Molecular study of congenital erythrocytosis in 70 unrelated patients revealed a potential causal mutation in less than half of the cases (Where is/are the missing gene(s)?).

INTRODUCTION: Congenital erythrocytosis can be classified as primary, when the defect is intrinsic to the RBC progenitors and independent of the serum erythropoietin (Epo) concentration, or secondary, when the erythrocytosis is the result of an upregulation of Epo production. Primary erythrocytosis is associated with mutations in the EPOR gene, secondary CE can de due to mutations that stabilize the hemoglobin in the oxygenated form or to mutations in the genes that control the transcriptional activation of the EPO gene - VHL, EGLN1, EPAS1. Chuvash polycythemia, caused by mutations in VHL gene, shares features of both primary and secondary erythrocytosis, with increased Epo production but also hypersensitivity of progenitors to Epo. MATERIAL AND METHODS: With the main objective of describing the etiology and molecular basis of CE, we have studied 70 consecutive unrelated patients presenting with idiopathic erythrocytosis from our hematology clinic or referred from other centers. According to a study algorithm, we have sequenced all the genes described as associated with CE. RESULTS AND DISCUSSION: Erythrocytosis molecular etiology was identify in 25 (36%) of the 70 subjects. High-affinity Hb variants were the most common cause, present in 20% of the cases. New mutations were identified in the JAK2, EPOR, VHL, and EGLN1 genes. CONCLUSIONS: High-affinity hemoglobin variants are a very rare cause of secondary CE, but it seems likely that their incidence may be underestimated. Our experience shows that in erythrocytosis with a dominant inheritance and normal or inappropriate high Epo levels, the HBB and HBA genes should be the first to be studied. In spite of the seven genes known to be involved in CE, the majority of the cases have unknown etiology.

Hb Iberia [α104(G11)Cys → Arg,TGC>CGC (α2) (HBA2:c.313T>C)], a new α-thalassemic hemoglobin variant found in the Iberian Peninsula: report of six cases.

We report a new structural defect of the α2-globin chain presenting with moderate microcytic hypochromic anemia, in six individuals from three unrelated families, living in Portugal and Spain. α-Globin gene deletions were ruled out by gap-polymerase chain reaction (gap-PCR) and multiplex ligation-dependent probe amplification (MLPA). Direct sequencing of the α2-globin gene revealed a substitution of codon 104 [α104(G11)Cys→Arg, TGC>CGC (α2) (HBA2:c.313T>C)]. This new variant, not detectable by high performance liquid chromatography (HPLC) or electrophoresis, was called Hb Iberia, as it was observed for the first time in families from the Iberian Peninsula. Although the mutant allele is transcribed, as indicated by the balanced mRNA α/ß ratio, the abnormal α2 chain could not form a stable tetramer as the cysteine and arginine residues, located at the α1ß1 contact, differ in size, charge and hydrophobicity. Hb Iberia is the third mutation described at codon 104 on the α-globin genes, namely, Hb Sallanches (α2, TGC>TAC) and Hb Oegstgeest (α1, TGC>AGC), also characterized as unstable hemoglobins (Hbs), present on an α-thalassemic phenotype.

Further psychometric validation of the GAH scale: Responsiveness and effect size.

OBJECTIVES: The purpose of this study was to assess the responsiveness of the newly developed Geriatric Assessment in Hematology (GAH) scale to clinical change in older patients diagnosed with hematologic malignancies. METHODS: A prospective observational study conducted in 164 patients aged ≥65years and diagnosed with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), multiple myeloma (MM), or chronic lymphocytic leukemia (CLL). Responsiveness of the GAH scales was studied by means of the Eastern Cooperative Oncology Group (ECOG) score, the Karnofsky performance status (KPS) score, the visual analog scale (VAS), and the physician's subjective assessment, used as clinical anchors to identify whether patients had changed clinically (either improved or worsened) or not since the baseline visit. Responsiveness was evaluated on the basis of effect size (ES). RESULTS: 164 patients (men, 63.7%; median age, 77.0 (72.8-81.4) participated. Statistically significant correlations were obtained between the investigator's qualitative assessment and changes in ECOG, KPS, and VAS scores. Likewise, a statistically significant correlation was obtained between the investigator's qualitative assessment and changes in the GAH scale score. Responsiveness of the GAH scale to detect clinical change was satisfactory (ES 0.34). CONCLUSION: Findings confirm that the GAH scale is responsive to clinical changes in patients' health status. Additionally, the GAH scale is a promising tool to improve clinical decision-making in older patients with hematological malignancies.

Hb La Coruña [beta38(C4)Thr-->Ile]: a new hemoglobin variant leading to familial polycythemia.

Hb La Coruña [beta38(C4)Thr --> Ile] is a new hemoglobin (Hb) variant that has an increased oxygen affinity. Clinically, this Hb leads to erythrocytosis. Hb La Coruña is an electrophoretically silent variant that can be detected by reversed phase high performance liquid chromatography (HPLC) and characterized by DNA sequencing. The patient was a 22-year-old Spanish male whose family lived in La Coruña, in the northwest of Spain. His mother was also a carrier.