We report clinical, hematological, biochemical, functional and molecular studies carried out on two first cousins from a Greek-Albanian family who have clinical and hematological findings consistent ...with the diagnosis of thalassemia intermedia. DNA studies determined that they had co-inherited a common Mediterranean β-thalassemia (thal) mutation, IVS-I-110 (G→A), in trans to a β-globin gene mutation at codon 107 (GGC→GAC), predicted to give rise to a rare unstable β chain variant Hb Lulu Island or β107(G9)Gly→Asp.
Trigonocephaly and Wilson's disease (WD) are two different entities. The former is a type of craniosynostosis that occurs because of fusion of the metopic suture and the latter, also called ...hepatolenticular degeneration, is caused by an accumulation of copper in tissues all over the body because of failure of copper excretion. No single gene has been identified for trigonocephaly whereas the ATP7B gene has been shown to be responsible for Wilson's disease. Here we present two siblings born to nonconsanguineous parents who both presented with trigonocephaly, Wilson's disease and facial dysmorphism. In addition, the female has renal agenesis and the male has a history of undescended testis. Karyotypes were normal and no mutation of the ATP7B gene has been identified in the patients or their parents.
Sarcoidosis is a multisystemic granulomatous disease of unknown etiology that primarily affects adults between the ages of 20 and 40years old. It is characterized by the activation of Th1 lymphocytes ...resulting in the production of inflammatory cytokines and the formation of noncaseating epithelioid cell granulomas in affected tissues. The lungs and lymphatic system are the ones most frequently affected. The disease usually presents spontaneous remission in the first two years and, in a few patients, the disease progresses to pulmonary fibrosis or other fatal complications depending on the affected organ. The pathogenesis of sarcoidosis is still not clearly defined, and is considered an interaction between the environment and risk alleles in many genes.
The present case control study consisted of 146 Greek patients with sarcoidosis and 90 healthy volunteers from the same ethnic group. The coding and neighboring intronic regions of the BTNL2 gene were sequenced and risk alleles were compared amongst the two groups. Thirty-seven different variants were detected from which 12 were synonymous substitutions and 25 non-synonymous. With the help of in silico tools (SIFT, PolyPhen, PROVEAN, PMut and EX_SKIP), 13 variants were classified as possible pathological risk variants including 4 novel ones. The most common risk variants contributing to phenotypic modulation of sarcoidosis were p.S360G and p.S334L, with the latter contributing to a more severe disease stage with extra-pulmonary manifestations such as skin granulomas and relapses being more common.
•Thirteen pathological risk variants were discovered in BTNL2 gene in sarcoidosis patients.•The common risk variant p.S360G was found in cases (37.67%) and controls (30%).•The 2nd most common variant p.S334L was found in cases (16.43%) and controls (12.22%).•Six novel variants were detected with 4 deemed pathological.•Coinheritance of common and novel variants affected the final clinical phenotype.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Haemoglobin H (Hb H) disease is the severest form of α‐thalassaemia compatible with post‐natal life and occurs when α‐thalassaemia mutations interact to reduce α‐globin synthesis to levels ...approximately equivalent to the output of a single α‐globin gene. Hb H disease has variable clinical expression, mainly related to underlying genotypes. The spectrum of α‐thalassaemia determinants in Greece appears greater than in any other population studied and, in 75 Greek Hb H disease patients, we found 12 α‐thalassaemia mutations interacting to produce 15 Hb H disease genotypes. Evaluation of haematological, biochemical and clinical findings, and correlation with genotypes, defined genetic predictors of disease severity and factors involved in disease progression. In accordance with previous reports, patients with non‐deletion α‐thalassaemia mutations had more severe clinical expression. Additionally, we found that all patients with the most severe phenotypes had α‐thalassaemic globin variants. Phenotypic severity was not simply related to the degree of α‐globin deficiency: high Hb H levels were found to exacerbate anaemia by negatively influencing tissue oxygenation, and both Hb H and α‐thalassaemic haemoglobin variants appear to reduce red cell survival within the bone marrow and circulation. Together with the long‐term follow‐up in many patients, this report provides comprehensive information for management of Hb H disease and appropriate family counselling.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
alpha-Thalassemia is usually due to deletions within the alpha-globin gene cluster, leading to loss of function of one (-alpha) or both -(alpha) or -- alpha-globin genes. Nondeletion mutations ...(denoted alpha alpha T or alpha T alpha) are less frequent and in Greece are not well defined. We report the analysis of 16 nondeletion alpha-thalassemia chromosomes using a polymerase chain reaction method to amplify specifically the alpha 2-globin gene, which was subsequently screened using ASO hybridization or restriction enzyme analysis for four mutations already characterized in other Mediterranean and Middle Eastern populations. Of the 16 nondeletion chromosomes, nine had the polyadenylation signal mutation (alpha PolyA alpha), two the IVSI 5' pentanucleotide deletion (alpha Hph alpha), two the Hb Icaria mutation (alpha Ic alpha), and one the initiation codon mutation (alpha Nco alpha). In two, the defects are still undefined. These findings show that nondeletion alpha-thalassemia in Greece is heterogeneous and that the most frequent mutation (accounting for > 50%) is the polyadenylation signal mutation, which to date was most commonly found in the Saudi Arabian population.
Thalassemia syndromes and unstable hemoglobins traditionally represent two phenotypically separate disorders of hemoglobin synthesis. Highly unstable hemoglobin variants, however, often have ...phenotypic characteristics associated with both ineffective erythropoiesis (thalassemias) and peripheral hemolysis (unstable hemoglobins). Many highly unstable β chain variants cause a dominant thalassemia-like phenotype, in which simple heterozygotes for such mutations have a clinical expression similar to thalassemia intermedia. The phenotypic expression of highly unstable α-globin variants is usually less severe, due mainly to a gene dosage effect, and they are often only characterized on interaction with other α-thalassemia mutations, whence they are classified as nondeletional α-thalassemia determinants. This study reports the clinical and hematological findings in five cases with rare α-thalassemia genotypes: a single patient with the thalassemic α2-globin gene codon 59 Gly→Asp hemoglobin variant in trans to an α+-thalassemia deletion, and four compound heterozygotes for the nondeletional α-thalassemia polyadenylation mutation (α2 gene AATXAA→AATAAG or aT-saudi α/-α) and an α+-thalassemia deletion. Evaluation of the clinical and hematological features in these two analogous genotypes clearly demonstrates the more severe clinical expression associated with the α-thalassemic unstable hemoglobin variant. In addition, the case in this study with the codon 59 α chain variant provides a further example illustrating the spectrum of phenotypes associated with the a-thalassemic hemoglobinopathies.
To initiate the complete characterization of mutations in the CFTR gene in Greek cystic fibrosis (CF) patients, we screened 184 patients for six relatively common mutations (delta F 508, G542X, ...G551D, 621 + 1 G-->T, N1303K, W1282X) using allele-specific hybridization and, in addition, analyzed exons 4, 5, 7, 8, 10, 11, 17b, 19, 20 and 21 using the method of denaturing gradient gel electrophoresis (DGGE). Six mutations accounted for 65.9% of the CF alleles in Greek patients, of which the delta F 508 mutation had a frequency of 52.7%. A further 15 previously described mutations accounted for another 8.3% CF alleles and one previously undescribed mutation (3272-4A-->G) was found in one chromosome. The W1282X mutation was not detected at all. Thus, so far, we have identified 21 mutations in the CFTR gene in Greek CF patients, accounting for 74.5% of the CF alleles.
To evaluate, the degree of tissue hypoxia in patients with hemoglobinopathy H disease, whole blood oxygen affinity was estimated and analyzed in 33 patients. Twenty patients with iron deficiency ...anemia, matched for degree of anemia, served as controls. The results were as follows: Whole blood oxygen equilibrium curves of patients with HbH disease are biphasic because of a combination of the rectangular hyperbolic curve of HbH and the normal sigmoid curve of HbA and are shifted toward the left (P50 3.66 ± 0.33 kPa). Patients with iron deficiency anemia have right-shifted oxygen equilibrium curves (P50 4.02 ± 0.13 kPa) compared with normal. Oxygen release to the tissues in HbH disease is decreased (1.4 ± 0.3 mmol/L) as compared with iron-deficient patients (1.6 ± 0.2 mmol/L) with a similar degree of anemia. Red cell indices vary between the two groups. In patients with HbH disease the mean corpuscular hemoglobin concentration was 268 ± 17 g/L as compared with 294 ± 18 g/L in iron deficiency anemia. These findings indicate that whole blood oxygen affinity is a reliable index of tissue oxygenation in patients with hemoglobinopathy H.
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