NORD gratefully acknowledges Bodo Grimbacher, MD, Professor of Immunology, Scientific Director, Centre of Chronic Immunodeficiency (CCI), University Medical Center, Freiburg and University of Freiburg, Germany, for assistance in the preparation of this report.
Autosomal recessive hyper IgE syndrome (AR-HIES) is a very rare primary immunodeficiency disorder. Symptoms often become apparent at birth or early during infancy or childhood. The disorder is characterized by the triad of highly elevated levels of IgE in serum, recurring abscesses of the skin, and recurrent pneumonia AR-HIES is inherited as an autosomal recessive trait and the first symptoms include the development of a dry, red, flaky skin rash (eczema).
The clinical triad of AR-HIES is shared with the more frequent autosomal dominant HIES syndrome (AD-HIES; see this term), but other features such as persistent cutaneous viral infections and neurological symptoms are unique to the AR-HIES form. For years, researchers considered them different expressions of the same disorder, but now researchers consider them similar, yet distinct disorders.
The first case of hyper IgE syndrome was described in the medical literature in 1966. The physicians termed the disorder Job syndrome after the biblical character of Job who was covered in boils and sores over his entire body.
The symptoms of AR-HIES vary from case to case. AR-HIES affects the immune system as well as the central nervous system. Symptoms may be apparent at birth or during infancy or early childhood.
AR-HIES is considered a rare primary immunodeficiency disorder, one of a group of disorders characterized by irregularities in the cell development and/or cell maturation process of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e., invading microscopic life-forms [microorganisms]). The T cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses, and some bacteria. The B cell system (humoral immune response) fights infection caused by other viruses and particularly encapsulated bacteria. It does so by secreting immune factors called antibodies (also known as immunoglobulins) into the fluid portion of the blood (serum) and body secretions (e.g., saliva). There are four major classes of immunoglobulins (Ig) known as IgM, IgG, IgA, and IgE. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells. (The white blood cells [leukocytes] are part of the body’s system of defenses, playing an essential role in protecting against infection as well as fighting infection once it occurs.) In addition, antibodies are produced following vaccination, providing protection from infectious diseases like polio, measles, and tetanus.
Individuals with AR-HIES have abnormally high levels of immunoglobulin IgE in the fluid portion of the blood (thus the term “hyper IgE”). Affected individuals also have abnormal numbers of white blood cells known as eosinophils throughout the body (eosinophilia). Because of problems within the immune system, individuals with AR-HIES are susceptible to recurrent episodes of certain bacterial infections that affect the skin and lungs as well as recurrent viral infections.
The first symptom of AR-HIES may be a dry, red flaky skin rash (eczema) that develops at birth or early during infancy. Itchiness (pruritus) may also occur. In addition, infants are particularly susceptible to bacterial infection, especially staphylococcal infections. Such infections may cause boils and pus-filled holes (abscesses) to form on the skin. These abscesses are referred to as “cold” abscesses because they lack the normal surrounding signs of infections such as warmth and redness. Abscesses may also be found on the bone behind the ear (mastoid), joints, gums, air passages in the lungs (bronchi), and in the lungs themselves.
Individuals with AR-HIES also develop recurrent lung infections (pneumonia). Pneumonia is often associated with fluid accumulation around the lungs (pleural effusion) or pus in the area between the outer surface of the lung and the chest wall (empyema). Individuals with AR-HIES may develop repeated episodes of respiratory (bronchitis), sinus (sinusitis), and middle ear infections (otitis media).
Skin infections associated with AR-HIES are most often caused by Staphylococcus aureus. Pneumonia and respiratory infections associated with AR-HIES are mainly due to a wide spectrum of gram-positive and gram-negative bacteria and fungi including Streptococcus pneumoniae, Haemophilus influenzae, Pneumocystis jirovecii and Histoplasma capsulaum.
In addition to bacterial infections, individuals with AR-HIES are especially susceptible to viral infections such as herpes simplex (HSV) and herpes zoster (VZV), molluscum contagiosum (MCV) and human papillomavirus (HPV). These infections which are extensive, difficult to control and mutilating, often occur concurrently.
Affected individuals have developed chronic orolabial or ulcerative anogenital infections with herpes simplex virus. Eczema herpeticum as well as inflammation of the cornea (keratitis) with herpes virus also occur. Some individuals with AR-HIES have developed a severe viral skin infection known as Molluscum contagiosum caused by the molluscum contagiosum virus (MCV). This infection is characterized by raised bumps or growths (nodules) on the skin that often become red or inflamed. Nodules may be tender and itchy as well. Repeated infections with the varicella zoster virus, the virus that causes chickenpox, have also been reported in literature.
In addition to susceptibility to infection, individuals with AR-HIES can present a variety of neurological symptoms. Such symptoms include partial facial paralysis, tissue degeneration due to lack of blood flow (ischemic infarction), inflammation of blood vessels (vasculitis) of the brain, and paralysis on one side of the body (hemiplegia). Neurological symptoms may progress to cause life-threatening complications including bleeding (hemorrhaging) in the brain or widening or bulging of the wall of a brain artery or vein (aneurysm).
Individuals with AR-HIES may also be prone to developing autoimmune disorders such as hemolytic anemia. The term autoimmune refers to conditions in which the body’s natural defenses against invading microorganisms mistakenly attack healthy tissue. Hemolytic anemia is characterized by the premature destruction of red blood cells faster than they can be reproduced. Anemia may result in fatigue, paleness, rapid heartbeat, shortness of breath, dark urine, and chills.
Unlike the more common AD-HIES, 50-70% of patients with AR-HIES develop severe allergies, including anaphylaxis to food and environmental antigens, and about 30% have asthma.
AR-HIES is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
All individuals, even healthy ones, carry abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Many patients with AR-HIES were from consanguineous parents.
Mutations of the dedicator of cytokinesis 8 (DOCK8) gene located on chromosome 9p are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome. Since the discovery that loss-of-function mutations in DOCK8 underlie AR-HIES in 2009, an estimated more than 100 patients worldwide have been identified. DOCK8 is involved in the regulation of cell migration, morphology, adhesion, and growth and is highly expressed within the immune system, suggesting crucial functions in these cell types.
AR-HIES affects males and females in equal numbers. These disorders may often go unrecognized or misdiagnosed, making it difficult to determine their true frequency in the general population. Although AR-HIES is present during infancy, diagnosis may not be made until adolescence and, in some cases, adulthood.
Due to the great variety of clinical features of AR-HIES early diagnosis can be challenging and genetic testing for DOCK8 deficiency may be essential.
A diagnosis of AR-HIES is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. Laboratory studies that may aid in a diagnosis include blood tests that demonstrate elevated levels of IgE in the blood and elevated levels of certain white blood cells known as eosinophils (eosinophilia).
X-ray studies such as computed tomography (CT scanning) may be used to detect lung infections. During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.
The treatment of AR-HIES is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, pneumologists, immunologists, and other health care professionals may need to systematically and comprehensively plan an affect child's treatment.
The therapeutic approach involves prevention and management of infections. Long-term administration of systemic antibiotics and antiviral drugs is recommended.
The mainstay for treatment of individuals with AR-HIES is preventative (prophylactic) antibiotic therapy against bacterial infection. Common antibiotic medications (e.g., anti-staphylococcal agents) used to treat individuals with AR-HIES include dicloxacillin, trimethoprim-sulfamethooxazole, cephalosporin, cotrimoxazole, and penicillin.
Surgical drainage of existing skin lesions, followed by a regimen of antibiotic therapy may be required in some cases. Topical steroids and moisturizing creams may also be used to treat skin lesions.
Genetic counseling may be of benefit for affected individuals and their families.
Recently it has been shown that hematopoietic stem cell transplantation (HSCT) may be curative for DOCK8 deficiency.
A variety of treatments are under investigation for the treatment of individuals with AR-HIES including cyclosporine A, immunoglobulin supplementation, interferons, or bone marrow transplantation. Most of these treatments are used for individuals who are unresponsive to other forms of treatment. More research is necessary to determine the long-term safety and effectiveness of such potential therapies for individuals with AR-HIES.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact:
Contact for additional information about autosomal recessive hyper IgE syndrome:
Univ.-Prof. Dr. med. B. Grimbacher
CCI – Centre of Chronic Immunodeficiency
Phone: 0761 270-77731 Fax: -77744
Engesserstraße 4, 79108 Freiburg
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