title: A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD).
abstract: Congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders identified by pathological erythroid precursors with perinuclear mitochondrial iron deposition in bone marrow. An international collaborative group of physicians and laboratory scientists collated clinical information on cases of CSA lacking known causative mutations, identifying a clinical subgroup of CSA associated with B immunodeficiency, periodic fevers, and development delay. Twelve cases from 10 families were identified. Median age at presentation was 2 months. Anemia at diagnosis was sideroblastic, typically severe (median hemoglobin, 7.1 g/dL) and markedly microcytic (median mean corpuscular volume, 62.0 fL). Clinical course involved recurrent febrile illness and gastrointestinal disturbance, lacking an infective cause. Investigation revealed B-cell lymphopenia (CD19⁺ range, 0.016-0.22 × 10⁹/L) and panhypogammaglobulinemia in most cases. Children displayed developmental delay alongside variable neurodegeneration, seizures, cerebellar abnormalities, sensorineural deafness, and other multisystem features. Most required regular blood transfusion, iron chelation, and intravenous immunoglobulin replacement. Median survival was 48 months, with 7 deaths caused by cardiac or multiorgan failure. One child underwent bone marrow transplantation aged 9 months, with apparent cure of the hematologic and immunologic manifestations. We describe and define a novel CSA and B-cell immunodeficiency syndrome with additional features resembling a mitochondrial cytopathy. The molecular etiology is under investigation.
authors.affiliation: Department of Haematology, Royal Manchester Children's Hospital, Manchester, United Kingdom. dwiseman@picr.man.ac.uk
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Wiseman
authors.forename: Alison
authors.initials: A
authors.lastname: May
authors.forename: Stephen
authors.initials: S
authors.lastname: Jolles
authors.forename: Philip
authors.initials: P
authors.lastname: Connor
authors.forename: Colin
authors.initials: C
authors.lastname: Powell
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Heeney
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Giardina
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klaassen
authors.forename: Pranesh
authors.initials: P
authors.lastname: Chakraborty
authors.forename: Michael T
authors.initials: MT
authors.lastname: Geraghty
authors.forename: Nathalie
authors.initials: N
authors.lastname: Major-Cook
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thuret
authors.forename: Alexis A
authors.initials: AA
authors.lastname: Thompson
authors.forename: Laura
authors.initials: L
authors.lastname: Marques
authors.forename: Stephen
authors.initials: S
authors.lastname: Hughes
authors.forename: Denise K
authors.initials: DK
authors.lastname: Bonney
authors.forename: Sylvia S
authors.initials: SS
authors.lastname: Bottomley
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.forename: Robert F
authors.initials: RF
authors.lastname: Wynn
mesh_terms: D000756:Anemia, Sideroblastic / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology*; D002658:Developmental Disabilities / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D010505:Familial Mediterranean Fever / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009422:Nervous System Diseases / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome
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