LIG4 syndrome D81.0

Very rare (<50 patients) complex immune deficiency syndrome in increased radiosensitivity (OMIM: 606593) associated with defects in the LIG4 gene. Clinically, it presents with a wide spectrum of (inconstant) clinical features, including microcephaly, growth retardation, developmental delay, often dysmorphic facial features, combined immunodeficiency, and a predisposition to malignancies (Sun B et al. 2020).

All patients reported by Sun B et al. had heterozygous mutations in the LIG4 gene consisting of a missense mutation (c.833G > T, p.R278L) and a deletion shift mutation, mainly c.1271_1275delAAAGA (p.K424Rfs*20). Two other deletion mutations, c.1144_1145delCT and c.1277_1278delAA, were novel.

Sun B et al. 2020 reported seven patients with combined immunodeficiency. The patients were growth restricted. Most patients (6/7) had significant microcephaly. Recurrent bacterial infections of the lung and intestine were the most common symptoms. One patient was diagnosed with myelodysplastic syndrome. In another, inflammatory bowel disease (IBD). The proportion of naive CD4+ and naive CD8+ T cells was significantly reduced in five patients.

O'Driscoll et al (2001) identified four patients with features such as immunodeficiency, developmental and growth retardation who had mutations in the LIG4 gene. The clinical phenotype, which they termed LIG4 syndrome, strongly resembled the DNA damage response disorder Nijmegen breakage syndrome. The patients' cell lines showed marked radiosensitivity.

Ben-Omran et al (2005) reported a 4-year-old boy with acute T-cell leukemia and a facial appearance reminiscent of Nijmegen-Breakage syndrome.

Van der Burg et al (2006) reported a patient with severe combined immunodeficiency and sensitivity to ionizing radiation. The patient (consanguineous Turkish parents), developed severe recurrent bacterial infections as well as candida infections in the second year of life. She had no dysmorphic features or neurologic abnormalities. Laboratory analysis revealed decreased immunoglobulins, decreased numbers of B and T cells, normal NK cell levels, and almost undetectable levels of LIG4 protein.

Umbilical Cord Blood Stem Cell Transplantation (UCBSCT).

1. Ben-Omran TI et al (2005) A patient with mutations in DNA ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet 137A: 283-287.
2. Girard PM et al (2004) Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms. Hum Molec Genet 13: 2369-2376.
3. O'Driscoll M et al (2001) DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Molec Cell 8: 1175-1185.
4. Sun B et al (2020) LIG4 syndrome: clinical and molecular characterization in a Chinese cohort. Orphanet J Rare Dis 15:131.