Severe combined immunodeficiency

Genetic disorder causing severe immunodeficiency

Severe Combined Immunodeficiency (SCID)
Synonyms	Alymphocytosis, Glanzmann–Riniker syndrome, Severe mixed immunodeficiency syndrome, Thymic alymphoplasia
Pronounce
Field	Immunology, Pediatrics, Medical genetics
Symptoms	Severe, recurrent infections, failure to thrive, chronic diarrhea, pneumonia, oral candidiasis
Complications	Life-threatening infections, sepsis, failure to thrive
Onset	Infancy
Duration	Lifelong (if untreated)
Types	X-linked SCID, ADA-SCID, JAK3-SCID, RAG1/RAG2-SCID, IL-7Rα-SCID, etc.
Causes	Genetic mutations affecting T-cell and B-cell function
Risks	Family history of SCID, consanguinity
Diagnosis	Newborn screening (TREC test), lymphocyte count, genetic testing
Differential diagnosis	Other primary immunodeficiencies, AIDS, leukemia
Prevention	Genetic counseling, prenatal diagnosis
Treatment	Bone marrow transplantation, gene therapy, enzyme replacement therapy, prophylactic antibiotics
Medication	IVIG, gene therapy, PEG-ADA for ADA-SCID
Prognosis	Without treatment: fatal in infancy; with treatment: improved survival
Frequency	1 in 50,000 to 100,000 (X-linked form)
Deaths	High without early intervention

David Vetter, famous SCID patient

Severe Combined Immunodeficiency (SCID) is a rare, genetically inherited disorder characterized by profound deficiencies in both T cell and B cell function. It is considered the most severe form of primary immunodeficiency, rendering affected infants highly susceptible to life-threatening infections. The condition results from mutations in genes essential for immune system development, leading to severe immune dysfunction.

SCID is often referred to as the "bubble boy disease" due to the case of David Vetter, who was forced to live in a sterile environment to avoid infections. Without hematopoietic stem cell transplantation (HSCT) or gene therapy, infants with SCID typically die within their first year of life due to severe infections.

Causes and Pathophysiology

SCID is caused by mutations in various genes involved in lymphocyte development and function. It leads to severe impairments in T-cell, B-cell, and sometimes natural killer (NK) cell function.

Genetic Causes

There are multiple forms of SCID, each associated with mutations in different genes:

• X-linked SCID (SCID-X1) – Caused by mutations in the IL2RG gene, leading to absence of T and NK cells but presence of dysfunctional B cells.
• Adenosine Deaminase Deficiency (ADA-SCID) – Caused by mutations in the ADA gene, leading to toxic metabolite accumulation, which destroys lymphocytes.
• JAK3 Deficiency – Affects cytokine signaling and prevents normal immune cell development.
• RAG1/RAG2 Deficiency – Disrupts V(D)J recombination, preventing B and T cell receptor formation.
• IL-7Rα Deficiency – Prevents T-cell development, leading to T-cell lymphopenia.
• Other rare forms – Include defects in CD45, ZAP70, and Artemis genes.

All forms of SCID result in absent or dysfunctional T cells, which in turn affects B-cell function, leading to profound immunodeficiency.

Symptoms and Clinical Manifestations

SCID presents early in infancy with symptoms such as:

• Severe, recurrent infections (bacterial, viral, fungal)
• Chronic diarrhea and failure to thrive
• Oral candidiasis (thrush)
• Persistent pneumonia, especially due to Pneumocystis jirovecii
• Skin rashes (may indicate maternal T-cell engraftment)
• Absent or very small tonsils and lymph nodes

Without intervention, SCID is universally fatal due to overwhelming infections.

Diagnosis

Early diagnosis of SCID is critical for survival. Newborn screening programs, particularly the T-cell receptor excision circle (TREC) test, have dramatically improved early detection.

Diagnostic Tests

• Complete blood count (CBC) – Shows low lymphocyte count (<3000 cells/µL).
• Flow cytometry – Identifies absence or dysfunction of T, B, and NK cells.
• Genetic testing – Identifies specific mutations causing SCID.
• Functional immune tests – Assess T-cell proliferation in response to stimuli.

Newborn Screening

• Many countries have adopted TREC-based screening, which detects low numbers of naïve T cells, allowing early intervention before infections occur.

Treatment

Without treatment, SCID is fatal. However, several treatment options restore immune function:

1. Hematopoietic Stem Cell Transplantation (HSCT)

• First-line curative treatment, ideally performed before 3 months of age.
• Best outcomes occur with matched sibling donors, but alternative donors (haploidentical or unrelated) can be used.

2. Gene Therapy

• Used in ADA-SCID and X-linked SCID.
• Involves correcting the patient's own stem cells using viral vectors.
• Trials show promising long-term immune restoration.

3. Enzyme Replacement Therapy (For ADA-SCID)

• Pegylated adenosine deaminase (PEG-ADA) provides temporary immune support.
• Used as a bridge to definitive therapy (HSCT or gene therapy).

4. Supportive Care

• Immunoglobulin replacement therapy (IVIG) – Prevents infections.
• Prophylactic antibiotics & antifungals – Reduces infection risk.
• Strict infection control measures – Isolation and avoidance of live vaccines.

Prognosis

The prognosis for SCID depends on early diagnosis and treatment:

• HSCT before 3 months of age – >90% survival rate.
• Late diagnosis (after severe infections occur) – Poorer outcomes.
• Untreated SCID – Death within 1–2 years due to infections.

Gene therapy holds long-term curative potential, especially for X-linked SCID and ADA-SCID.

Epidemiology

• SCID affects ~1 in 50,000 to 100,000 live births.
• X-linked SCID is the most common form (~45%).
• Higher prevalence in consanguineous populations.
• Newborn screening programs have increased detection rates, leading to earlier treatment and better outcomes.

Notable Cases

• David Vetter ("Bubble Boy") – Lived in a sterile plastic enclosure due to SCID, raising awareness about the disease.
• Ashanti DeSilva – First SCID patient successfully treated with gene therapy.

See Also

• Primary immunodeficiency
• Hematopoietic stem cell transplantation
• Gene therapy
• Adenosine deaminase deficiency
• Bubble Boy disease
• Adaptive immune system

External Links

Classification	ICD-10: D81.0 ICD-9-CM: 279.2 OMIM: 300400 MeSH: D007724 DiseasesDB: 11824
External resources	MedlinePlus: 001248 eMedicine: ped/2817

NIH genetic and rare disease info

• NIH info on Severe combined immunodeficiency

Severe combined immunodeficiency is a rare disease.

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