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IMMUNODEFICIENCY 73B WITH DEFECTIVE NEUTROPHIL CHEMOTAXIS AND LYMPHOPENIA; IMD73B

IMMUNODEFICIENCY 73B WITH DEFECTIVE NEUTROPHIL CHEMOTAXIS AND LYMPHOPENIA; IMD73B

Immunodeficiency-73B with defective neutrophil chemotaxis (IMD73B) is an autosomal dominant immunologic disorder characterized by onset of recurrent infections i...

Immunodeficiency-73B with defective neutrophil chemotaxis (IMD73B) is an autosomal dominant immunologic disorder characterized by onset of recurrent infections in infancy or early childhood. Affected individuals develop respiratory infections, cellulitis, and severe invasive infections or sepsis; organisms include bacteria such as Staphylococcus, as well as viruses, fungi, and mycobacterial species. Laboratory studies show variable abnormalities, including B- and T-cell lymphopenia, decreased immunoglobulin subsets, decreased TRECs and dysfunctional T cells, decreased NK cells, neutropenia, and impaired neutrophil chemotaxis. Hematopoietic stem cell transplantation is curative (summary by Hsu et al., 2019; review by Lougaris et al., 2020).

In a review of autosomal forms of chronic granulomatous disease (see 306400 for genetic heterogeneity of CGD), Roos et al. (2021) noted that patients with RAC2 mutations may manifest CGD-like symptoms due to defects in neutrophil NADPH oxidase activity.

▼ Clinical Features
Hsu et al. (2019) reported 3 unrelated patients with IMD73B. The first patient presented at age 37 years with a history of recurrent infections, including sinusitis, pneumonia, sepsis, cellulitis, and lymphadenitis, from the age of 2 years. Identified organisms included Aspergillus, varicella, Staphylococcus, and Mycobacterium. She had pancytopenia and underwent splenectomy. At age 42, she had hematopoietic stem cell transplantation, which led to full immune reconstitution. The second patient was a 14-year-old boy who presented with recurrent otitis media, herpes stomatitis, chronic cough, and shingles after varicella vaccination. He had B- and T-cell lymphopenia, normal IgG and IgA, and decreased IgM. The third patient was identified through newborn screening by the finding of low TRECs and decreased T-cell counts. She developed acute bronchitis and later underwent successful hematopoietic stem cell transplantation. Neutrophils derived from all patients showed abnormal large vacuoles resembling macropinosomes.

Lougaris et al. (2019) reported a father and his 2 daughters with IMD73B. The 39-year-old father had a history of recurrent sinopulmonary infections, bronchiectasis, cutaneous HPV infections, and basal cell carcinoma. At age 34, he developed antiphospholipid syndrome and an IgM monoclonal gammopathy associated with a low-grade B-cell lymphoma. His daughters had early-onset recurrent sinopulmonary infections, severe lymphopenia affecting both B and T cells, hypogammaglobulinemia, poor response to vaccination, and mild intermittent neutropenia. Laboratory studies showed reduced CD4+ and C8+ T cells, decreased naive T cells, increased senescent T cells, increased lymphocyte apoptosis, and impaired proliferative responses. All patients received immunoglobulin therapy. The findings were consistent with combined immunodeficiency. Tabellini et al. (2019) noted that the patients reported by Lougaris et al. (2019) had persistently decreased NK cells. Analysis of NK cell function showed aberrant NK cell degranulation and maturation. The findings expanded the immune cell repertoire affected in this disorder.

Sharapova et al. (2019) reported a 10-year-old girl with combined immunodeficiency presenting as recurrent chest infections, chronic lung disease, lymphadenopathy, hepatosplenomegaly, and severe viral infections with herpes and varicella. Immunologic studies showed decreased TRECs, decreased memory B cells, and low IgG. Patient neutrophils showed absence of a chemotactic response to fMLF as well as the presence of abnormal macropinocytic vesicles. The patient underwent 2 hematopoietic stem cell transplantations but died due to overwhelming adenoviral infection.

Smits et al. (2020) reported a proband, father, and grandfather with IMD73B. All had recurrent respiratory infections since early childhood. The father and grandfather developed end-stage pulmonary failure necessitating lung transplantation; the grandfather did not survive the procedure. The 1-year-old son and his father both had T- and B-cell lymphopenia without bone marrow abnormalities. The son underwent hematopoietic stem cell transplantation, but had complications and was being treated at the time of report.

▼ Inheritance
The heterozygous mutations in the RAC2 gene that were identified in patients with IMD73B by Hsu et al. (2019) occurred de novo.

The transmission pattern of IMD73B in the family reported by Smits et al. (2020) was consistent with autosomal dominant inheritance.

▼ Molecular Genetics
In 3 unrelated patients with IMD73B, Hsu et al. (2019) identified a de novo heterozygous missense mutation in the RAC2 gene (E62K; 602049.0003). The mutation, which was found by exome sequencing or targeted sequencing of a gene panel, was confirmed by Sanger sequencing in all cases. Patient neutrophils had increased production of reactive oxygen species (ROS) in response to fMLF and impaired fMLF-induced chemotaxis associated with abnormal actin cycling compared to controls. Cells transfected with the mutation showed elevated basal ROS production, increased ruffling, and large vesicle formation compared to controls. Further studies suggested that E62K favors the active GTP-bound state and causes impaired GTP hydrolysis compared to wildtype, resulting in prolonged activation of downstream effectors. The mutation caused a dominant gain-of-function effect.

In a father and his 2 daughters with IMD73B, Lougaris et al. (2019) identified a heterozygous missense mutation in the RAC2 gene (P34H; 602049.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed normal levels of the RAC2 protein, but in vitro cellular functional studies showed that the mutant RAC2 protein had increased binding to the PAK effector protein compared to wildtype, consistent with a gain-of-function effect. Patient neutrophils showed increased filamentous actin content and an increased oxidative respiratory burst after stimulation with fMLP compared to controls. Response to PMA was normal.

In 3 members of a 3-generation family with IMD73B, Smits et al. (2020) identified a heterozygous E62K mutation in the RAC2 gene. In vitro studies of patient neutrophils showed defective migration and reduced bacterial killing, although there was an increase of GTP-bound RAC2 after fMLF stimulation compared to controls, consistent with a gain-of-function activating effect. T-cell subsets showed increased effector T cells and decreased recent thymic emigrant cells, suggesting disturbances in RAC2 signal-mediated chemotactic function of T cells. The authors suggested that increased GTP-bound RAC2 may impede physiologic actin polymerization.

In a 10-year-old girl with IMD72B, Sharapova et al. (2019) identified a heterozygous missense mutation in the RAC2 gene (N92T; 602049.0004). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the mother; DNA from the father was not available. The mutation was not found in public databases, including gnomAD. Cell lines transfected with the N92T mutation showed characteristics of active GTP-bound RAC2, including enhanced NADHPH oxidase activity both at rest and in response to PMA. The findings suggested that the N92T mutation confers a gain-of-function activating effect resulting in defects in both the lymphoid and myeloid lineages.

Tags: 22q13.1