The patient is a 3-year-old female with a history of hypoxic-ischemic encephalopathy, cerebral palsy, global developmental delay, hypotonia, epilepsy, feeding intolerance with known aspirations, and chronic lung disease who presented to immunology for evaluation of recurrent, severe upper and lower respiratory tract infections. In the past year, she reported monthly upper respiratory infections, three of which progressed to pneumonia requiring antibiotic treatment, and two of which required hospitalization for severe respiratory failure. She denied lifetime otitis, sinusitis, cutaneous, or other invasive or serious infections.
Immunological evaluation demonstrated normal lymphocyte subsets, B cell phenotyping, naïve/memory T cell phenotyping, immunoglobulins, non-protective tetanus titer, protective diphtheria titer, and protective hepatitis B titer. The patient had 2/23 Streptococcus pneumoniae titers protective above 1.3 mcg/mL after initial Prevnar 13 administration and then only 4/14 S. pneumoniae titers protective above 1.3 mcg/mL after Pneumovax 23 booster. The patient had normal lymphocyte proliferative responses to PHA, PWM, soluble anti-CD3, and anti–CD3+IL-2 though decreased to soluble anti–CD+anti-CD28.
Genetic testing detected a heterozygous known pathogenic VARS2 variant (c.1546G>T and p.Glu516*) associated with autosomal recessive combined oxidative phosphorylation deficiency in addition to 9p24.2 duplication. VARS2 encodes a key enzyme for mitochondrial protein synthesis 1. 9p duplication is associated with global developmental delay similar to the patient’s phenotype but has not been specifically linked to abnormalities in the immune system.
Despite initial treatment with prophylactic azithromycin and revaccination for S. pneumoniae, the patient developed COVID-19 pneumonia and rhino enterovirus with severe respiratory failure requiring two separate hospitalizations over three months and no significant improvement in strep pneumoniae titers. Subcutaneous immunoglobulin replacement therapy was initiated, and she has been on biweekly subcutaneous immunoglobulin replacement for four months with symptomatic improvement and no further infectious diagnosis.
This case highlights that patients with 9p duplication and other rare genetic disorders are at risk for immune dysfunction and can benefit from replacement immunoglobulin. Patients with rare genetic disorders that have not been previously linked to immune dysfunction should be evaluated by an immunologist if recurrent infections.
