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Referred to as combined immunodeficiencies and severe combined immunodeficiency (SCID)
A group of inherited diseases with a frequency of 1 in 50-100,000 live births.
The most severe primary immunodeficiency.
Severe combined immunodeficiency syndromes (SCID) are group of rare congenital genetic diseases that result in combined T lymphocyte and B lymphocyte deficiencies.
SCIDs are a genetically heterogeneous group of inherited defects manifested by severe immune system abnormalities and dysfunction.
Deficiency of adenosine deaminase (ADA) is one cause of severe combined immunodeficiency (SCID), particularly of autosomal recessive inheritance.
SCID due to adenosine deaminase deficiency is an ultra rare, genetic disease that results in the accumulation of toxic adenine metabolites that severely impaired lymphocyte development.
Patients with this disease have profound lymphopenia with susceptibility to life-threatening infections.
Without treatment life expectancy is two years or less.
Non-immunologic features of the disease include sensorineural deafness, developmental delay, behavioral challenges, genotourinary abnormalities are variable but common and not ameliorated by treatment.
Genetic defects that can cause SCID, including IL-7 receptor deficiency, common gamma chain deficiency, and recombination activating gene deficiency.
SCID syndromes are caused by defective hematopoietic progenitor cells which are the precursors of both B- and T cells.
There is a severe reduction in developing thymocytes in the thymus and consequently thymic atrophy.
SCID-X1 caused by mutations in IL2RG gene.
Characterized by severe T-cell lymphocytopenia and lack of antigen specific T cells and B cell immune responses.
The genetic defects have been isolated in 90% of the cases.
All patients have abnormalities in thymopoiesis and T-cell maturation and function.
Associated with primary or secondary defects of B lymphocytes.
Patients have impairment of a adaptive immunity causing increased susceptibility to early onset, severe infections with a variety of viruses, bacteria, fungi, and parasites.
May manifest as autoimmune diseases, allergies and cancers.
Invariably fatal without definitive treatment.
It affects infants in the first few months of life with severe, recurrent and opportunistic infections.
It affects infants usually the first months of life with pneumocystis jerovecii pneumonia, bacterial sepsis, chronic cytomegalic virus or Candida infection, persistent respiratory or gastrointestinal viral infections, often associated with diarrhea and failure to thrive (Dvorak CC et al ).
Leads to death in infancy from impaired immunity unless treated by hematopoietic stem cell transplantation.
Babies with combined immunodeficiency have increased susceptibility to pathogens, and without treatment they die within 6-12 months.
Impaired T cell immunity is the main immunologic abnormalities: most patients have low numbers of T cells or none at all.
Some children may have normal T-cell counts associated with a severe immune cell activation defect (Notarangelo LD et al).
Infants with severe T cell lymphopenia, but often appear normal at birth and have no family history of immunodeficiency.
Many children are not identified until T cell deficiencies lead to life threatening infections.
Hematopoietic stem cell transplantation provides T cells which are missing in such individuals.
Genetic defects identified in more than 95% of patients.
10 different molecular defects identified for the various types of SCID, with each defect corresponding to a step in the differentiation of T cells.
Long-term prognosis is markedly improved if the diagnosis is made early, before serious infections occur.
The main therapeutic interventions for SCID are ADA enzyme replacement therapy and allogeneic  hematopoietic stem cell transplantation.
Incomplete immune reconstitution is associated with the progressive long-term risk of death from breakthrough opportunistic infections, autoimmunity, and cancer.
Guidelines recommend enzyme replacement therapy as a stabilizing measure before definitive treatment with allogeneic HSCT or autologous gene therapy.
Hematopoietic stem cell transplantation is more successful when performed in the firt three months of life (Puck JM).
Allogeneic hematopoietic transplantation with the use of bone marrow from an identical sibling or an unrelated donor, T cell depleted marrow or peripheral blood stem cells from a haploid identical related donor or umbilical cord blood can fully correct T cell deficiency and less often the B cell deficiency in such patients.
Children diagnosed at birth or before the onset of infectious processes who receive transplants from mismatch related donors, transplants from unrelated donors, or cord blood transplants soon after diagnosis have a 90% probability of survival with T-cell and variable B cell immune reconstitution.
Mortality rate is increased for patients with active infection at the time of transplantation.
Adenosine deaminase (ADA)deficiency causes 15-20% of cases resulting in pan-lymphocytopenia.
For adenosine deaminase deficiency allogeneic transplantation usually results in complete and enduring restoration of immunity.
Alloreactivity leads to HSCT related complications, and graft versus host disease is a substantial source of complications and, rarely, death.
Studies show that there is sustained clinical efficacy and safety with autologous CD 34+ hematopoietic, stem cell lentiviral gene therapy for ADA-SCID indicating that it is a curative treatment.
Vaccines administered in early infancy with patients with T cell lymphopenia can prevent serious infections (Werther RL).
T cell receptor excision circles (TRECs) by PCR in DNA from newborn blood screening cards can identify infants with T cell lymphopenia. (Routes JM).