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DNA ligase IV deficiency

MedGen UID:
339855
Concept ID:
C1847827
Disease or Syndrome
Synonym: Lig4 syndrome
SNOMED CT: LIG4 syndrome (724177005); Deoxyribonucleic acid ligase IV deficiency (724177005); DNA (deoxyribonucleic acid) ligase IV deficiency (724177005); LIG4 (ligase 4) syndrome (724177005); Ligase 4 syndrome (724177005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): LIG4 (13q33.3)
 
Monarch Initiative: MONDO:0011686
OMIM®: 606593
Orphanet: ORPHA99812

Definition

A hereditary disorder associated with impaired DNA double-strand break repair mechanisms with characteristics of microcephaly, unusual facial features, growth and developmental delay, skin anomalies, and pancytopenia, which is associated with combined immunodeficiency. Caused by mutations in the LIG4 gene (13q22-q34). The resulting defect of DNA ligase IV, a component of the classical non-homologous end-joining (NHEJ) pathway, affects the major mechanism of DNA double-strand break repair. Transmission is autosomal recessive. [from SNOMEDCT_US]

Clinical features

From HPO
Myelodysplasia
MedGen UID:
10231
Concept ID:
C0026985
Congenital Abnormality
Clonal hematopoietic stem cell disorders characterized by dysplasia (ineffective production) in one or more hematopoietic cell lineages, leading to anemia and cytopenia.
Amenorrhea
MedGen UID:
8016
Concept ID:
C0002453
Finding
Absence of menses for an interval of time equivalent to a total of more than (or equal to) 3 previous cycles or 6 months.
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Psoriasiform dermatitis
MedGen UID:
75508
Concept ID:
C0262985
Disease or Syndrome
A skin abnormality characterized by redness and irritation, with thick, red skin that displays flaky, silver-white patches (scales).
Prominent nose
MedGen UID:
98423
Concept ID:
C0426415
Finding
Distance between subnasale and pronasale more than two standard deviations above the mean, or alternatively, an apparently increased anterior protrusion of the nasal tip.
Narrow forehead
MedGen UID:
326956
Concept ID:
C1839758
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
Telangiectasia
MedGen UID:
21088
Concept ID:
C0039446
Finding
Telangiectasias refer to small dilated blood vessels located near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. Telangiectasia are located especially on the tongue, lips, palate, fingers, face, conjunctiva, trunk, nail beds, and fingertips.
Cutaneous photosensitivity
MedGen UID:
87601
Concept ID:
C0349506
Pathologic Function
An increased sensitivity of the skin to light. Photosensitivity may result in a rash upon exposure to the sun (which is known as photodermatosis). Photosensitivity can be diagnosed by phototests in which light is shone on small areas of skin.
Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
Deficiency of thyroid hormone.
Hypotelorism
MedGen UID:
96107
Concept ID:
C0424711
Finding
Interpupillary distance less than 2 SD below the mean (alternatively, the appearance of an decreased interpupillary distance or closely spaced eyes).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVDNA ligase IV deficiency
Follow this link to review classifications for DNA ligase IV deficiency in Orphanet.

Professional guidelines

PubMed

Carrozzo R, Verrigni D, Rasmussen M, de Coo R, Amartino H, Bianchi M, Buhas D, Mesli S, Naess K, Born AP, Woldseth B, Prontera P, Batbayli M, Ravn K, Joensen F, Cordelli DM, Santorelli FM, Tulinius M, Darin N, Duno M, Jouvencel P, Burlina A, Stangoni G, Bertini E, Redonnet-Vernhet I, Wibrand F, Dionisi-Vici C, Uusimaa J, Vieira P, Osorio AN, McFarland R, Taylor RW, Holme E, Ostergaard E
J Inherit Metab Dis 2016 Mar;39(2):243-52. Epub 2015 Oct 16 doi: 10.1007/s10545-015-9894-9. PMID: 26475597

Recent clinical studies

Etiology

Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, Booth C, Buechner J, Buckley RH, Ouachée-Chardin M, Deripapa E, Drabko K, Eapen M, Feuchtinger T, Finocchi A, Gaspar HB, Ghosh S, Gillio A, Gonzalez-Granado LI, Grunebaum E, Güngör T, Heilmann C, Helminen M, Higuchi K, Imai K, Kalwak K, Kanazawa N, Karasu G, Kucuk ZY, Laberko A, Lange A, Mahlaoui N, Meisel R, Moshous D, Muramatsu H, Parikh S, Pasic S, Schmid I, Schuetz C, Schulz A, Schultz KR, Shaw PJ, Slatter MA, Sykora KW, Tamura S, Taskinen M, Wawer A, Wolska-Kuśnierz B, Cowan MJ, Fischer A, Gennery AR; Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiencies; Stem Cell Transplant for Immunodeficiencies in Europe (SCETIDE); Center for International Blood and Marrow Transplant Research; Primary Immunodeficiency Treatment Consortium
J Allergy Clin Immunol 2018 Jan;141(1):322-328.e10. Epub 2017 Apr 7 doi: 10.1016/j.jaci.2017.02.036. PMID: 28392333Free PMC Article
Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M
Orphanet J Rare Dis 2012 Feb 28;7:13. doi: 10.1186/1750-1172-7-13. PMID: 22373003Free PMC Article
Chistiakov DA, Voronova NV, Chistiakov AP
Eur J Med Genet 2009 Nov-Dec;52(6):373-8. Epub 2009 May 23 doi: 10.1016/j.ejmg.2009.05.009. PMID: 19467349

Diagnosis

Castro ACE, Maia R, Batalha S, Freixo JP, Martins C, Neves C, Cordeiro AI, Neves JF
Front Immunol 2022;13:869728. Epub 2022 May 3 doi: 10.3389/fimmu.2022.869728. PMID: 35592332Free PMC Article
Schober S, Schilbach K, Doering M, Cabanillas Stanchi KM, Holzer U, Kasteleiner P, Schittenhelm J, Schaefer JF, Mueller I, Lang P, Handgretinger R
BMC Pediatr 2019 Oct 11;19(1):346. doi: 10.1186/s12887-019-1724-z. PMID: 31604460Free PMC Article
Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, Booth C, Buechner J, Buckley RH, Ouachée-Chardin M, Deripapa E, Drabko K, Eapen M, Feuchtinger T, Finocchi A, Gaspar HB, Ghosh S, Gillio A, Gonzalez-Granado LI, Grunebaum E, Güngör T, Heilmann C, Helminen M, Higuchi K, Imai K, Kalwak K, Kanazawa N, Karasu G, Kucuk ZY, Laberko A, Lange A, Mahlaoui N, Meisel R, Moshous D, Muramatsu H, Parikh S, Pasic S, Schmid I, Schuetz C, Schulz A, Schultz KR, Shaw PJ, Slatter MA, Sykora KW, Tamura S, Taskinen M, Wawer A, Wolska-Kuśnierz B, Cowan MJ, Fischer A, Gennery AR; Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiencies; Stem Cell Transplant for Immunodeficiencies in Europe (SCETIDE); Center for International Blood and Marrow Transplant Research; Primary Immunodeficiency Treatment Consortium
J Allergy Clin Immunol 2018 Jan;141(1):322-328.e10. Epub 2017 Apr 7 doi: 10.1016/j.jaci.2017.02.036. PMID: 28392333Free PMC Article
Altmann T, Gennery AR
Orphanet J Rare Dis 2016 Oct 7;11(1):137. doi: 10.1186/s13023-016-0520-1. PMID: 27717373Free PMC Article
Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M
Orphanet J Rare Dis 2012 Feb 28;7:13. doi: 10.1186/1750-1172-7-13. PMID: 22373003Free PMC Article

Therapy

Schober S, Schilbach K, Doering M, Cabanillas Stanchi KM, Holzer U, Kasteleiner P, Schittenhelm J, Schaefer JF, Mueller I, Lang P, Handgretinger R
BMC Pediatr 2019 Oct 11;19(1):346. doi: 10.1186/s12887-019-1724-z. PMID: 31604460Free PMC Article
Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, Booth C, Buechner J, Buckley RH, Ouachée-Chardin M, Deripapa E, Drabko K, Eapen M, Feuchtinger T, Finocchi A, Gaspar HB, Ghosh S, Gillio A, Gonzalez-Granado LI, Grunebaum E, Güngör T, Heilmann C, Helminen M, Higuchi K, Imai K, Kalwak K, Kanazawa N, Karasu G, Kucuk ZY, Laberko A, Lange A, Mahlaoui N, Meisel R, Moshous D, Muramatsu H, Parikh S, Pasic S, Schmid I, Schuetz C, Schulz A, Schultz KR, Shaw PJ, Slatter MA, Sykora KW, Tamura S, Taskinen M, Wawer A, Wolska-Kuśnierz B, Cowan MJ, Fischer A, Gennery AR; Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiencies; Stem Cell Transplant for Immunodeficiencies in Europe (SCETIDE); Center for International Blood and Marrow Transplant Research; Primary Immunodeficiency Treatment Consortium
J Allergy Clin Immunol 2018 Jan;141(1):322-328.e10. Epub 2017 Apr 7 doi: 10.1016/j.jaci.2017.02.036. PMID: 28392333Free PMC Article

Prognosis

Castro ACE, Maia R, Batalha S, Freixo JP, Martins C, Neves C, Cordeiro AI, Neves JF
Front Immunol 2022;13:869728. Epub 2022 May 3 doi: 10.3389/fimmu.2022.869728. PMID: 35592332Free PMC Article
Schober S, Schilbach K, Doering M, Cabanillas Stanchi KM, Holzer U, Kasteleiner P, Schittenhelm J, Schaefer JF, Mueller I, Lang P, Handgretinger R
BMC Pediatr 2019 Oct 11;19(1):346. doi: 10.1186/s12887-019-1724-z. PMID: 31604460Free PMC Article
Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, Booth C, Buechner J, Buckley RH, Ouachée-Chardin M, Deripapa E, Drabko K, Eapen M, Feuchtinger T, Finocchi A, Gaspar HB, Ghosh S, Gillio A, Gonzalez-Granado LI, Grunebaum E, Güngör T, Heilmann C, Helminen M, Higuchi K, Imai K, Kalwak K, Kanazawa N, Karasu G, Kucuk ZY, Laberko A, Lange A, Mahlaoui N, Meisel R, Moshous D, Muramatsu H, Parikh S, Pasic S, Schmid I, Schuetz C, Schulz A, Schultz KR, Shaw PJ, Slatter MA, Sykora KW, Tamura S, Taskinen M, Wawer A, Wolska-Kuśnierz B, Cowan MJ, Fischer A, Gennery AR; Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiencies; Stem Cell Transplant for Immunodeficiencies in Europe (SCETIDE); Center for International Blood and Marrow Transplant Research; Primary Immunodeficiency Treatment Consortium
J Allergy Clin Immunol 2018 Jan;141(1):322-328.e10. Epub 2017 Apr 7 doi: 10.1016/j.jaci.2017.02.036. PMID: 28392333Free PMC Article
Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M
Orphanet J Rare Dis 2012 Feb 28;7:13. doi: 10.1186/1750-1172-7-13. PMID: 22373003Free PMC Article
Gruhn B, Seidel J, Zintl F, Varon R, Tönnies H, Neitzel H, Bechtold A, Hoehn H, Schindler D
Orphanet J Rare Dis 2007 Jan 15;2:5. doi: 10.1186/1750-1172-2-5. PMID: 17224058Free PMC Article

Clinical prediction guides

Karanjawala ZE, Adachi N, Irvine RA, Oh EK, Shibata D, Schwarz K, Hsieh CL, Lieber MR
DNA Repair (Amst) 2002 Dec 5;1(12):1017-26. doi: 10.1016/s1568-7864(02)00151-9. PMID: 12531011

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