Severe Combined Immunodeficiency (SCID)

Overview

Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency, characterised by profound defects in both humoral (B-cell) and cellular (T-cell) immunity. It presents in infancy with recurrent, severe, and opportunistic infections, chronic diarrhoea, and failure to thrive. Without curative therapy, most infants die within the first year of life. Incidence is ~1 in 50,000–100,000 live births. Newborn screening with T-cell receptor excision circles (TRECs) has enabled earlier detection.

Definition

Opportunistic infection: Infection by organisms that usually do not cause disease in immunocompetent hosts (e.g., Candida, Pneumocystis jirovecii).
TRECs: T-cell receptor excision circles, used in newborn screening to detect impaired thymic T-cell production.
X-linked SCID: Caused by mutations in the common γ-chain (IL2RG gene), the most common form.
ADA deficiency: Adenosine deaminase deficiency; a metabolic cause of SCID.

Anatomy & Physiology

Normal lymphocyte development:
- T cells mature in the thymus → mediate cellular immunity, help B cells.
- B cells mature into plasma cells → produce immunoglobulins.
In SCID → T-cell development is severely impaired → defective cellular and humoral immunity.
NK cell numbers may also be reduced depending on subtype.

In SCID, defective T cells mean defective B-cell, even if B cells are present.

Aetiology

Genetic causes (major):
- X-linked SCID (IL2RG mutation, defective common γ-chain).
- ADA deficiency.
- JAK3 deficiency.
- RAG1/2 mutations (V(D)J recombination defect).
- IL-7 receptor mutations.
Inheritance: Mostly X-linked (IL2RG), others autosomal recessive.

Risk Factors

Family history of early infant deaths due to infections.
Consanguinity (in AR forms).

Pathophysiology

Genetic mutation affecting lymphocyte development/signalling.
Severe impairment of T-cell development (± B and NK cells).
Absent/ineffective cellular immunity → viral, fungal, protozoal infections.
Absent/ineffective humoral immunity (no T-cell help) → bacterial infections.
Consequence: recurrent, severe, opportunistic infections early in life.

“No T = No B help.”

Clinical Manifestations

Onset in first months of life.
Severe, recurrent infections:
- Viral: CMV, RSV, adenovirus.
- Fungal: Candida albicans, Pneumocystis jirovecii.
- Bacterial: otitis, pneumonia, sepsis.
Failure to thrive, chronic diarrhoea.
Persistent thrush, severe eczema-like rashes.
BCGosis (disseminated BCG after vaccination).
Absent tonsils and lymph nodes (due to absent lymphocytes).

“Severe infections + failure to thrive + absent lymphoid tissue in an infant” = SCID.

Diagnosis

Newborn screening: Low TRECs.
CBC: Lymphopenia.
Flow cytometry: Absent/low T cells; classify by T/B/NK phenotype.
Immunoglobulin levels: Very low IgG, IgA, IgM.
Genetic testing: Identify mutation (IL2RG, ADA, RAG, etc).
Exclude secondary causes (HIV).

Differential Diagnosis

Condition	Differentiator
HIV in infancy	Maternal transmission, positive HIV PCR
DiGeorge syndrome	Absent thymus, hypocalcaemia, heart defects
CVID	Later onset, not in early infancy
Chronic mucocutaneous candidiasis	Candida infections only, not combined defect

Classification

SCID Subtypes (T/B/NK classification)

Subtype	Mutation	T cells	B cells	NK cells	Notes
X-linked (IL2RG)	Common γ-chain	–	+	–	Most common
JAK3 deficiency	JAK3	–	+	–	Similar to X-linked
ADA deficiency	ADA enzyme	–	–	–	Toxic metabolite buildup
RAG1/2 deficiency	RAG recombination	–	–	+	V(D)J recombination defect
IL-7R deficiency	IL-7 receptor	–	+	+	Isolated T-cell defect

Treatment

Curative:
- Haematopoietic stem cell transplantation (HSCT) = standard of care.
- Gene therapy (IL2RG, ADA) increasingly available.
Supportive:
- Antimicrobial prophylaxis (TMP-SMX for Pneumocystis).
- Antifungal, antiviral prophylaxis as indicated.
- IVIG replacement.
- Isolation (“bubble boy”).
Avoid live vaccines (e.g., BCG, MMR, rotavirus).

HSCT early in life (<3 months) → best outcomes.

“Bubble boy disease” – historical description, emphasising extreme infection risk and need for isolation.

Complications & Prognosis

Fatal in first year if untreated.
Severe opportunistic infections (viral, fungal, bacterial).
GVHD if transfused with unirradiated blood.
Long-term: survival improving with newborn screening and early HSCT.

Without HSCT/gene therapy, SCID is uniformly fatal.

References

Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S182–94.
Pai SY, Logan BR, Griffith LM, et al. Transplantation outcomes for severe combined immunodeficiency. N Engl J Med. 2014;371(5):434–46.
Kohn DB, Booth C, Kang EM. Gene therapy for SCID: progress and challenges. J Allergy Clin Immunol. 2020;146(4):948–961.
Al-Herz W, Bousfiha A, Casanova JL, et al. Primary immunodeficiency diseases: IUIS classification. J Clin Immunol. 2014;34(8):896–907.
Buckley RH. The multiple causes of human SCID. J Clin Invest. 2004;114(10):1409–11.