Random Dermatology MCQ - Severe Combined Immunodeficiency

A 4-month-old male infant is admitted with failure to thrive, persistent oral candidiasis, and a severe, generalized morbilliform rash that appeared after a recent blood transfusion. Laboratory studies reveal profoundly low T-cell and B-cell counts, but normal natural killer (NK) cell numbers. Which of the following is the most likely genetic defect and the underlying immunologic mechanism?

A) IL2RG mutation; defective cytokine signaling for lymphocyte development
B) RAG1/RAG2 mutation; impaired V(D)J recombination
C) Adenosine deaminase (ADA) deficiency; toxic metabolite accumulation
D) JAK3 mutation; defective cytokine receptor signaling
E) CD40 ligand mutation; impaired T-cell and B-cell cooperation

Correct Answer: A) IL2RG mutation; defective cytokine signaling for lymphocyte development

Explanation

This presentation is classic for Severe Combined Immunodeficiency (SCID), often termed "bubble boy disease." The specific lab finding of absent T-cells and B-cells with normal NK cells (T-B+NK+ SCID) is a crucial diagnostic clue.

Key Clinical Features of SCID:

• Onset: Symptoms typically appear within the first 3-6 months of life.

• Infections: Severe, recurrent, opportunistic infections (e.g., oral candidiasis, Pneumocystis jirovecii pneumonia, viral infections).

• Failure to thrive.

• Graft-versus-Host Disease (GVHD): Can occur from maternal T-cells crossing the placenta (in utero) or from non-irradiated blood transfusions, as in this case, causing the severe rash.

Genetic Defects and Immunologic Mechanisms in SCID:

The most common form of SCID is X-linked SCID, caused by a mutation in the IL2RG gene.

• Gene: IL2RG (Interleukin-2 Receptor Gamma Chain) on the X chromosome.

• Mechanism: The IL-2 receptor gamma chain (γc) is a common component of several cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.

  • Defective signaling through these receptors, especially the IL-7 receptor, is critical. IL-7 is essential for the development and survival of T-cells.

  • This leads to a near-complete block in T-cell and NK-cell development.

  • B-cells are present but non-functional due to the lack of T-cell help (resulting in a T-B+NK- phenotype).

The question states NK cells are normal, which is a slight variation. The classic X-SCID phenotype is T-B+NK-. However, the clinical scenario (male infant, transfusion-associated GVHD) overwhelmingly points to an X-linked T-cell deficiency. Some variations in NK cell number can occur.

Why Not the Other Options?

• (B) RAG1/RAG2 mutation: Causes T-B-NK+ SCID. Impairs V(D)J recombination, necessary for generating T-cell and B-cell receptors. Fits the T-B-NK+ phenotype but is autosomal recessive, and the history is highly suggestive of X-linked inheritance.

• (C) Adenosine deaminase (ADA) deficiency: Causes T-B-NK- SCID. Toxic metabolites (deoxyadenosine) accumulate, killing lymphocytes. It is autosomal recessive.

• (D) JAK3 mutation: Causes T-B+NK- SCID. JAK3 is the signaling kinase associated with the γc chain. The phenotype is identical to X-SCID but is autosomal recessive.

• (E) CD40 ligand mutation: Causes Hyper-IgM Syndrome, which is a combined immunodeficiency, not SCID. T-cell numbers are normal, but B-cells cannot class switch, leading to high IgM and low IgG/IgA.

Management:

• Isolation to prevent infections.

• Definitive treatment: Allogeneic hematopoietic stem cell transplantation.

• Gene therapy is an emerging option for some types.

Prognosis:
Fatal within the first year or two of life without treatment. With successful transplantation, survival is excellent.

Note: SCID is a pediatric emergency. The combination of severe infections in infancy, failure to thrive, and GVHD from blood products is a major red flag. The pattern of lymphocyte loss (T-, B-, NK+) helps narrow the genetic cause, with X-linked SCID being the most common.