title: Extreme growth failure is a common presentation of ligase IV deficiency.
abstract: Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho-reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC -10.1 s.d., height -5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype-phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Jennie E
authors.initials: JE
authors.lastname: Murray
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.forename: Gökhan
authors.initials: G
authors.lastname: Yigit
authors.forename: Angela L
authors.initials: AL
authors.lastname: Duker
authors.forename: Margriet
authors.initials: M
authors.lastname: van Kogelenberg
authors.forename: Sara
authors.initials: S
authors.lastname: Haghayegh
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wise
authors.forename: January
authors.initials: J
authors.lastname: Brandon
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Adilia
authors.initials: A
authors.lastname: Warris
authors.forename: Michiel
authors.initials: M
authors.lastname: van der Flier
authors.forename: J Steven
authors.initials: JS
authors.lastname: Bamforth
authors.forename: Kurston
authors.initials: K
authors.lastname: Doonanco
authors.forename: Lesley
authors.initials: L
authors.lastname: Adès
authors.forename: Alan
authors.initials: A
authors.lastname: Ma
authors.forename: Michael
authors.initials: M
authors.lastname: Field
authors.forename: Diana
authors.initials: D
authors.lastname: Johnson
authors.forename: Fiona
authors.initials: F
authors.lastname: Shackley
authors.forename: Helen
authors.initials: H
authors.lastname: Firth
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gatti
authors.forename: Matthew
authors.initials: M
authors.lastname: Hurles
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bober
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D056704:Adaptive Immunity; D000293:Adolescent; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000172:deficiency* / Q000235:genetics*; D004392:Dwarfism / Q000235:genetics*; D059472:Exome; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007970:Leukopenia / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics; D009369:Neoplasms / Q000235:genetics; D049932:Nijmegen Breakage Syndrome / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D013921:Thrombocytopenia / Q000235:genetics*
chemical_list: C000607893:LIG4 protein, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP
keywords: DNA repair; LIG4; cytopenia; immunodeficiency; ligase IV; malignancy; nonhomologous end joining; radiosensitivity