Combined Immunodeficiency Due To Crac Channel Dysfunction

Watchlist

(log in to enable)

Retrieved

2021-01-23

Source

Orphanet

Trials

—

Genes

ORAI1, RAI1

Drugs

Allogeneic multi-virus specific T lymphocytes targeting BK virus, cytomegalovirus, human herpesvirus-6, Epstein Barr virus and adenovirus, haematopoietic stem cells and blood progenitors umbilical cord-derived expanded with (1R, 4R)-N1-(2-benzyl-7-(2-methyl-2H-tetrazol-5-yl)-9H-pyrimido[4,5-b]indol-4-yl)cyclohexane-1,4-diamine dihydrobromide dihydrate

Interested in hearing about new therapies?

Combined immunodeficiency (CID) due to Ca2+ release activated Ca2+(CRAC) channel dysfunction is a form of CID characterized by recurrent infections, autoimmunity, congenital myopathy and ectodermal dysplasia. It comprises two sub-types that are due to mutations in the ORAI1 and STIM1 genes: CID due to ORAI1 deficiency and CID due to STIM1 deficiency.

Epidemiology

CID due to CRAC channel dysfunction has been reported in 10 patients from 5 families, 6 patients in 3 families with ORAI1 mutations and 4 patients in two families with STIM1 mutations.

Clinical description

CID due to CRAC channel dysfunction is characterized by recurrent viral, bacterial, mycobacterial and fungal infections from birth, chronic diarrhea, pneumonia, meningitis, enteritis, gastrointestinal candidiasis, sepsis and otitis media. In addition, patients present at birth with congenital myopathy, which is characterized by non-progressive generalized muscular dysplasia. For cases with ORAI1 mutations this presents as poor head control after birth, delayed ambulation and a positive Gower's sign, while patients with STIM1 mutations present with global muscular hypotonia and partial iris hypoplasia. All patients present with ectodermal dysplasia that is characterized by hypocalcified amelogenesis imperfecta (see this term) and leads to the loss of soft dental enamel. Patients with ORAI1 mutations also have anhydrosis, which is characterized by inability to sweat and recurrent fever episodes associated with impaired thermoregulation. Patients with STIM1 mutations also show signs of lymphoproliferative and autoimmune disease including lymphadenopathy, hepatosplenomegaly, autoimmune thrombocytopenia and autoimmune hemolytic anemia.

Etiology

CID due to CRAC channel dysfunction is caused by mutations in the ORAI1 and STIM1 genes (12q24 and 11p15.5).

Diagnostic methods

Diagnosis is based on clinical features and testing the function and proliferation of T cells. Patients have normal lymphocyte counts and serum immunoglobulin levels but severely compromised T cell activation.

Differential diagnosis

Differential diagnoses include combined immunodeficiency (CID) due to ZAP70 deficiency, CID due to CD3gamma deficiency, immunodeficiency due to CD25 deficiency, hypohidrotic ectodermal dysplasia with immunodeficiency and anhidrotic ectodermal dysplasia - immunodeficiency - osteopetrosis - lymphedema syndrome.

Antenatal diagnosis

Prenatal diagnosis can be performed where there is a family history and where the genetic mutation has been identified.

Genetic counseling

Transmission is autosomal recessive.

Management and treatment

Treatment with hematopoietic stem cell transplantation (HSCT) has been successful in some cases.

Prognosis

Without treatment, patients fail to thrive and die in their first year of life.