Lung Disease, Immunodeficiency, And Chromosome Breakage Syndrome

A number sign (#) is used with this entry because of evidence that lung disease, immunodeficiency, and chromosome breakage syndrome (LICS) is caused by homozygous or compound heterozygous mutation in the NSMCE3 gene (608243) on chromosome 15q13.

Description

LICS is an autosomal recessive chromosome breakage syndrome characterized by failure to thrive in infancy, immune deficiency, and fatal progressive pediatric lung disease induced by viral infection. Some patients may have mild dysmorphic features (summary by van der Crabben et al., 2016).

Clinical Features

Van der Crabben et al. (2016) reported 4 children from 2 unrelated families who died in early childhood after developing rapidly progressive pulmonary disease following multiple episodes of viral pneumonia. Two sisters from a Dutch family were noted to have feeding difficulties, failure to thrive, mild psychomotor retardation, axial hypotonia, eczema, and increased susceptibility to infection. One sister had mild dysmorphic features, including large open fontanel and thin translucent skin with prominent veins. Karyotyping of peripheral lymphocytes showed multiple de novo supernumerary marker chromosomes and chromosome rearrangements. Immunologic work-up showed decreased numbers of T cells, decreased T-cell proliferative response, and impaired antibody responses. B lymphocytes levels were normal. One sister had thymic hypoplasia. Two sibs with a similar disorder from the other family had thymic hypoplasia. One sib had mild dysmorphic features, including large anterior fontanel, widely spaced eyes, flat midface, and flat nasal bridge. Lymphocytes from 1 sib showed increased sensitivity to ionizing radiation. Patients from both families died before 3 years of age. Lung abnormalities included interstitial infiltrates, alveolar damage, eosinophilic and lymphocytic pneumonia, lobular fibrosis, lobular remodeling, bronchiolitis obliterans, organizing pneumonia, interstitial fibroplasia, cystic remodeling, hyperinflation, emphysema, and interstitial hemorrhage.

Inheritance

The transmission pattern of LICS in the families reported by van der Crabben et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 children from 2 unrelated families with LICS, van der Crabben et al. (2016) identified homozygous or compound heterozygous missense mutations in the NSMCE3 gene (L264F, 608243.0001 and P209L, 608243.0002). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing, were confirmed by Sanger sequencing and segregated with the disorder in the families. Patient cells from both families showed undetectable levels of NSMCE3 as well as decreased levels of SMC5 (609386) and SMC6 (609387). In vitro studies showed that the L264F mutation abolished binding of NSMCE3 to NSMCE4 (612987) and the P209L mutation abolished binding to both NSMCE4 and NSMCE1 (617263). Patient cells showed increased sensitivity to genotoxins and impaired DNA repair due to defective homologous recombination. Nonhomologous recombination, and thus V(D)J recombination, was normal.