Delayed-Onset ADA1 (ADA) Deficiency Not Detected by TREC Screen

Abstract

A 9-month-old boy presented to a community pediatrician with a recent history of failure to thrive. Workup revealed neutropenia and lymphopenia. Subsequent admission for fever and pneumonia revealed an absolute neutrophil count of 860 and absolute lymphocyte count of 214. Lymphopenia affected all lymphocyte subsets and his naïve and memory CD4+ T-cell ratio was inverted for age. Immunoglobulin levels were normal for age, and tetanus and diphtheria antibody titers were protective. The profound lymphopenia raised suspicion for severe combined immunodeficiency (SCID), despite a normal newborn screening by T-cell receptor excision circle analysis. He did not have a previous history of recurrent fevers or infections, had attended day care, and had received all age-appropriate vaccines. He subsequently was diagnosed with Pneumocystis jirovecii pneumonia, adenovirus upper respiratory infection, and rotaviral diarrhea. An enzyme assay revealed absent adenosine deaminase (ADA) activity and elevated erythrocyte deoxyadenosine nucleotides. With genetic sequencing, 2 pathogenic variants in the ADA gene were confirmed. Acute management of ADA-SCID is aimed at restoration of enzyme activity, followed by curative therapy. The patient is currently on immunoglobulin therapy and recombinant ADA (Revcovi), with an excellent immune response, while awaiting sibling hematopoietic cell transplant from a matched sibling. Hypomorphic ADA variants can present with delayed-onset SCID, and some of these patients are missed by SCID newborn screening. A careful review of a complete blood cell count might offer clues and promote confirmatory diagnostic investigation.

Review of Treatment for Adenosine Deaminase Deficiency (ADA) Severe Combined Immunodeficiency (SCID)

“… 5 Late onset ADA can also be severe with <1% activity and lead to ADA SCID, or it can be less severe with partial activity causing a combined immune deficiency (CID), and either of these may be missed on T cell receptor excision circle (TREC) newborn screening (NBS) which is done in the first days of life. 6 Combined immune deficiency from ADA deficiency may present later in life with varying degrees of B cell, T cell, and NK cell dysfunction. To assure that no cases of ADA SCID are missed at least one state, Michigan, now adds ADA enzyme screening to its newborn screening panel.…”