Immunodeficiency 19

A number sign (#) is used with this entry because immunodeficiency-19 (IMD19) is caused by homozygous mutation in the CD3D gene (186790) on chromosome 11q23.

Description

Immunodeficiency-19 (IMD19) is an autosomal recessive form of severe combined immunodeficiency (SCID) characterized by onset in early infancy of recurrent bacterial, viral, and fungal infections. Patients usually have chronic diarrhea, recurrent respiratory infections, and failure to thrive. Immunologic work-up shows a T cell-negative, B cell-positive, natural killer (NK) cell-positive phenotype. The disorder is lethal in early childhood without bone marrow transplantation (summary by Yu et al., 2011).

Clinical Features

Dadi et al. (2003) reported 3 members of a kindred of Mennonite descent who had T-, B+, NK+ SCID. The proband was diagnosed immediately after birth because of 2 previous cases in the family. The proband subsequently underwent bone marrow transplantation and was alive and well, with full immune reconstitution, 3 years later. A male cousin of the proband was admitted at the age of 2 months with fever, tachypnea, and tachycardia and died of multiorgan failure. Adenovirus was identified in stool, urine, and bronchial secretions. Another male cousin of the proband was well and thriving until 2.5 months of age, when chronic diarrhea developed. He died at 3.5 months of age with respiratory distress and liver failure. Cytomegalovirus was identified in multiple tissues obtained at autopsy. That 2 of the 3 affected infants in this kindred died from viral infections before 4 months of age was a striking demonstration of the essential role of T cells in the defense against viruses, even weakly pathogenic adenoviruses and cytomegalovirus. The number of NK cells, as determined by staining for CD56 (116930), was normal in all patients.

De Saint Basile et al. (2004) reported 3 children and 2 fetuses from 2 consanguineous families with IMD19. In 1 family, the first affected child presented with diarrhea and failure to thrive at 3 months of age. At age 5 months, she developed CMV hepatitis and died shortly afterward. The second child was diagnosed with T-,B+, NK+ SCID shortly after birth and received a bone marrow transplant, but died 6 months later. In the second family, the first affected child presented with candidiasis at 2 months of age. This was followed by diarrhea and pneumonitis. He received a bone marrow transplant, but later died. No T cells were detected by prenatal analysis of fetal blood samples from 2 subsequent pregnancies, and the pregnancies were terminated. Thymi from the 2 fetuses were smaller than normal and lacked normal corticomedullary differentiation. Thymocyte T-cell development was blocked at the CD3-positive/CD4 (186940)-positive/CD8 (see 186910)-negative/CD45RO (151460)-negative stage. No circulating CD3-positive T cells were found in any of the patients, and lymph nodes from the fetuses contained no CD3-positive T cells. These findings indicated that CD3D is necessary for early T-cell development.

Yu et al. (2011) retrospectively studied a brother and sister with T-, B+, NK+ SCID who were homozygous for a truncating mutation in the CD3D gene (R68X; 186790.0001). The patients presented with typical clinical features, including failure to thrive, diarrhea, and recurrent and/or opportunistic infections, including fungal and CMV. Both had lymphopenia and absence of circulating CD3+ T cells, as well as decreased T-cell proliferative responses in vitro. Both underwent bone marrow transplantation; 1 sib died shortly thereafter, whereas the other was alive and well at age 16 years.

Gil et al. (2011) reported 2 unrelated Ecuadorian male children from nonconsanguineous parents who presented at 13 and 5 months of age with IMD19 manifesting as SCID and low CD3 expression. Both patients were T-alpha/beta negative, T-gamma/delta positive, B positive, and NK positive. The patients received haploidentical CD34 (142230)-positive stem cell transplants at ages 23 and 8 months, respectively. The latter patient died, probably due to cytomegalovirus found in multiple organs at necropsy, but the former was well at age 4 years.

Inheritance

The transmission pattern of IMD19 in the family reported by Dadi et al. (2003) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 affected patients from a Mennonite kindred with T-, B+, NK+ SCID, Dadi et al. (2003) identified a homozygous nonsense mutation in the CD3D gene (R68X; 186790.0001).

In 2 patients with T-, B+, NK+ SCID, both from consanguineous families, de Saint Basile et al. (2004) identified homozygosity for different mutations in the CD3D gene. One patient had the previously reported R68X mutation, and the other had a C93X mutation (186970.0002).

Gil et al. (2011) identified a homozygous splice-site mutation in the CD3D gene (IVS2+5G-A; 186790.0003) in the 2 unrelated Ecuadorian children they reported with IMD19.