Newborn Screening for Severe Combined Immunodeficiency (SCID) Leads to Early Identification of Ataxia-Telangiectasia (AT) Complicated By Neutropenia: A Case Report

Abstract

RationaleAT is an autosomal recessive disorder due to defects in the ATMgene leading to impaired DNA repair and progressive neurological deterioration after the first year of life. Neutropenia is rare and unreported in infants with AT. Here we present an infant with AT complicated by neutropenia detected by newborn screening.MethodsT-cell receptor (TCR)-Vbeta spectrotyping was performed using RT-PCR. Analysis of radiosensitivity and ATM expression were performed at the UCLA DNA Repair Clinical Laboratory. Sequencing of the ATMgene was performed by City of Hope.ResultsA healthy-appearing young male presented at 11 days of life with a presumptive positive newborn screen for SCID (TCR excision circle count of 6 and beta-actin of 42,800). Workup demonstrated low T-cell and B-cell counts, normal NK cells and decreased CD4/CD45RA/CD62L+ cells without maternal engraftment. IgG, lymphocyte mitogen stimulation and TCR-Vbeta repertoire were normal. IgA and IgM were undetectable. ANC at presentation was 1080, and decreased to 320 three weeks later. Antineutrophil antibodies were negative and a bone marrow biopsy was normal. Neutropenia persisted until 10 months of age and resolved without intervention. At 2 months of age, testing revealed increased radiosensitivity and absent ATM expression. ATMgene sequencing demonstrated a nonsense mutation at codon 1268(c.3802del) and a frameshift alteration (c.4358_4359; p.Ile1453Lysfs*37).ConclusionsAlthough newborn screening has previously identified infants with AT, this is the first report of transient, asymptomatic neutropenia associated with AT found in infancy. Early identification of AT may identify other novel clinical variants and further define the disease process and treatment strategies. RationaleAT is an autosomal recessive disorder due to defects in the ATMgene leading to impaired DNA repair and progressive neurological deterioration after the first year of life. Neutropenia is rare and unreported in infants with AT. Here we present an infant with AT complicated by neutropenia detected by newborn screening. AT is an autosomal recessive disorder due to defects in the ATMgene leading to impaired DNA repair and progressive neurological deterioration after the first year of life. Neutropenia is rare and unreported in infants with AT. Here we present an infant with AT complicated by neutropenia detected by newborn screening. MethodsT-cell receptor (TCR)-Vbeta spectrotyping was performed using RT-PCR. Analysis of radiosensitivity and ATM expression were performed at the UCLA DNA Repair Clinical Laboratory. Sequencing of the ATMgene was performed by City of Hope. T-cell receptor (TCR)-Vbeta spectrotyping was performed using RT-PCR. Analysis of radiosensitivity and ATM expression were performed at the UCLA DNA Repair Clinical Laboratory. Sequencing of the ATMgene was performed by City of Hope. ResultsA healthy-appearing young male presented at 11 days of life with a presumptive positive newborn screen for SCID (TCR excision circle count of 6 and beta-actin of 42,800). Workup demonstrated low T-cell and B-cell counts, normal NK cells and decreased CD4/CD45RA/CD62L+ cells without maternal engraftment. IgG, lymphocyte mitogen stimulation and TCR-Vbeta repertoire were normal. IgA and IgM were undetectable. ANC at presentation was 1080, and decreased to 320 three weeks later. Antineutrophil antibodies were negative and a bone marrow biopsy was normal. Neutropenia persisted until 10 months of age and resolved without intervention. At 2 months of age, testing revealed increased radiosensitivity and absent ATM expression. ATMgene sequencing demonstrated a nonsense mutation at codon 1268(c.3802del) and a frameshift alteration (c.4358_4359; p.Ile1453Lysfs*37). A healthy-appearing young male presented at 11 days of life with a presumptive positive newborn screen for SCID (TCR excision circle count of 6 and beta-actin of 42,800). Workup demonstrated low T-cell and B-cell counts, normal NK cells and decreased CD4/CD45RA/CD62L+ cells without maternal engraftment. IgG, lymphocyte mitogen stimulation and TCR-Vbeta repertoire were normal. IgA and IgM were undetectable. ANC at presentation was 1080, and decreased to 320 three weeks later. Antineutrophil antibodies were negative and a bone marrow biopsy was normal. Neutropenia persisted until 10 months of age and resolved without intervention. At 2 months of age, testing revealed increased radiosensitivity and absent ATM expression. ATMgene sequencing demonstrated a nonsense mutation at codon 1268(c.3802del) and a frameshift alteration (c.4358_4359; p.Ile1453Lysfs*37). ConclusionsAlthough newborn screening has previously identified infants with AT, this is the first report of transient, asymptomatic neutropenia associated with AT found in infancy. Early identification of AT may identify other novel clinical variants and further define the disease process and treatment strategies. Although newborn screening has previously identified infants with AT, this is the first report of transient, asymptomatic neutropenia associated with AT found in infancy. Early identification of AT may identify other novel clinical variants and further define the disease process and treatment strategies.