alleles of the HBB gene. We report a patient with late-onset beta-thalassemia major that evolved from beta-thalassemia minor in which only one of her parents had the diseased HBB gene. To study the cause of beta-thalassemia major in this patient, we performed the 100K single nucleotide polymorphism genotyping assay, fluorescence in situ hybridization, and DNA methylation analysis of the imprinting genes near the HBB gene. The results showed a loss of heterozygosity in the region of chromosome 11p14.3 to 11p15.5, which perfectly matched one allele of her father. Our study demonstrates that paternal uni-parental isodisomy [A type of uniparental disomy in which two copies of the same chromosome are inherited from one parent, with resultant homozygosity at all gene loci on the chromosome.] of chromosomal 11p15.5 is associated with the beta-thalassemia major in this patient.

What this says is that in this case, thal minor developed into major because two copies of the same chromosme were inherited from the same parent, resulting in two beta thal genes and eventual development of thal major as a result.

So, have you ever had a DNA analysis of chromosome 11?

To study the cause of beta-thalassemia major in this patient, we performed the 100K single nucleotide polymorphism genotyping assay, fluorescence in situ hybridization, and DNA methylation analysis of the imprinting genes near the HBB gene

A further note on PHT. To diagnose PHT, it takes a combination of tests and observations to determine, so a good EKG does not necessarily rule it out. I would agree that it is most likely the anemia causing your symptoms. Hb below 7 is a problem and will cause all sorts of health issues.

A DNA test could possibly shed some light on your condition and whether or not you should be treated as a thal major. My feeling is that with your constant low HB, you fall into the category of intermedia and may need occasional transfusions, especially as you get older, which is quite common with intermedias as they age. One other thing that may possibly help, if it turns out your low Hb is completely related to thalassemia would be hydroxyurea treatment. This is often used to raise Hb levels in thal intermedia and even in major, but it also has some effects on eliminating some of the "junk" globin chains produced when beta thal is present. Hydroxyurea can also suppress the formation of extramedullary hematopoiesis, which are attempts by the body to grow red blood cells outside of the bone marrow. Masses of red blood cells build up in places like the abdominal cavity, but can appear anywhere in the body (the blood filled cyst does make me curious).

And to answer your question, yes, symptoms can get worse with age, and with your Hb dropping even lower than previously, I think you have dropped down to where you will experience the symptoms of thal intermedia. Since no sign of internal bleeding has been found to account for the low Hb, it may be time to look elsewhere and a DNA analysis would be the place to begin.

How are you doing now Valkyria?

Hello again, thanks for your concern. Not doing great unfortunately, I've been on 5mg of folic acid for almost a year now but it has not helped at all, my hb was 64, when it was last checked 2 weeks ago, it has been hovering in the 60-70g/L range since early 2009; in retrospect I will say I was asymptomatic prior to then . I feel the palpitations and shortness of breath from normal activities (climbing 2 flights of stairs, vacuuming). The fatigue is awful; I fall asleep for up to 3hrs after work even with a full 7-8hr sleep at night. A nephrologist who sees me for a minor congenital defect (multiple calcyeal diverticula) related to the BWS recently confirmed that I have low blood pressure, which explains 3 fainting episodes and feeling very lightheaded and dizzy upon standing, especially after crouching or kneeling.

On the bright side, I’m finally getting somewhere with a proper diagnosis and possibly treatment. I asked my family doctor to refer me to a different heamatologist, whom I saw 3 weeks ago; I’m very happy with the new heamatologist, he’s taking me seriously, and referred me to a brilliant geneticist. This geneticist believes I have beta thalassemia intermedia via uniparental paternal disomy, (figured this out on his own; I did not bring it up). Nevertheless, thank you so much for the literature Andy, it’s really helped me understand the genetics better, and inspired me to seek this 2nd opinion.

My records confirm that my BWS was caused by mosaic uniparental paternal disomy on part of the short arm of chromosome 11, and I’m getting a DNA test to confirm whether or not my UPD extended to the beta globin gene. I will be getting the results in early August.

The only thing that does not add up is my alleged history of iron deficiency (determined by low ferritin and symptoms such as chapped lips and craving to chew ice), since iron overload is the norm even for never transfused intermedias. Of course this does not explain my current anemia, my ferritin has been maintained in the 200s for the past year and a half with 300mg ferrous gluconate, and seasonale (birth control pill reducing periods to 4/year).

I will be interested in seeing the results of the DNA analysis. Even though BWS has nothing to do with hemoglobin production, its proximity to the beta globin gene could have some relevance. This is not uncommon at all with the beta gene, as it is known to be greatly affected by nearby genes. If a connection is suspected, a case study should be published, as these unique syndromes greatly enhance the understanding of blood disorders. Thalassemia is actually a group of hundreds of different mutations, deletions, amino acid substitutions, MRNA messaging problems and gene defects that act in combination with other gene variations. I would also suggest caution with iron. Thal intermedia patients often do not show high ferritin levels but still build up iron in their organs. In a paradox of thalassemia, the body will actually absorb new iron from the gut, even when there exists a tissue iron load. It is easier for the body to absorb new iron than move it out of tissue, so caution has to be observed with long term iron supplements. Intermedias often have liver iron MRI scans to assess the state of their liver, because ferritin tells them nothing about their true iron load. Some patients never have this problem, while other end up with iron loads that require chelation to remove. Since your condition manifests more like intermedia than minor, there is a risk that iron load will not be seen in ferritin testing. Many intermedia thals show good ferritin levels but when their livers are scanned, iron is detected.

Because BWS can affect both the liver and kidneys, there may be an explanation of your inability to maintain normal iron levels without supplements, but this is something to bring up with your hematologist. I cannot say I understand enough about the workings of BWS to do anything other than suggest that this may be a factor. If this is a possibility, it would explain the low iron numbers and would probably eliminate any possibility that you share the intermedia trait of absorbing excess iron. Your medical history should give you some clues, if you know that kidney or liver issues have been a result of BWS. Your hematologist should be able to tell you if this could affect your body's ability to absorb and use iron.