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.

Synonyms and Keywords: Combined Immunodeficiencies; SCID; Immunodeficiency Syndrome, Severe Combined;

Overview

Severe combined immunodeficiency syndromes (SCID) are a heterogeneous group of diseases owing to numerous molecular defects in the development and function of both T and B cells. SCID is a life-threatening condition of overwhelming infections, typically in the first year of life, unless the underlying defect is corrected.The accepted classification system for SCID is based upon particular molecular defect, which is detected. The most common genetic condition responsible for SCID is a mutation of the common γ chain of the interleukin (IL) receptors, and accounts for approximately 50% of all patients with SCID. Adenosine deaminase (ADA) deficiency is an another significant mutation accounts for 20% of all SCID cases. Symptoms of SCID are recurrent severe infections, chronic diarrhea, and failure to thrive (FTT). Without newborn screening for SCID, a diagnosis is often not made until the infant develops several episodes of severe infections. Early diagnosis through population-wide newborn screening and early hematopoietic cell transplantation (HCT) improve outcomes. Among patients transplanted under 3.5 months of age without infection, survival post-transplant is about 95 percent, and overall survival is 90 percent.

Historical Perspective

• Severe combined immunodeficiency was first reported by Glanzmann and Riniker in 1950. Swiss infants with the condition were profoundly lymphopenic and died of infection before their first or second birthdays.
• The first discovered molecular cause of SCID, adenosine deaminase deficiency, was reported in 1972.
• Severe Combined Immunodeficiency may be best known from news stories and a movie in the 1980s about David Vetter, the Boy in the Bubble, who was a prominent sufferer of severe combined immunodeficiency and became famous for living in a sterile environment.

• In 1993, the molecular basis of X-linked human SCID was discoverd. Progress in molecular biology and the Human Genome Project, as well as increased knowledge of diverse components of the immune system through evaluations of mutant mice and humans with genetically diagnosed immunodeficiencies, have all contributed to this comprehension.

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- (cell type present: + and cell type abscent: -).

• Beyond this phenotypic classification and the functional status of these cells, since the mutated genes responsible for the majority of patients with SCID are now recognized,Then, it is more acceptable to classify SCID based upon the particular molecular defect once it is detected, in addition, the genotype identification can affect treatment methods and measurements for post treatment complications:

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 the mutation in the gene coding for tyrosine kinase, which is important in T-cell signalling and it is critical 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
Ligase 4 deficiency (T– B– NK+)
CD45 deficiency
Omenn syndrome	RAG-1 or RAG-2	Recombination activating genes (RAG) mutations result in recombinase enzymes disturbances. These enzymes are essential for 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. 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 associated with 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

Differentiating Severe combined immunodeficiency from Other Diseases

• Severe combined immunodeficiency must be differentiated from other diseases that cause recurrent and/or opportunistic infection, chronic diarrhea, and failure to thrive (FTT), such as:

• Agammaglobulinemia
• HIV/AIDS
• Syndromes like DiGeorge, CHARGE, Wiskott-Aldrich, cartilage-hair hypoplasia
• Extreme malnutrition

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 Pneumocystis jiroveci .

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 hematopoietic cell transplantation (HCT) outcomes. Among patients transplanted under 3.5 months of age without infection, survival post-transplant is about 95 percent, and overall survival is 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

Clinically, most patients present before age 3 months. 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

Lymphopenia is the typical hallmark of severe combined immunodeficiency (SCID). Although, normal or even elevated lymphocyte counts may be observed in a remarkable number of patients. which makes the diagnosis a challenge especially in patients with Omenn syndrome, bare lymphocyte syndrome, and interleukin (IL)–2 deficiency. Obtaining lymphocyte subpopulations as determined by flow cytometry and evaluation of T cell proliferative responses to mitogens are laboratory findings which can help to diagnose among patients lymphopenia is not frankly detected.

The classic laboratory findings in SCID include low to absent T cell count 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 necessary to confirm the diagnosis and used for diagnostic criteria include an absolute CD3+ T cell count of <300 cells/microL and/or maternal T cells in the circulation.

Imaging Findings

A chest x-ray may be helpful in the diagnosis of SCID. The thymic shadow is absent on chest radiography among the majority of patients with SCID, thus, a chest x-ray may be helpful in the newborn suspected of SCID. In addition, obtaining a chest x-ray may be helpful to assess pneumonia secondary to SCID.

Other Diagnostic Studies

Detection of maternal T cell engraftment : Since normal or even elevated lymphocyte counts may be observed in a remarkable number of patients, then such patients should be evaluated for maternal T cell engraftment. In some patients with SCID, maternal T cells which cross the placenta and enter the circulation of a fetus engraft subsequently may expand to levels >8000 cells/microL, that causes the total T cell count to appear incorrectly normal. A majority of the maternally engrafted T cells express CD45RO while normal infant T cells are predominantly naïve and express CD45RA. These surface markers can be enumerated by flow cytometry.

Treatment

Medical Therapy

The mainstay of treatment for all forms of SCID is hematopoietic cell transplantation (HCT). The majority of cases of adenosine deaminase deficiency require enzyme replacement therapy (polyethylene glycol-adenosine deaminase [PEG-ADA]) or gene therapy, Gene therapy is also becoming an alternative for X-linked SCID (common gamma-chain deficiency) and other genetic forms of SCID.

Viral infections are a leading cause of death in patients with SCID, both before and in the first several months after HCT before T cell engraftment has occurred. The most commonly implicated viruses are CMV, EBV, and adenovirus. Pharmacologic treatment and prophylactic options for viral infections remain limited and often ineffective, with associated morbidities notably from acute kidney injury and myelosuppression. Treatment may also generate resistance, and does not confer extended protection leaving patients at risk for viral reactivation. Adoptive immunotherapy with virus-specific T cells (VST) can be used along with antiviral agents to treat these life-threatening viral infections.

Primary Prevention

• There are no established measures for the primary prevention of SCID.

Secondary Prevention

Effective measures for the secondary prevention of SCID include:

• Mothers with a history of a prior affected child with SCID should receive recommended booster vaccines prior to delivery to provide transplacental antibodies
• Protective isolation for neonates with suspected SCID before receiving definitive treatment
• All blood products must be irradiated, leukodepleted, and cytomegalovirus (CMV) negative

Typical prophylaxis against infection includes:

• Immune globulin replacement therapy
• Prophylaxis for Pneumocystis jirovecii pneumonia with trimethoprim-sulfamethoxazole.
• Antifungal prophylaxis with fluconazole
• Monoclonal antibody against respiratory syncytial virus (RSV) with palivizumab
• Antiviral agent for prophylaxis against HSV, CMV, EBV