From the Guidelines
Ligase IV syndrome is a rare genetic disorder that requires prompt diagnosis and management to prevent severe immunodeficiency, developmental delay, and increased risk of cancer, and should be suspected in patients with recurrent infections, growth retardation, and distinctive facial features. The disorder is characterized by immunodeficiency, developmental delay, microcephaly, and sensitivity to ionizing radiation, resulting from mutations in the LIG4 gene, which encodes DNA ligase IV, an enzyme crucial for repairing double-strand DNA breaks through non-homologous end joining 1. Patients typically present with:
- Recurrent infections due to combined immunodeficiency affecting both B and T lymphocytes
- Growth retardation
- Distinctive facial features, including bird-like facies
- Hypogammaglobulinemia G and A with normal IgM levels, reported in about one third of patients, supporting a defect in class-switch recombination 1
- T-cell responses to mitogens are variably affected in 90% of patients 1 Management focuses on:
- Preventing and treating infections through immunoglobulin replacement therapy
- Prophylactic antibiotics
- Careful monitoring of immune function
- Hematopoietic stem cell transplantation may be considered for severe immunodeficiency cases, though patients require reduced-intensity conditioning regimens due to their heightened sensitivity to radiation and chemotherapy
- Developmental support services are essential for addressing neurological manifestations
- Patients should avoid unnecessary radiation exposure, including diagnostic X-rays when possible Early diagnosis through genetic testing is important for implementing appropriate management strategies and genetic counseling, as Ligase IV syndrome follows an autosomal recessive inheritance pattern, meaning both parents must carry a mutation for a child to be affected 1.
From the Research
Clinical Features of Ligase IV Syndrome
- Ligase IV syndrome is a rare autosomal recessive disorder characterized by progressive bone marrow failure, predisposition to malignancy, and severe combined immunodeficiency (SCID) 2
- Patients with Ligase IV syndrome often present with microcephaly, growth failure, and pancytopenia, as well as hypogonadism and immunodeficiency 3
- The syndrome can also present with radial ray anomalies and fatal kidney malformations, similar to Fanconi anemia 4
- Common features of Ligase IV syndrome include primordial growth failure, severe microcephaly, learning difficulties, marrow hypoplasia, and a predisposition to lymphoid malignancy 5
- Extreme growth failure is a common presentation of Ligase IV deficiency, with patients often having restricted prenatal growth and extreme postnatal global growth failure 6
Diagnosis and Treatment of Ligase IV Syndrome
- Diagnostic investigations for Ligase IV syndrome include immunophenotyping and testing for radiosensitivity 5
- Treatment for Ligase IV syndrome is mainly supportive, although hematopoietic stem cell transplantation (HSCT) has been used in a few cases 2, 5
- HSCT can be an effective treatment option for Ligase IV syndrome, with some patients achieving full reconstitution of their immune system and living a normal life 2
Genetic Basis of Ligase IV Syndrome
- Ligase IV syndrome is caused by hypomorphic mutations in the DNA ligase IV (LIG4) gene 2
- The LIG4 gene is essential for the development of a healthy immune system and for the protection of genomic integrity 2
- Biallelic truncating mutations in LIG4 can result in a range of phenotypes, from normal to severe combined immunodeficiency 5, 6
- A genotype-phenotype correlation has been noted, with the position of truncating mutations corresponding to disease severity 6