The fact that the doctors themselves are not sure if hydroxyurea will work demonstrates how complex and confusing this topic is. While the XmnI polymorphism can be used to predict that hydroxyurea may work, there are other factors that may have an effect, as seen with your cases. The article below explains some of the factors that determine the severity of thalassemia.
From
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11132233&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusGenetic factors affecting clinical severity in beta-thalassemia syndromes.
Winichagoon P, Fucharoen S, Chen P, Wasi P.
Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Nakornpathom, Thailand. stpfc@mahidol.ac.th
PURPOSE: Heterogeneity in the clinical manifestation of beta-thalassemic diseases may occur from the nature of beta-globin gene mutations, alpha-thalassemia gene interaction, or differences in the amount of hemoglobin (Hb) F production. This study was conducted to determine whether these genetic determinant factors can predict phenotypic severity of patients with beta-thalassemia and to assess the relationship between the genotype and phenotype of the disease. MATERIALS AND METHODS: A total of 144 patients with beta-thalassemia were divided into mild (46 patients), intermediate (55 patients), and severe groups (43 patients). DNA analysis based on polymerase chain reaction technique was performed to characterize types of beta-thalassemia mutation, interaction of alpha-thalassemia, and XmnI polymorphism 5' to Ggamma-globin gene. RESULTS: Two alleles of mild beta-thalassemia mutation (beta+/beta+-thalassemia or beta+-thalassemia/Hb E) resulted in a mild clinical symptom whereas two alleles of severe beta-thalassemia mutation (betao/betao) produced a severe clinical phenotype. Compound heterozygosity for mild and severe alleles of beta-thalassemia (betao/ beta+-thalassemia or betao-thalassemia/Hb E) led to variable severity of anemia. Coinheritance of alpha-thalassemia alleviated the severity of beta-thalassemia disease in those patients with at least one allele of the mild beta-thalassemia genotype. DNA polymorphism at position-158 nt 5' to the Ggamma-globin gene was demonstrated by XmnI restriction enzyme. Homozygote of the XmnI site, +/+, was found to have a strong linkage with high Hb F levels and high hemoglobin production in two patients who had mild clinical symptoms. However, some patients who had XmnI site -/- also had mild clinical symptoms because the XmnI- was found to be associated with beta+-thalassemia mutation. CONCLUSION: Types of beta-thalassemia mutation and coinheritance of alpha-thalassemia in the patient who has at least one allele of the mild beta-thalassemia genotype are predictive for the clinical severity of the disease. However, a mild clinical symptom in some patients with betao/beta+-thalassemia or betao-thalassemia/Hb E who do not have a detectable alpha-thalassemia haplotype and no linkage with XmnI++ suggests that there are other confounding factors responsible for the severity differences of the disease.
PMID: 11132233 [PubMed - indexed for MEDLINE]
Not everything about thalassemia is understood and much that is understood is incomplete. Even though some patients may be better candidates for hydroxyurea in theory, it does not mean that other patients should not try it. If your child can avoid transfusion by using hydroxyurea, it is the preferable treatment of the two.
I found the case below to be very interesting as a clear demonstration of how much things can vary in thal. One would normally expect severe thalassemia when the patient has two completely non-functioning beta hemoglobin genes, but in this case, the patient has mild thal with moderate but manageable anemia.
From
http://lib.bioinfo.pl/meid:8881 Ann Biol Clin (Paris). ;64 (4):341-5 16829478
[Beta(o)/beta(o) thalassemia with a mild phenotype]
[My paper] C Hémar , O Nibourel , P Maboudou , C Méreau-Richard , C Badens , J Rousseaux , C Rose
We report the case of a 30 years old patient of Algerian origin, presenting a beta-thalassemia major with a phenotype of intermediate severity. Its genotype is beta(o)/beta(o), leading to a complete absence of beta-globin synthesis. This genotype is usually responsible for major clinical complications and a severe anaemia requiring regular transfusions. However, the patient presents with a mild form of the disease and a moderate relatively well tolerated anaemia. This phenotype was found related to a high level of synthesis of foetal haemoglobin, dependent most probably on an homozygous state for the polymorphism (XmnI -158, C>T) in the promoter of the Ggamma gene. This observation shows that it is important to keep in mind that beta-thalassemia major may have a mild or intermediate phenotype because of polymorphisms of the beta locus.
In this case, the XmnI polymorphism is such that the level of fetal hemoglobin produced naturally is sufficient to avoid transfusion. One day they will be able to accurately predict what to expect in thals by what their exact mutations and related mutations are, but the science is not close to exact enough to say positively that fetal Hb induction won't work on a patient.