Severe Combined Immunodeficiency
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Direct answer
Severe combined immunodeficiency is a group of inherited defects that cause near absence of T cells and variable B and NK cell function, leading to life-threatening infections in early infancy. The chest radiograph may show an absent thymic shadow, and lymphopenia is typical. Haematopoietic stem cell transplantation is the curative treatment and works best when given before infections or live vaccines cause lasting harm.
What you must remember
- Clinical picture: failure to thrive, chronic diarrhoea, oral thrush and recurrent severe infections within the first months of life.
- Pneumocystis pneumonia: a classic life-threatening presentation in early infancy, often the first clue to the diagnosis.
- Absent thymic shadow: the normal thymus shadow is absent on chest radiograph, a supportive sign that T cell production is absent.
- Lymphopenia and T cells: low total lymphocytes with markedly reduced CD3 T cells on flow cytometry define the diagnosis.
- Commonest genetic form: X-linked SCID from IL2RG mutations, which affect the common gamma chain and remove T and NK cells.
- ADA deficiency: adenosine deaminase deficiency causes toxic purine metabolites, and PEG-ADA or elapegademase replacement can be used as a bridge.
- RAG1 and RAG2 defects: block V(D)J recombination, so both T and B cells are absent.
- Live vaccines: BCG and other live vaccines are contraindicated and can cause disseminated infection.
A pathway from suspicion to transplant
Early recognition matters more than any single test, because infants with SCID die of infection within months if untreated. The steps below are taken in parallel where the child is unwell.
- Recognise the picture: an infant with recurrent infections, thrush, chronic diarrhoea and poor weight gain in the first months needs immune evaluation at once.
- Count lymphocytes: total lymphocytes and CD3 T cell counts by flow cytometry confirm the lymphopenia, and B cell and NK cell counts classify the subtype.
- Image the thymus: a chest radiograph looks for an absent thymic shadow, which supports the diagnosis but does not confirm it alone.
- Protect the child: co-trimoxazole prophylaxis against Pneumocystis, irradiated blood products and strict avoidance of live vaccines are started without waiting for the genotype.
- Confirm the genotype: genetic testing identifies the defect, which guides transplant donor choice, gene therapy eligibility and counselling for the family.
- Transplant early: haematopoietic stem cell transplantation, ideally in the first few months of life, is curative, and PEG-ADA is used as a bridge in ADA deficiency.
Where the exam tests severe combined immunodeficiency
Questions focus on the lymphocyte pattern, the thymus shadow and the vaccine rule. These traps appear in standard paediatrics papers.
- Trap: giving BCG to an infant with suspected SCID because the child looks well. Correct: BCG is a live vaccine that can cause disseminated infection, so it is withheld until SCID is excluded.
- Trap: attributing an absent thymic shadow to DiGeorge syndrome by default. Correct: DiGeorge syndrome also shows thymic hypoplasia, but hypocalcaemia, conotruncal heart defects and dysmorphism distinguish it from SCID.
- Trap: assuming a normal B cell count excludes SCID. Correct: B cell positive and B cell negative forms both exist, so the T cell count is the defining feature.
Frequently asked questions
Which genetic defect causes the most common form of severe combined immunodeficiency?
X-linked severe combined immunodeficiency, caused by IL2RG mutations affecting the common gamma chain, is the most frequent form. It produces absent T cells and NK cells, with B cells present but non-functional.
Why is an absent thymic shadow important in severe combined immunodeficiency?
An absent thymic shadow on the chest radiograph suggests absent T cell production, which supports severe combined immunodeficiency. It is a supportive rather than diagnostic finding, and flow cytometry of T cell counts confirms the diagnosis.
What is the cure for severe combined immunodeficiency?
Haematopoietic stem cell transplantation is the curative treatment for severe combined immunodeficiency. Early transplant, ideally in the first few months of life, gives the best immune reconstitution, while gene therapy is an option for some genotypes.
How does DiGeorge syndrome differ from severe combined immunodeficiency?
DiGeorge syndrome is caused by a 22q11 deletion and produces thymic hypoplasia with hypocalcaemia, conotruncal heart defects and dysmorphic features. Severe combined immunodeficiency lacks these features, so hypocalcaemia and cardiac defects point to DiGeorge syndrome.