Age: 7.0
Sex: M
Vaccine: PPV
Symptoms: Adenosine deaminase decreased, Blood immunoglobulin G decreased, Combined immunodeficiency
Clinical narrative: This literature marketed report has been received from the author of a published article and referring to a 7 year old male patient. Objectives: The patient presents for evaluation of bronchiectasis of bilateral lower lobes and poor growth. Past medical history was significant for gastroesophageal reflux disease (GERD) with poor weight gain during infancy and childhood, oral thrush, recurrent respiratory infections and bilateral partial hearing loss. The bronchoalveolar lavage (BAL) showed abundant neutrophils and was positive for Strep pneumoniae and Haemophilus influenza. Methods: Serum immunoglobulins were normal with an elevated IgA (369) and mildly elevated IgE (361). Tetanus IgG was protective (0.4 IU/mL) but post-vaccine responses to the pneumococcal vaccine, polyvalent (23-valent) (manufacturer unknown) were poor with protective titers achieved to 3/14 serotypes. Lymphocyte phenotyping was remarkable for a complete absence of B and NK cells. CD4:CD8 ratio was inverted (0.25) and the majority of the CD45+ T cells were memory phenotype. Mitogen proliferation was essentially normal. Due to the absence of B cells and despite normal total serum immunoglobulins, the patient was started on subcutaneous immunoglobulin (SC IG) weekly and antibiotic prophylaxis with trimethoprim-sulfamethoxazole and fluconazole. Clinically he demonstrated good weight gain and a reduction in cough and respiratory symptoms. Results: Whole exome sequencing was performed. A single base mutation in ADA1 (c.320 T>C) was identified in one allele. This mutation (p.L107P) is known to be deleterious and when homozygous is associated with typical severe combined immunodeficiency (SCID). However, this mutation was not present on the other allele. Secondary analysis looking for large deletions and duplications failed to identify any abnormality in sequence in the normal allele. But the expression of this allele was markedly diminished causing us to suspect that its function might be impaired. Functional testing was performed and demonstrated that there was no adenosine deaminase (ADA) activity in the patient's red blood cells, thus confirming a diagnosis of combined immune deficiency due to ADA deficiency. Conclusions: Null mutations in ADA result in an absence of ADA function with profound CD3 cell lymphopenia and dysfunction. Clinically affected infants have typical SCID. Hypomorphic mutations may lead to partial function of ADA with more variable immune defects. Interestingly, most patients with ADA deficiency have neurologic complications, frequently hearing loss. We believe that most likely this patient has had some degree of spontaneous reversion of the mutation in the normal allele leading to a less severe phenotype. As reported previously in a case involving a mutation in Interleukin 2 Receptor Subunit Gamma (IL2RG) chain, normal function was not restored and the patient remains with a combined immune deficiency. This case highlights an important limitation of whole exome sequencing and the need for confirming the impact of a genetic defect with a functional assay. The outcome of post-vaccine responses were poor with protective titers achieved to 3/14 serotypes was unknown. The author considered the event to be related to pneumococcal vaccine, polyvalent (23-valent) (manufacturer unknown).