Novel exon 2   spectrin mutation and intragenic crossover: three morphological phenotypes associated with four distinct   spectrin defects

Abstract

© F e r r a t a S t o r t i F o u n d a t i o n 2 0 1 3Furthermore, the HPP phenotype is normocytic and not microcytic, and there are also numerous elliptocytes present on the peripheral smear; hence, we designate it as atypical HPP. In this manuscript, we clarify the molecular basis of these three phenotypes associated with the novel SPTA R34P mutation and provide new insight into the complexity of erythrocyte membrane disorders. Methods Clinical and routine laboratory studiesAll patients provided written, informed consent before participation in the study. The studies were approved by the University of Utah Institutional Review Board (IRB_00027669). Family AA 79-year old man (propositus of family A, A-I-3) ( Figure 1A) presented with a life-long history of anemia and intermittent jaundice. He and his extended family trace their ancestry to Scottish and Scandinavian forebears who were among the first Mormon settlers of Utah Territory. He had a splenectomy two years prior to presentation that resulted in a partial amelioration of his anemia. He was aware that multiple family members had a history of abnormal red blood cell morphology and some were anemic. His erythrocyte morphology revealed anisopoikilocytosis, fragmented cells, microspherocytes, elliptocytosis and polychromasia ( Figure 2A). Eleven first-degree relatives of his extended family over three generations were evaluated ( Figure 1A). Family BAn apparently unrelated 39-year old female (propositus of family B, B-I-1) ( Figure 3A) was referred to one of the Authors (JTP) for evaluation of very high platelet count and suspected essential thrombocythemia. Since red cell fragmentation can be mistakenly reported as elevated platelet count by laboratory instruments, the accuracy of elevated platelet count has been verified by semiquantitative estimation of platelet count by microscopic evaluation of blood smear by one of the Authors experienced with RBC fragmentation in several HPP patients identified over the last three decades (JTP). She had neonatal hyperbilirubinemia, and since birth has had episodes of jaundice with severe anemia (hemoglobin 70g/L). She had undergone splenectomy three years earlier, with improved anemia and no further episodes of jaundice. HerNovel α spectrin mutation and intragenic crossover haematologica | 2013; 98(12) 1973 ancestors were also among the first Mormon settlers of Utah Territory and were of north European ancestry. After splenectomy, she has had persistently elevated platelet counts (up to 1 million/mL), and was assumed to have essential thrombocythemia and treated intermittently with hydroxyurea. Her physical examination was unremarkable. Peripheral smear revealed significant anisopoikilocytosis, microspherocytes, elliptocytosis, and polychromasia ( Figure 2B). Further studies revealed polyclonal hematopoiesis determined by the X-chromosome transcriptional assay 12 and the absence of JAK2 and cMPL somatic mutations. The clinical diagnosis of atypical HPP and secondary thrombocytosis due to hemolytic anemia ...

Three Novel Spectrin Variants in Jaundiced Neonates

“…As in our Patient 1, certain SPTA1 variants in trans are known to cause HPP in an autosomal recessive manner. 12 As in our Patient 2, other SPTA1 variants in trans are known to cause HS in an autosomal recessive manner, 6 and as in our Patient 3, certain heterozygous SPTB variants are known to cause HS in an autosomal dominant manner. 6 In our Patient 3, the SPTB variant was paternally inherited and was not identified in the other relatives tested (mother and older female sibling).…”

“…This same SPTB variant was also found in the father but not in the mother or older sibling. Prediction of the References [11][12][13][14][15]. significance of this novel variant, by MutationTaster, 11 was "disease causing."…”