Severe combined immunodeficiency

Severe combined immunodeficiency
ICD-10	D81.0-D81.2
ICD-9	279.2
DiseasesDB	11978
eMedicine	med/2214
MeSH	D016511

Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mohsen Basiri M.D.

Classification

Previous classification system for SCID was based upon the presence of molecular defects affecting T cell numbers and presence or absence of defects affecting B and/or NK cell numbers, and SCID syndromes were classified as T-B+NK+, T-B+NK-, T-B-NK+, or T-B-NK- regardless of the functional status of these cells, since genetic diagnosis was more difficult to establish meanwhile, the mutated genes responsible for the majority of patients with SCID are known and can be readily defined. Then, it is more acceptable to classify SCID based upon the particular molecular defect once it is detected, especially the genotype can affect treatment methods and mesuarments for post treatment complications.

Beyond this phenotypic classification

Type	Gene defects	Description
X-linked severe combined immunodeficiency	IL-2R common gamma chain	IL2RG is a protein that is shared by the receptors for interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. These interleukins and their receptors are involved in the development and differentiation of T and B cells. mutations cause widespread defects in interleukin signalling. The result is a near complete failure of the immune system to develop and function, with low or absent T cells and NK cells and non-functional B cells. IL2RG is encoded on the X chromosome; therefore, this variant of SCID is X-linked, and account for approximately 50% of all patients with SCID.
Janus-associated kinase 3 deficiency (T– B+NK–)	Janus kinase 3	JAK3 is a protein tyrosine kinase (PTK) that associates with the common γ chain of the IL receptors. Deficiency of this protein results in the same clinical manifestations as those of XL-SCID.
Adenosine deaminase deficiency	ADA	ADA deficiency accounts for 20% of all SCID cases. Adenosine deaminase (ADA), is necessary for the breakdown of purines. Lack of ADA leads to the accumulation of intermediate dATP, which results in lymphocyte toxicity,particularly with immature thymic lymphocytes, then lymphocyte proliferation is inhibited and the immune system is compromised.
Bare lymphocyte syndrome	gene regulating expression of MHC type II	Bare lymphocyte syndrome is a deficiency of major histocompatibility complex (MHC). MHC type II is decreased on mononuclear cells. MHC type I levels may be decreased or absent entirely. The defect occurs in a gene regulating expression of MHC type II
ζ chain–associated protein (ZAP)-70 deficiency	Tyrosine kinase	Due to mutation in the gene coding for throsine kinase, which is important in T-cell signaling and is t icritical in positive and negative selection of T cells in the thymus

.

Reticular dysgenesis	Adenylate kinase 2	Reticular dysgenesis is a rare variant of SCID arising from the inability of granulocyte precursors to form granules secondary to mitochondrial adenylate kinase 2 malfunction.
IL-7R α chain deficiency	IL-7RA
Deficiency of the recombination-activating genes RAG1 and RAG2 (T– B– NK+)	RAG1/RAG2
Ligase 4 deficiency (T– B– NK+)
CD45 deficiency
Omenn syndrome		The manufacture of immunoglobulins requires recombinase enzymes derived from the recombination activating genes RAG-1 and RAG-2. These enzymes are involved in the first stage of V(D)J recombination, the process by which segments of a B cell or T cell's DNA are rearranged to create a new T cell receptor or B cell receptor (and, in the B cell's case, the template for antibodies). Certain mutations of the RAG-1 or RAG-2 genes prevent V(D)J recombination, causing SCID.
Artemis/DCLRE1C	DCLRE1C	An enzyme that opens DNA hairpin during variable diversity joining [VDJ] rearrangement and RAG1 and RAG2 deficiencies

Pathophysiology

SCID is a syndrome caused by mutations in any of more than 15 known genes, whose products are pivotal for the development, function, differentiation and proliferation of both T and B cells and may also affect natural killer (NK) cells. Antibody production is severely impaired even when mature B cells are present, since B cells require signals from T cells to produce antibody. NK cells are present in approximately 50 percent of patients with SCID and may provide a degree of protection against bacterial and viral infections in these patients. Determining the presence or absence of NK cells is also helpful in classifying patients with SCID.

Causes

Combined immunodeficiency diseases are a heterogeneous group of disorders arising from mutations in any of more than 15 known gene, the most common genetic condition responsible for SCID is a mutation of the common γ chain of the interleukin (IL) receptors. A list of gene defects that cause SCID is presented in the below table:

Gene defects causing severe combined immunodeficiency

IL-2R common gamma chain	ILR2
Janus kinase 3	JAK3
IL-7Ra chain	IL7RA
IL-2Ra chain (CD25) deficiency	ILR2
CD45	PTPRC
CD3 delta OR epsilon OR zeta	CD3
Coronin 1A	CORO1A
Recombinase activating genes 1 and 2	RAG1/RAG2
DNA cross-link repair enzyme 1C	DCLRE1C(Artemis)
Adenosine deaminase	ADA
Adenylate kinase 2	AK2
DNA ligase IV	LIG4
Nonhomologous end-joining protein 1	NHEJ1

Epidemiology and Demographics

A study using data from newborn screening for SCID in the United States found an incidence of 1 in 58,000 livebirths for SCID, inclusive of typical SCID, leaky SCID, and Omenn syndrome. The incidence of autosomal-recessive SCID is higher in cultures in which consanguineous marriage is common.

Risk Factors

There are no established risk factors for SCID, however, the incidence of autosomal-recessive SCID is higher in cultures in which consanguineous marriage is common.

Screening

preferably, SCID can be diagnosed in a newborn before the beginning of infections, with one well-documented example by screening of T-cell–receptor excision circles(TRECs). Since the goal of newborn screening is to detect treatable disorders that are threatening to life or long-term health before they become symptomatic and prompt treatment of SCID may notably reduce mortality and morbidity among patients. Infants with SCID without reconstitution of a functioning immune system generally die of overwhelming infection by one year of age.

T cell receptor excision circles (TRECs) as a biomarker of naïve T cells, is a sensitive and specific, as well as cost effective, method for SCID newborn screening.

Natural History, Complications, and Prognosis

Natural History

Patients with severe combined immunodeficiency (SCID) may present with multiple recurrent severe infections, chronic diarrhea, and failure to thrive (FTT) In the past, SCID was often diagnosed after children acquired serious infections, such as pneumonia due to P jiroveci (carinii).

Complications

Patients are at risk for infections from Opportunistic infections usually follow more common infections. P jiroveci and fungal pneumonias cause death in classic cases. CMV, VZV, and HSV infections typically occur in infants who have already had treatable infections. Neurologic compromise from polio and other enteroviruses impedes stem cell reconstitution.

Prognosis

SCID is fatal, generally within the first year of life, unless the underlying defect is corrected.Early diagnosis through population-wide newborn screening and early transplantation in the absence of infectious complications may improve HCT outcomes. Among patients transplanted under 3.5 months of age without infection, survival posttransplant is about 95 percent, and overall survival 90 percent.

Diagnosis

Diagnostic Criteria

The diagnosis of SCID is made when patient is less than two years of age with either an absolute CD3 T cell count of less than 300/mm3, or an absolute CD3 T cell count of greater than 300/mm3 with absent naïve CD3/CD45RA T cells, at least one of the following diagnostic criteria are met:

1. Male with deleterious mutation in the X-linked IL2RG gene encoding the cytokine receptor common gamma chain (gamma-c).
2. Male or female patient with deleterious homozygous or compound heterozygous mutations in any of the genes listed in the Gene Defects table other than IL2RG.
3. ADA activity of less than 2% of control or mutations in both alleles of the ADA gene.
4. Engraftment of transplacentally acquired maternal T cells.

History and Symptoms

The diagnosis of SCID should be suspected in children with any of the following:

• Positive newborn screening result for SCID
• Unexplained lymphopenia
• Recurrent fevers
• Failure to thrive (FTT)
• Chronic diarrhea
• Recurrence of severe episodes of thrush, mouth ulcers, respiratory syncytial virus (RSV), herpes simplex virus (HSV), varicella zoster virus (VZV), measles, influenza, or parainfluenza 3
• Adverse reactions (infections) caused by live vaccines, such as Bacillus Calmette-Guérin (BCG), rotavirus vaccine, or varicella vaccine
• A family history of SCID (seen in <20 percent of cases)

Physical Examination

Physical findings are multisystemic. The patient may present with the following:

• Fever
• Failure to thrive
• Dehydration due to chronic diarrhea
• Acute otitis media
• Absent lymphatic tissue
• Extensive candidiasis in the mouth and diaper area
• Recurrent skin abscesses and/or other severe skin infections

Laboratory Findings

The classic laboratory findings in SCID include low to absent T cell counts and function, as evaluated by T cell enumeration by flow cytometry and T cell proliferation to mitogens such as phytohemagglutinin (PHA) and concanavalin A (ConA).

Laboratory findings used for diagnostic criteria include an absolute CD3+ T cell count of <300 cells/microL or maternal T cells in the circulation.

External links

• Learning About Severe Combined Immunodeficiency (SCID) NIH
• Buckley RH (2004). "Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution". Annu Rev Immunol. 22: 625–55. doi:10.1146/annurev.immunol.22.012703.104614. PMID 15032591.
• Chinen J, Puck JM (2004). "Successes and risks of gene therapy in primary immunodeficiencies". J Allergy Clin Immunol. 113 (4): 595–603, quiz 604. doi:10.1016/j.jaci.2004.01.765. PMID 15100660.
• Church AC (2002). "X-linked severe combined immunodeficiency". Hosp Med. 63 (11): 676–80. PMID 12474613.
• Gennery AR, Cant AJ (2001). "Diagnosis of severe combined immunodeficiency". J Clin Pathol. 54 (3): 191–5. doi:10.1136/jcp.54.3.191. PMID 11253129.
• Concept of gene therapy for SCID