T-cell and combined immunodeficiencies — formative SAQs

SAQ 1 (10 marks)

A six-week-old boy is referred to the paediatric clinic because his newborn screening dried blood spot returned a low T-cell receptor excision circle (TREC) result. He was born at term, is feeding and growing well, and has had no infections. His maternal uncle died in infancy decades ago, "before they could find out what was wrong." His absolute lymphocyte count is 1.8 × 10⁹/L (low for age). [1]

Question: Outline the stepwise management of this infant, from confirmation of the newborn screen through to the curative decision and family counselling. (10 marks) [2]

Model answer

Confirmation and phenotyping (2 marks). A low TREC result on the newborn screen means the infant has few naive T cells leaving the thymus, and the differential includes SCID but also other causes of T-cell lymphopenia. The immediate next step is confirmatory flow cytometry for lymphocyte subsets — CD3, CD4, CD8, CD19/CD20 (B cells), and CD16/CD56 (NK cells) — to determine the immunophenotype. The family history of an affected maternal uncle and the low lymphocyte count make X-linked SCID the leading diagnosis, so the flow cytometry is likely to show a T⁻B⁺NK⁻ pattern. Genetic testing (a targeted SCID gene panel or whole-exome sequencing) then confirms the IL2RG mutation and triggers maternal carrier testing. [7]

Immediate protection — the non-negotiables (3 marks). While the diagnosis is being confirmed, the infant must be protected from iatrogenic harm. Stop all live vaccines — BCG, rotavirus, oral polio, and MMR are absolutely contraindicated because the attenuated organisms disseminate fatally in a child without T cells. Ensure that any blood product the child receives is irradiated, leucocyte-depleted, and CMV-negative, because non-irradiated blood causes transfusion-associated graft-versus-host disease, which is fatal in SCID. Start Pneumocystis prophylaxis with co-trimoxazole and antifungal prophylaxis with fluconazole. Begin immunoglobulin replacement (intravenous or subcutaneous, 400 to 600 mg per kilogram every three to four weeks) to provide passive humoral protection, because the child cannot mount antibody responses. [9] [10]

Urgent transplant referral (2 marks). Refer the infant urgently to a paediatric immunology and stem cell transplant centre. SCID is a medical emergency, and the timing of haematopoietic stem cell transplantation is the single most powerful determinant of survival. The donor search begins immediately — first a matched sibling donor (which gives the best outcomes), then a matched unrelated donor from a registry, then a haploidentical parent. Because this infant is only six weeks old and infection-free, the goal is transplant before 3.5 months of age and before any infection, a window in which survival exceeds 90 percent. [2] [10]

Family genetic counselling (2 marks). Confirming an IL2RG mutation identifies the mother as a carrier and has immediate implications for the wider family. Offer maternal carrier testing, sibling screening, and prenatal or preimplantation genetic diagnosis for future pregnancies. The power of early intervention on an affected sibling — transplant before infection — is the difference between near-normal survival and high mortality, so reproductive counselling is part of the management, not an afterthought. The family must understand that SCID is a genetic condition, that future pregnancies carry a one-in-four risk (for autosomal recessive forms) or a one-in-two risk of affected males (for X-linked forms), and that prenatal diagnosis is available. [6]

Disposition and long-term plan (1 mark). The infant is transferred to the transplant centre for haematopoietic stem cell transplantation. After transplant, long-term follow-up monitors immune reconstitution (T-cell subset recovery, thymic output by TREC), manages graft-versus-host disease, maintains malignancy surveillance, and plans transition to adult immunology care. The arc of the disease — from a near-uniformly fatal condition to one with over 90 percent survival when managed well — rests on the twin pillars of newborn screening and curative transplantation, and this infant, detected by TREC before symptoms, is the beneficiary of both. [1] [2]