Immunodeficiency 56

A number sign (#) is used with this entry because of evidence that immunodeficiency-56 (IMD56) is caused by homozygous mutation in the IL21R gene (605383) on chromosome 16p12.

Description

Immunodeficiency-56 is an autosomal recessive primary immunodeficiency characterized by B- and T-cell defects and variable dysfunction of NK cells. Patients tend to have normal numbers of lymphocytes, but show defective class-switched B cells, low IgG, defective antibody response, and defective T-cell responses to certain antigens (summary by Kotlarz et al., 2013).

Clinical Features

Kotlarz et al. (2013) reported 2 sibs, born of consanguineous Lebanese parents, with immunodeficiency. The patients had early onset of recurrent infections, as well as chronic cholangitis and biliary and hepatic cirrhosis associated with Cryptosporidium infection. One patient died after complications of liver transplantation and the other patient died after complications from hematopoietic stem cell transplantation. Laboratory studies showed relatively normal numbers of lymphocytes, but decreased numbers of class-switched B cells, defective antibody responses, reduced proliferative capacity of B cells, decreased T-cell proliferation in responses to certain antigens, and decreased NK cell-mediated lysis. Serum IgE was increased and IgG was decreased. Patient cells also showed decreased secretion of certain cytokines, including IL17F (606496) and IL22 (605330), which may have explained the increased susceptibility to Cryptosporidium infection. Two sibs from a second family had recurrent respiratory and gastrointestinal infections and liver disease due to Cryptosporidium infection. Laboratory studies showed normal lymphocyte numbers, but there were functional abnormalities, including decreased IgG, decreased antibody and T-cell responses to activation, increased IgE, and decreased IL21-dependent class-switching. One patient had impaired NK cell-mediated cytotoxicity.

Stepensky et al. (2015) reported an 8-year-old girl, born to consanguineous Palestinian parents, with immunodeficiency-56. Her early development was normal, but at age 2 years she presented with recurrent otitis media. At age 5 years, she was admitted with severe interstitial pneumonia that rapidly progressed to acute respiratory distress syndrome requiring prolonged ventilation. Routine immune testing was normal except for reduced IgG and IgA, and increased IgM. She was treated with monthly immunoglobulin infusions. At age 6 years, she presented with respiratory distress and hypoxia due to Pneumocystis jirovecii pneumonia, indicating severe T-cell deficiency. Chest CT showed bronchiectasis at the bases of both lungs. Her liver was normal by ultrasound and laboratory evaluation, suggesting that liver disease seen in previous patients was secondary to cryptosporidial infection, rather than being an intrinsic manifestation of IMD56. Because of the poor outcome of previously reported patients after cryptosporidial infection, early hematopoietic stem cell transplantation (HSCT) was performed using the patient's fully matched healthy sister as a donor, with 100% donor chimerism and normal immunoglobulins at 6 months posttransplantation. Stepensky et al. (2015) emphasized the importance of early diagnosis and treatment with HSCT in the management of patients with IMD56.

Inheritance

The transmission pattern of immunodeficiency-56 in the families reported by Kotlarz et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 2 unrelated consanguineous families with immunodeficiency-56, Kotlarz et al. (2013) identified 2 different homozygous loss-of-function mutations in the IL21R gene (605383.0002 and 605383.0003, respectively). Patient cells showed impaired IL21R-mediated signaling and severe abrogation of phosphorylation of downstream mediators, including STAT proteins (see, e.g., STAT3, 102582).

In an 8-year-old girl, born of consanguineous Palestinian parents, with immunodeficiency-56, Stepensky et al. (2015) identified a homozygous missense mutation in the IL21R gene (R201Q; 605383.0004). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family.