LIG4 syndrome

Overview

LIG4 syndrome is a rare autosomal recessive genetic disorder caused by mutations in the LIG4 gene, which plays a critical role in DNA repair. The condition is classified as a DNA repair disorder and is part of the group of syndromes known as "chromosomal instability syndromes." Individuals with LIG4 syndrome typically present with microcephaly, growth retardation, immune system defects (especially severe combined immunodeficiency or SCID-like features), and increased sensitivity to ionizing radiation. Due to impaired DNA repair, affected individuals may also have an increased risk of cancer, particularly hematologic malignancies.

Causes

LIG4 syndrome is caused by biallelic mutations in the LIG4 gene, located on chromosome 13. This gene encodes DNA ligase IV, an enzyme essential for repairing double-strand DNA breaks through the non-homologous end joining (NHEJ) pathway. When this gene is mutated, cells are unable to efficiently repair DNA damage, particularly during V(D)J recombination, which is necessary for the development of functional immune cells. The disorder follows an autosomal recessive inheritance pattern, meaning a child must inherit two defective copies of the LIG4 gene (one from each parent) to be affected.

Symptoms

The clinical presentation of LIG4 syndrome is variable but may include:

• Microcephaly – abnormally small head size, usually present at birth

• Growth retardation – failure to thrive and short stature

• Developmental delays – affecting motor and cognitive milestones

• Immunodeficiency – ranging from mild immune dysfunction to severe combined immunodeficiency (SCID), leading to recurrent infections

• Pancytopenia or bone marrow failure – in some patients

• Increased sensitivity to ionizing radiation

• Facial dysmorphism – such as a prominent forehead, deep-set eyes, or other subtle features

• Increased cancer risk – especially leukemia or lymphoma in childhood

Diagnosis

Diagnosis of LIG4 syndrome is based on a combination of clinical features, laboratory findings, and genetic testing. Diagnostic steps include:

• Complete blood count (CBC) – may show cytopenias or signs of bone marrow dysfunction

• Immunological workup – to assess levels and function of B and T cells, immunoglobulins, and response to vaccines

• Cellular sensitivity assays – measuring increased sensitivity to ionizing radiation or DNA-damaging agents

• Genetic testing – confirmation of mutations in both alleles of the LIG4 gene through whole exome or targeted gene panel sequencing

Early diagnosis is essential for initiating protective measures and tailored treatment.

Treatment

Treatment for LIG4 syndrome is supportive and focuses on managing immunodeficiency, preventing infections, and minimizing DNA damage exposure. Options include:

• Immunoglobulin replacement therapy – for patients with antibody deficiencies

• Prophylactic antibiotics – to reduce the frequency of infections

• Avoidance of radiation exposure – including diagnostic imaging like CT scans

• Hematopoietic stem cell transplantation (HSCT) – considered in cases with severe immunodeficiency or bone marrow failure

• Growth and developmental support – through physical, occupational, and speech therapies

• Oncology surveillance – for early detection of hematological malignancies

Prognosis

The prognosis for individuals with LIG4 syndrome varies based on the severity of the immunodeficiency and the risk of malignancy. Some patients may have a milder form and survive into adolescence or adulthood with supportive care, while others may develop life-threatening infections or cancers at an early age. Hematopoietic stem cell transplantation can improve survival in severe cases, but outcomes depend on timing and donor availability. Lifelong medical follow-up and multidisciplinary care are essential for managing complications and improving quality of life.