Severe Combined Immunodeficiency (SCID)

Content of This Page

1- Overview and Pathophysiology

2- Classification

3- Genetic Causes

4- Clinical Features in Infancy

5- Diagnosis

6- Management

Overview and Pathophysiology

SCID is a group of rare, inherited disorders that cause a profound defect in both:

  • T-cell–mediated immunity (cellular immunity)

  • B-cell–mediated immunity (humoral immunity)

“Combined” = both arms of adaptive immunity are affected.

 

–Pathophysiology:

  • T cells fail to develop or function → no help for B cells

  • B cells may be present but produce little or no antibody

  • Sometimes NK cells are also absent

  • Result: infants are highly vulnerable to infections from bacteria, viruses, fungi, and opportunistic organisms

Classification

SCID can be classified by flow cytometry into immunophenotypes, based on which lymphocytes are absent: 

SCID TypeT CellsB CellsNK Cells
X-linked (IL2RG)−+−
ADA deficiency−−−
JAK3 deficiency−+−
RAG1/2 mutations−−+

“T−” is the hallmark in all SCID forms. B cells may be present but ineffective without T-cell help.

Genetic Causes

Most common genetic causes:

  • X-linked SCID (IL2RG mutation)

    • Defective common γ-chain (γc) in IL-2, IL-7, IL-15 receptors

    • Accounts for ~50% of cases

    • T− B+ NK− phenotype

  • ADA Deficiency (autosomal recessive)

    • Toxic buildup of deoxyadenosine → kills lymphocytes

    • T− B− NK− phenotype

    • Also causes skeletal and CNS issues

  • Others: JAK3, RAG1/2, Artemis, IL-7Rα, etc.

-Some SCID types are autosomal recessive, others X-linked (mainly IL2RG).

Clinical Features in Infancy

SCID presents in early infancy, often within the first 3–6 months.

-Key features:

  • Recurrent severe infections (respiratory, GI, oral)

  • Failure to thrive

  • Persistent diarrhoea

  • Oral thrush

  • Absent tonsils and lymph nodes

  • Opportunistic infections (e.g. Pneumocystis jirovecii, CMV, candida)

Think: a previously healthy newborn who suddenly becomes very sick with common or unusual infections.

Diagnosis

Initial clues:

  • Low lymphocyte count (absolute lymphopenia < 2.5 x10⁹/L)

  • Low immunoglobulins (IgG, IgA, IgM)

  • Abnormal TREC (T-cell receptor excision circles) in newborn screening

–Flow cytometry:

  • Identifies presence/absence of T, B, NK cells

  • Helps classify SCID subtype

–Genetic testing confirms the exact mutation

Management

-Definitive treatment:

  • Hematopoietic stem cell transplantation (HSCT) – curative if done early

  • Gene therapy – especially for ADA-SCID or IL2RG SCID in some centres

–Supportive care:

  • Immunoglobulin replacement

  • Antibiotic, antifungal, and antiviral prophylaxis

  • Strict isolation until immune system restored

Vaccination Contraindications

Live vaccines are strictly contraindicated:

  • BCG (may cause fatal disseminated TB)

  • MMR, varicella, oral polio, rotavirus

-Even household contacts should avoid live oral vaccines (e.g. OPV) to prevent transmission.

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