Newborn screening for severe combined immunodeficiency: an opportunity for intervention

Abstract

Severe combined immunodeficiency (SCID) is a potentially fatal disorder characterized by defective T- and B-lymphocyte function. We describe a 34-week female twin who had developed feeding intolerance, perioral cyanosis, abdominal distension and neutropenia at 1 month of age. Despite several evaluations including an ‘inconclusive’ newborn screening result for SCID, the presence of profound lymphopenia was unappreciated. Eventually a diagnosis of SCID in association with adenosine deaminase deficiency was made. This case serves to emphasize the importance of newborn screening for SCID in the context of careful evaluation of clinical and laboratory findings that may be overlooked and result in a delay in the diagnosis of a potentially life-threatening condition.

Introduction

Life-threatening primary immunodeficiency disorders (PIDDs), such as severe combined immunodeficiency (SCID), may present in the neonatal period.^{1, 2} Despite the increasing adoption of newborn screening for SCID, clinical and laboratory findings suggestive of SCID may be overlooked. We describe a 1-month-old Caucasian female twin with feeding intolerance, perioral cyanosis, abdominal distension and laboratory evidence of neutropenia. Despite an ‘inconclusive’ newborn screen result for SCID, the presence of persistent lymphopenia was unappreciated. The neonate was subsequently diagnosed with SCID due to adenosine deaminase (ADA) deficiency. This case highlights the importance of newborn screening for SCID and the recognition of factors that support the consideration of a SCID diagnosis in the neonatal period.

Case

A Caucasian female twin was born at 34 weeks of gestation following a cesarean delivery. The perinatal history was remarkable for pregnancy-induced hypertension, HELLP syndrome and a dizogotic twin pregnancy. At 1 month of age she was referred for evaluation of feeding intolerance, perioral cyanosis and abdominal distension. The family history was non-contributory, and there was no reported consanguinity. Her birth weight was 2.4 kg (80th percentile), length was 44.5 cm (57th percentile) and head circumference was (81st percentile). Physical examination revealed intermittent, mild respiratory distress, which resolved without intervention. Laboratory examination on the first day of life revealed the following: hemoglobin 20.4 g dl⁻¹, hematocrit 59.0%, platelet count 31 000 μl⁻¹, and white blood cell count 2700 per μl with 57% segmented neutrophils, 5% band neutrophils, 13% lymphocytes (351 per μl), 16% monocytes, 8% eosinophils and 1% basophils. The thrombocytopenia was presumed to be secondary to maternal HELLP syndrome. Sepsis evaluation was also negative; she remained asymptomatic and was discharged at day of life 14.

At day of life 23, the patient was readmitted to the hospital for feeding intolerance, perioral cyanosis and abdominal distension. At that time her physical examination was otherwise unremarkable. Radiographic examination demonstrated lung changes consistent with bronchiolitis. Repeat laboratory examination revealed hemoglobin 15.7 g dl⁻¹, hematocrit 46.8%, platelet count 545 000 per μl and white blood cell count of 1300 per μl with 34% segmented neutrophils, 2% band neutrophils, 9% lymphocytes (117 per μl), 12% monocytes and 42% eosinophils. Again, evaluation for sepsis was negative. Her absolute neutrophil count improved to 1386 cells per μl before discharge. SCID newborn screen results returned ‘inconclusive’ with T-cell receptor excision circles (TRECs) 5 per μl (normal>25 per μl) and actin 4890 per μl (normal>5000 per μl). She remained clinically asymptomatic and was discharged at day of life 28. Shortly thereafter a repeat SCID screen was reported to be positive (TREC 0 per μl and actin 5410 per μl), and at day of life 30 quantification of lymphocyte subsets could not be performed because of profound lymphopenia.

She was readmitted at day of life 34 for evaluation for SCID. Table 1 details the patient’s erythrocyte ADA levels and deoxyadenosine metabolites. ADA deficiency was diagnosed and the patient was started on pegylated ADA, antimicrobial prophylaxis and intravenous immunoglobulin. ADA genetic analysis demonstrated the following mutations: a missense mutation c.320 T>C causing the amino-acid substitution L107P in exon 4 and a single-base deletion c.790delT in exon 9, which causes a shift in reading frame resulting in the addition of 46 new amino-acid residues before coming to a premature stop codon.

Table 1 Erythrocyte enzyme activity and nucleotides

Discussion

PIDDs including various forms of SCID may present in the neonatal period; however, the majority of cases are initially asymptomatic.^{1, 2} Despite the expansion of newborn screening for SCID, clinical and laboratory findings such as lymphopenia are often unappreciated.^{3, 4}

Recognition of lymphopenia during the neonatal period is vital in the identification of SCID. Other clinical findings such as pulmonary infections, chronic diarrhea, failure to thrive and rash should also raise the suspicion of SCID. The failure to make a timely diagnosis of SCID may result in preventable morbidity and mortality.⁵

SCID is a heterogeneous group of PIDDs that result from a lack of T- and B-lymphocyte immunity. ADA deficiency is the second most common form of SCID.^{6, 7, 8} The ADA enzyme catalyzes the deamination of adenosine and deoxyadenosine. A lack of ADA function results in a build-up of metabolites, including deoxyadenosine and deoxyadenosine triphosphate, which inhibit the activity of ribonucleotide reductase and ultimately DNA synthesis. Impairment in DNA synthesis results in a myriad of complications, such as musculoskeletal, central nervous system, endocrine and gastrointestinal dysfunction. As demonstrated in this case, bone marrow function may be impaired and result in neutropenia and thrombocytopenia.⁹ These manifestations of SCID present a challenge for clinicians who routinely recognize neutropenia and thrombocytopenia but often overlook lymphopenia. The lower limit of normal (5th percentile) lymphocyte counts among preterm and term neonates is 2000 per μl.¹⁰

Newborn screening efforts have focused on the early identification of SCID and associated disorders.¹¹ TRECs, by-products of T-cell receptor gene rearrangements, are present in a proportion of mature peripheral blood T cells. TRECs are measured with quantitative PCR on specimens obtained from routine newborn blood spots. Analysis of the actin gene, a normal housekeeping gene, is used as a positive control. A low to absent TREC with normal actin gene level suggests profound T lymphopenia. The time required for the completion of the screening exam is short (72 h) and inexpensive (approximately $5.50). Newborn screening for SCID, now being conducted in a growing number of states (currently eleven states and territories), has demonstrated the ability to identify babies for early intervention. Despite the success of these efforts, important limitations remain. As demonstrated in our patient, 2 to 4 weeks may elapse between an initial ‘inconclusive’ TREC result and confirmatory flow cytometry. Further, the detection of SCID by newborn screening must be complemented by astute clinical judgment.