Hereditary stomatocytosis: An underdiagnosed condition

Andolfo, Immacolata; Russo, Roberta; Gambale, Antonella; Iolascon, Achille

doi:10.1002/ajh.24929

Cited by 53 publications

(106 citation statements)

References 124 publications

(229 reference statements)

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“…Among the patients originally diagnosed as DHS we identified a 35‐year‐old male, RP1_5, showing a causative PIEZO1 mutation in heterozygous state, thus confirming the clinical suspicion of DHS1 . Interestingly, the patient exhibited also homozygosity for the most common causative mutation of CDAII, the Glu109Lys‐ SEC23B (Table ) .…”

Section: Resultssupporting

confidence: 62%

“…Diagnosis was based on history, clinical findings, laboratory data, morphological analysis of peripheral blood and/or aspirated bone marrow, whenever available . For HS/HST patients, diagnosis was also based on indirect tests (osmotic fragility of erythrocyte, AGLT50, EMA binding test), as well as on ektacytometry.…”

Section: Methodsmentioning

confidence: 99%

“…Mutations in these genes can lead to alterations in hemoglobin (Hb) levels, RBC differentiation and proliferation, cell membrane structure, defective activity of erythrocyte enzymes. Within this large group of diseases, we included: (1) hyporegenerative anemias, as congenital dyserythropoietic anemias (CDA) and Diamond‐Blackfan anemia (DBA); (2) erythrocyte membrane defects, as hereditary spherocytosis (HS) and hereditary stomatocytosis (HST); hemolytic anemias due to enzymatic defects, as glucose‐6‐phosphate dehydrogenase (G6PD) and pyruvate kinase (PK) deficiency …”

Section: Introductionmentioning

confidence: 99%

“…Indeed, the variety of unspecific and overlapping phenotypes often hampers a correct clinical management of the patients. Particularly, the diagnosis of these conditions may require several lines of investigation . The first is based on clinical features (evaluation of complete blood count), positive familial history, and the observation of a peripheral blood smear.…”

Section: Introductionmentioning

confidence: 99%

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Multi‐gene panel testing improves diagnosis and management of patients with hereditary anemias

et al. 2018

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Mutations in more than 70 genes cause hereditary anemias (HA), a highly heterogeneous group of rare/low frequency disorders in which we included: hyporegenerative anemias, as congenital dyserythropoietic anemia (CDA) and Diamond-Blackfan anemia; hemolytic anemias due to erythrocyte membrane defects, as hereditary spherocytosis and stomatocytosis; hemolytic anemias due to enzymatic defects. The study describes the diagnostic workflow for HA, based on the development of two consecutive versions of a targeted-NGS panel, including 34 and 71 genes, respectively. Seventy-four probands from 62 unrelated families were investigated. Our study includes the most comprehensive gene set for these anemias and the largest cohort of patients described so far. We obtained an overall diagnostic yield of 64.9%. Despite 54.2% of cases showed conclusive diagnosis fitting well to the clinical suspicion, the multi-gene analysis modified the original clinical diagnosis in 45.8% of patients (nonmatched phenotype-genotype). Of note, 81.8% of nonmatched patients were clinically suspected to suffer from CDA. Particularly, 45.5% of the probands originally classified as CDA exhibited a conclusive diagnosis of chronic anemia due to enzymatic defects, mainly due to mutations in PKLR gene. Interestingly, we also identified a syndromic CDA patient with mild anemia and epilepsy, showing a homozygous mutation in CAD gene, recently associated to early infantile epileptic encephalopathy-50 and CDA-like anemia. Finally, we described a patient showing marked iron overload due to the coinheritance of PIEZO1 and SEC23B mutations, demonstrating that the multi-gene approach is valuable not only for achieving a correct and definitive diagnosis, but also for guiding treatment.

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Section: Resultssupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multi‐gene panel testing improves diagnosis and management of patients with hereditary anemias

et al. 2018

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“…Iron overload represents the most harmful complication of the chronic anemia, as it can lead to organ damage with subsequent failure of the involved tissues. Indeed, we can observe liver cirrhosis, heart failure, diabetes, and hypergonadotropic hypogonadism with related subfertility in some patients . We recently demonstrated that the pathogenesis of iron overload in CDAII is related to the over‐expression of the erythroblast‐derived hormone ERFE, leading to hepcidin suppression …”

Section: Discussionmentioning

confidence: 99%

The BMP‐SMAD pathway mediates the impaired hepatic iron metabolism associated with the ERFE‐A260S variant

et al. 2019

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The erythroferrone (ERFE) is the erythroid regulator of hepatic iron metabolism by suppressing the expression of hepcidin. Congenital dyserythropoietic anemia type II (CDAII) is an inherited hyporegenerative anemia due to biallelic mutations in the SEC23B gene. Patients with CDAII exhibit marked clinical variability, even among individuals sharing the same pathogenic variants. The ERFE expression in CDAII is increased and related to abnormal erythropoiesis. We identified a recurrent low‐frequency variant, A260S, in the ERFE gene in 12.5% of CDAII patients with a severe phenotype. We demonstrated that the ERFE‐A260S variant leads to increased levels of ERFE, with subsequently marked impairment of iron regulation pathways at the hepatic level. Functional characterization of ERFE‐A260S in the hepatic cell system demonstrated its modifier role in iron overload by impairing the BMP/SMAD pathway. We herein described for the first time an ERFE polymorphism as a genetic modifier variant. This was with a mild effect on disease expression, under a multifactorial‐like model, in a condition of iron‐loading anemia due to ineffective erythropoiesis.

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2021

Haematology

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Anaplasticlargecelllymphomawith haemophagocyticsyndrome ALK-negativeanaplasticlargecelllymphoma: 1) GenerallyoccursatanolderagethanALK-positivecases 2) HasabetterprognosisthanALK-positiveanaplasticlargecelllymphoma 3) Hassimilarhistologicalandimmunophenotypicfeaturestobreastimplant-associatedanaplasticlargecelllymphoma 4) Isusuallyassociatedwitht(2;5)(p23.2-23.1;q35.1) 5) Usuallypresentswithlocaliseddisease Correct answers 1, 3ALK-negativeanaplasticlargecelllymphomatypicallyoccursatanolderagethanALK-positive casesandhasaworseprognosis.PresentationisusuallywithstageIIIorIVdisease.Althoughthey arehistologicallyindistinguishable,thesearequitedifferentconditions.ItisALK-positivecases thatareassociatedwitht(2;5),leadingtoformationofanNPM1-ALKfusiongene.Breastimplantassociatedcasesarealsohistologicallyindistinguishablebutareaquitedistinctdiseasethat usually remainslocalisedandhasamuchbetterprognosis. BonemarrowALamyloidosisAmyloidintissuesectionscanbeidentifiedbypositivestainingwith:1) Congored 2) Martiusscarletblue 3) Methenaminesilver 4) Prussianblue 5) Siriusred Correct answers 1, 5CongoredandSiriusredbothstainamyloidand,onexaminationbypolarisedlight,thereisapplegreen birefringence. Martius scarlet blue stains collagen, methenamine silver stains fungi and Prussianbluestainshaemosiderin.

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Hereditary stomatocytosis: An underdiagnosed condition

Cited by 53 publications

References 124 publications

Multi‐gene panel testing improves diagnosis and management of patients with hereditary anemias

Multi‐gene panel testing improves diagnosis and management of patients with hereditary anemias

The BMP‐SMAD pathway mediates the impaired hepatic iron metabolism associated with the ERFE‐A260S variant

Further discussion of the themes

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