Cornelia de Lange syndrome (CdLS) is a rare genetic disorder with an estimated prevalence of 1 in 10,000 live births worldwide. It presents with a spectrum of severity, ranging from mild to severe marked by characteristic facial features, growth delay, intellectual disability, heart defects, gastrointestinal issues, hearing loss, myopia, and frequent upper and lower respiratory infections. The majority of genetic variants found in CdLS are associated with variants in the NIPBL gene, which encodes a regulatory protein crucial for the function of the cohesin complex.
We present an 8-year-old male with a history of dysmorphic facial features, global developmental delay, aortic coarctation, lagophthalmos, hearing loss, and recurrent upper and lower sinopulmonary infections. There is no family history of immunodeficiencies or other genetic syndromes and patients born outside the United States. Commercial whole-exome sequencing performed at 7 years of age revealed a heterozygous de novo pathogenic variant in NIPBL (c.8257 C>G, p.R2753G). Complete blood count with differential, basic lymphocyte subsets, and immunoglobulins were within normal limits. Patient was immune to varicella, hepatitis B, tetanus, and diphtheria post-vaccination but only had 1/23 strep pneumoniae titers above 1.3 ug/mL and only 4/23 above 0.5 ug/mL after primary Prevnar 13 series. Advanced phenotyping showed increased percentage of transitional B cells, increased proportion of CD8+ TEMRA cells, reverse CD4/CD8 ratio at 0.69, and normal mitogen-induced lymphocyte proliferation to PHA and ConA with PWM at 50% below the lower limit of normal. Patient given booster vaccination with Pneumovax and had improvement in strep pneumoniae titers to 16/23 protective above 1.3 ug/mL and decreased clinical infections.
The cohesin protein complex plays a significant role in the immune system, and altered expression of immune-related genes in patients with CdLS may explain the varying degrees of immunodeficiency observed in these individuals. Although no specific immune defect has been universally identified in CdLS, and there are no established guidelines for managing immune issues or vaccination in this population, it is important to conduct clinical immunologic evaluations for CdLS patients who experience recurrent infections as booster vaccinations can significantly improve these patients’ quality of life.
