Contract grant sponsors: MRC; Wellcome Trust (WT098051); Texas Scottish Rite Hospital for Children Research Fund; Potentials Foundation and Walking With Giants Foundation (WWGF).
Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency
Article first published online: 8 NOV 2013
© 2013 The Authors. *Human Mutation published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 35, Issue 1, pages 76–85, January 2014
How to Cite
Murray, J. E., Bicknell, L. S., Yigit, G., Duker, A. L., van Kogelenberg, M., Haghayegh, S., Wieczorek, D., Kayserili, H., Albert, M. H., Wise, C. A., Brandon, J., Kleefstra, T., Warris, A., van der Flier, M., Bamforth, J. S., Doonanco, K., Adès, L., Ma, A., Field, M., Johnson, D., Shackley, F., Firth, H., Woods, C. G., Nürnberg, P., Gatti, R. A., Hurles, M., Bober, M. B., Wollnik, B. and Jackson, A. P. (2014), Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency. Hum. Mutat., 35: 76–85. doi: 10.1002/humu.22461
Communicated by Arnold Munnich
- Issue published online: 18 DEC 2013
- Article first published online: 8 NOV 2013
- Accepted manuscript online: 10 OCT 2013 11:57AM EST
- Manuscript Accepted: 24 SEP 2013
- Manuscript Received: 25 MAR 2013
- Wellcome Trust. Grant Number: WT098051
- Texas Scottish Rite Hospital for Children Research Fund
- Potentials Foundation and Walking With Giants Foundation (WWGF)
- ligase IV;
- nonhomologous end joining;
- DNA repair;
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.