Autosomal recessive hyper-IgE syndrome – DOCK8 gene.

Autosomal recessive hyper-IgE syndrome (AR-HIES), also known as DOCK8 immunodeficiency syndrome, is an alteration of the immune system that leads to the development of serious recurrent infections caused by bacteria, viruses or fungi and which can be fatal.

These infections cause rashes, blisters, abscesses and open wounds. People with AR-HIES also tend to have frequent episodes of pneumonia and other respiratory tract infections. Other problems related to the immune system in people with AR-HIES include eczema, food or environmental allergies and asthma. In some affected individuals, the immune system malfunction causes an autoimmune disease. For example, autoimmunity can lead to hemolytic anemia in people with AR-HIES.

Autosomal recessive hyper-IgE syndrome (AR-HIES) is characterized by abnormally high concentrations of immunoglobulin E (IgE) in the blood. The concentrations of this protein are more than 10 times higher than normal concentrations. IgE normally triggers an immune response against foreign invaders in the body, especially helminths, and also plays a role in allergies. However, it is not clear why people with AR-HIES have such high concentrations of this protein. In addition, affected people suffer from eosinophilia. Some individuals have neurological problems, such as hemiplegia, or they may have obstruction of blood flow or abnormal bleeding in the brain, which can lead to a stroke. People with AR-HIES have a higher than average risk of developing cancer, especially hematologic or skin malignancies.

This process is due to mutations in the DOCK8 gene (dedicator of cytokinesis 8), located on the short arm of chromosome 9 (9p24.3). This gene encodes a protein that plays a critical role in the survival and function of several types of immune system cells. One of the functions of the protein is to help maintain the structure and integrity of T immune cells and NK cells, which recognize and attack foreign invaders. In addition, DOCK8 protein is involved in chemical signaling pathways that stimulate immune B cells to mature and produce antibodies.

At least 130 mutations in the DOCK8 gene have been identified in people with autosomal recessive hyper-IgE syndrome (AR-HIES). Most of the mutations described result in the synthesis of a protein with reduced or non-functional function. Deficiency of this protein affects the development and normal function of immune cells. It is believed that T cells and NK cells that lack DOCK8 cannot maintain their shape as they move through dense spaces, such as those found inside the skin. Abnormal cells die, which results in the decrease of this number of cells. A deficiency of these immune cells affects the response to foreign invaders, which explains the usual skin infections. The absence of DOCK8 also impairs B cell maturation and antibody production. The lack of this type of immune response results in recurrent respiratory tract infections in people with the disease. It is not clear how mutations of the DOCK8 gene are involved in other features of AR-HIES, such as elevated levels of IgE, autoimmunity and neurological problems. Some people with AR-HIES do not have mutations in the DOCK8 gene. The genetic cause of the disease in these individuals is unknown.

This disease is inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI we detect mutations associated with autosomal recessive hyper-IgE syndrome, by complete PCR amplification of the exons of the DOCK8 gene, and subsequent sequencing.

Recommended samples: blood taken with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).