Immunodeficiency 8

A number sign (#) is used with this entry because immunodeficiency-8 (IMD8) is caused by homozygous or compound heterozygous mutation in the CORO1A gene (605000) on chromosome 16p11.

Clinical Features

Shiow et al. (2009) reported a girl with a primary immunodeficiency characterized by early-onset recurrent infections, including oral thrush, and postvaccination varicella at age 13 months. Immunologic workup showed decreased numbers of lymphocytes, poor T-cell function with decreased proliferative response and lack of helper T-cell function for antibody isotype switching, and low immunoglobulins. B and NK cells were normal. Proliferative responses to mitogens were low, and specific antibody titers to tetanus and pneumococcal antigens were low to undetectable despite prior vaccinations. Her thymus was present. She also showed delayed psychomotor development and attention deficit-hyperactivity disorder. Bone marrow transplant was successful.

Moshous et al. (2013) reported 3 sibs, born of consanguineous parents of Moroccan ancestry, who developed an aggressive Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorder at ages 12, 7.5, and 14 months, respectively. The proband was the third-born child, a 14-month-old girl who had recurrent upper and lower respiratory infections during the first year of life and was found to have diffuse lymphadenopathy associated with significant CD4+ lymphopenia. Lymph node biopsy was positive for EBV, consistent with a diagnosis of EBV-induced B-cell lymphoproliferative syndrome. She was treated with chemotherapy, but died of complications 4 months after bone marrow transplantation. Family history revealed 2 affected older sibs who presented with B-cell lymphoma, which was retrospectively diagnosed as EBV-induced B-cell lymphoproliferation. One child died in infancy during induction chemotherapy, and the other underwent successful chemotherapy. At the time of the report, the surviving child was 11.5 years old and in remission, but with neurocognitive impairment and behavioral dysfunction, particularly attention deficit and hyperactivity. Lymph node biopsies from all 3 patients showed EBV infection. Detailed immunologic workup showed generalized lymphopenia, severe CD4+ T-cell lymphopenia, and significantly reduced numbers of CD4+ and CD8+ naive T cells, consistent with a primary immunodeficiency. One patient had decreased numbers of invariant natural killer T and mucosal-associated invariant T cells. T-cell proliferative responses were normal in 1 patient, but lower than normal in another, and immunoglobulin levels were essentially normal. There was a bias in the TCR repertoire, indicating expansion of a limited number of T-cell clones. Postvaccination antibodies levels were protective for some antigens, but decreased for others. Immunoglobulin substitution resulted in clinical improvement in the surviving child. All patients had a normal thymus.

Stray-Pedersen et al. (2014) reported 2 sibs from Louisiana, born of unrelated parents, with relatively late onset of IMD8. After normal early development, the proband presented at age 7 years with severely disfiguring granulomatous tuberculoid leprosy. A few years later, she developed disseminated cutaneous epidermodysplasia verruciformis-human papilloma virus (EV-HPV) and oral-cutaneous herpetic ulcers. At age 15, she developed Hodgkin and then non-Hodgkin lymphoma associated with EBV, resulting in death at age 16. Her younger brother also presented at age 7 with EV-HPV and molluscum contagiosum. He had seizures and anemia associated with parvovirus B19 infection and was found to have shortened telomeres (below the first percentile). Both patients had recurrent sinopulmonary infections and bronchiectasis; neither patient had fungal infections. Immunologic work-up over the course of the disease in both patients showed moderate lymphopenia, mildly low CD3+/CD4+ absolute T cells, nearly absent naive CD4CD45RA+ T cells, a preponderance of double-negative CD3+/CD4-/CD8- gamma-delta T cells, undetectable memory B cells, low NK cells, and modestly suppressed mitogen-induced lymphoproliferation. Both patients had increased IgE; the sister had decreased IgA and IgG. Thymus was present in both patients. However, antigen-induced lymphoproliferation in response to tetanus and candida was present. The parents had no clinical disease, but laboratory studies showed low NK cells in the mother and low CD4+ T cells in the father.

Inheritance

The transmission pattern of immunodeficiency-8 in the family reported by Moshous et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a girl with immunodeficiency-8, Shiow et al. (2009) identified compound heterozygosity for a truncating mutation in the CORO1A gene (605000.0001) and a de novo heterozygous 600-kb deletion of chromosome 16p11.2 (611913) encompassing 24 genes, including CORO1A. Thus, she had a homozygous absence of the CORO1A gene, with absent expression of the protein in her lymphocytes.

In affected members of a consanguineous Moroccan family with immunodeficiency-8, Moshous et al. (2013) identified a homozygous mutation in the CORO1A gene (V134M; 605000.0002). The mutation, which was found by homozygosity mapping and exome sequencing, segregated with the disorder in the family and was not found in the dbSNP or Exome Variant Server databases. Patient lymphocytes showed normal levels of mutant mRNA, but significantly decreased amounts of the mutant protein, suggesting that the mutation causes decreased CORO1A stability. Cells from the heterozygous mother showed a moderate decrease in mutant protein expression. Patient T-cell blasts showed delayed activation of signaling molecules ERK1 (601795) and ERK2 (176948), but further functional studies could not be performed because of lack of material. Overall, the findings were consistent with an immunodeficiency characterized by a defect in naive T cells and a defect in expansion of oligoclonal T cells associated with increased susceptibility to EBV infection. Impaired survival of mature T cells in turn likely affected lymphocyte homeostasis, repertoire selection, and lineage commitment. Moshous et al. (2013) noted that the immunodeficiency phenotype in their patients was less severe than that reported by Shiow et al. (2009), suggesting that the missense mutant protein may have retained some residual function.

In 2 sibs with IMD8, Stray-Pedersen et al. (2014) identified compound heterozygous truncating mutations in the CORO1A gene (605000.0001 and 605000.0003). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Western blot analysis showed absence of the CORO1A protein in the surviving affected brother.

Animal Model

Shiow et al. (2008) demonstrated that Coro1a is mutated in a mouse model with peripheral T-cell deficiency (Ptcd). Mutant T cells had an intrinsic migration defect, impaired lymphoid tissue trafficking, and irregularly shaped protrusions, suggestive of an abnormal actin cytoskeleton.