The ERCC2 gene, located on chromosome 19, is essential for transcription and DNA repair via its protein product, XPD. Mutations in ERCC2 cause disorders such as trichothiodystrophy-1, xeroderma pigmentosum, Cockayne syndrome, or overlapping phenotypes. XPD functions as a helicase within the nucleotide excision repair pathway, correcting single-stranded DNA damage from ultraviolet radiation and chemical exposures. Immunologically, ERCC2 deficiency has been associated with increased infection susceptibility, potentially due to impaired adaptive immune responses.
A female term infant was noted to be small for gestational age (2nd percentile) and microcephalic. She was admitted at 7 days of life (DOL) with acute hypoxemic respiratory failure secondary to Rhinovirus/Enterovirus infection. After initial improvement, she clinically worsened on DOL 12, requiring intubation, and was diagnosed with Haemophilus influenzae pneumonia and conjunctivitis. An immunologic evaluation on DOL 22 showed age-appropriate CD3, CD4, CD8, and CD19 counts but decreased CD16/56 cells, normal thymic T cell output (54% CD3+CD4+CD45RA+CD31+ cells), and a decrease in PHA-induced T cell proliferation. Immunoglobulins (mg/dL) were notable for elevated IgM and undetectable IgA (IgM 112, IgG 500). At DOL 36, infectious symptoms had improved on antibiotic therapy, and immunoglobulin levels normalized (IgM 58, IgG 292, IgA 11.6). Whole-genome sequencing, pursued due to neurologic concerns, revealed 2 inherited pathogenic ERCC2 variants in trans (c.1847 G>C; p.R616P and c.1996 C>T; p.R666W), consistent with compound heterozygosity and autosomal recessive ERCC2-related disorder.
Family history was largely unremarkable aside from reported adverse reactions to vaccines, resulting in reduced vaccinations of siblings (including no vaccines against Haemophilus influenzae B) who experienced upper respiratory infections at the time of her birth.
This case describes an infant with an ERCC2-related disorder who developed an invasive H. influenzae infection. Given the patient’s age, the infection was likely due to reduced herd immunity in her household rather than a direct consequence of ERCC2 dysfunction. However, early identification of the mutations is important, as ongoing immunologic assessment and characterization of her clinical phenotype will be required. Furthermore, impaired nucleotide excision repair increases long-term malignancy risk, underscoring the need for close multidisciplinary follow-up.
