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Disease Profile

Autosomal dominant hyper IgE syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 100 000

3,310 - 29,790

US Estimated

1-9 / 100 000

5,135 - 46,215

Europe Estimated

Age of onset

Infancy

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ICD-10

D82.4

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

AD-HIES; Hyper Ig E syndrome, autosomal dominant; HIES autosomal dominant;

Categories

Congenital and Genetic Diseases; Immune System Diseases; Skin Diseases

Summary

Autosomal dominant hyper IgE syndrome (AD-HIES), formerly known as Job syndrome, affects several body systems including the immune system. AD-HIES is characterized by abnormally high levels of an immune system protein called immunoglobulin E (IgE) in the blood. Signs and symptoms may include recurrent infections (e.g., pneumonia, skin infections), eczema, and occasionally bone and tooth abnormalities. The eczema and skin infections may cause rashes, blisters, collections of pus (abscesses), open sores, and scaling of the skin. Some cases of AD-HIES are caused by mutations in the STAT3 gene. In other cases, the cause is unknown.[1]

Symptoms

Recurrent infections are common in people with autosomal dominant hyper IgE syndrome (AD-HIES). Affected individuals tend to have frequent bouts of pneumonia, which are caused by certain kinds of bacteria that infect the lungs and cause inflammation. Recurrent skin infections and an inflammatory skin disorder called eczema are also very common in AD-HIES). These skin problems cause rashes, blisters, collections of pus (abscesses), open sores, and scaling.[1]

This condition also affects other parts of the body, including the bones and teeth. Many people with this condition have skeletal abnormalities such as an unusually large range of joint movement (hyperextensibility), an abnormal curvature of the spine (scoliosis), reduced bone density (osteopenia), and a tendency for bones to fracture easily. Dental abnormalities are also common in AD-HIES. The primary (baby) teeth do not fall out at the usual time during childhood, but are retained as the adult teeth grow in. Other signs and symptoms of AD-HIES can include distinctive facial features and structural abnormalities of the brain, which typically do not affect a person's intelligence.[1]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Atelectasis
Partial or complete collapse of part or entire lung
0100750
Eczema
0000964
Generalized abnormality of skin
Generalised abnormality of skin
0011354
Increased circulating IgE level
0003212
Pruritus
Itching
Itchy skin
Skin itching

[ more ]

0000989
Recurrent respiratory infections
Frequent respiratory infections
Multiple respiratory infections
respiratory infections, recurrent
Susceptibility to respiratory infections

[ more ]

0002205
Skin rash
0000988
Skin ulcer
Open skin sore
0200042
30%-79% of people have these symptoms
Abnormal hair morphology
Abnormality of the hair
Hair abnormality

[ more ]

0001595
Chronic otitis media
Chronic infections of the middle ear
0000389
Cleft palate
Cleft roof of mouth
0000175
Cough
Coughing
0012735
Deeply set eye
Deep set eye
Deep-set eyes
Sunken eye

[ more ]

0000490
Delayed eruption of teeth
Delayed eruption
Delayed teeth eruption
Delayed tooth eruption
Eruption, delayed
Late eruption of teeth
Late tooth eruption

[ more ]

0000684
Dystrophic fingernails
Poor fingernail formation
0008391
Eosinophilia
High blood eosinophil count
0001880
Gingivitis
Inflamed gums
Red and swollen gums

[ more ]

0000230
Joint hyperflexibility
Joints move beyond expected range of motion
0005692
Osteopenia
0000938
Papule
0200034
Paronychia
0001818
Prominent forehead
Pronounced forehead
Protruding forehead

[ more ]

0011220
Recurrent fractures
Increased fracture rate
Increased fractures
Multiple fractures
Multiple spontaneous fractures
Varying degree of multiple fractures

[ more ]

0002757
Scoliosis
0002650
Wide nasal bridge
Broad nasal bridge
Broad nasal root
Broadened nasal bridge
Increased breadth of bridge of nose
Increased breadth of nasal bridge
Increased width of bridge of nose
Increased width of nasal bridge
Nasal bridge broad
Wide bridge of nose
Widened nasal bridge

[ more ]

0000431
5%-29% of people have these symptoms
Cellulitis
Bacterial infection of skin
Skin infection

[ more ]

0100658
Craniosynostosis
0001363
Fever
0001945
Lymphoma
Cancer of lymphatic system
0002665
Osteomyelitis
Bone infection
0002754
Skin vesicle
0200037
Vascular dilatation
Wider than typical opening or gap
0002617
Percent of people who have these symptoms is not available through HPO
Autosomal dominant inheritance
0000006
Chronic mucocutaneous candidiasis
0002728
Coarse facial features
Coarse facial appearance
0000280
Eczematoid dermatitis
0000976
Erythema
0010783
Frontal bossing
0002007
High palate
Elevated palate
Increased palatal height

[ more ]

0000218
Hypertelorism
Wide-set eyes
Widely spaced eyes

[ more ]

0000316
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]

0003593
Joint hypermobility
Double-Jointed
Flexible joints
Increased mobility of joints

[ more ]

0001382
Persistence of primary teeth
Delayed loss of baby teeth
Failure to lose baby teeth
Retained baby teeth

[ more ]

0006335
Recurrent fungal infections
0002841
Recurrent pneumonia
0006532
Recurrent sinopulmonary infections
Recurrent sinus and lung infections
0005425
Recurrent Staphylococcus aureus infections
0002726
Wide nose
Broad nose
Increased breadth of nose
Increased nasal breadth
Increased nasal width
Increased width of nose

[ more ]

0000445

Cause

Most cases of AD-HIES are caused by mutations in the STAT3 gene . This gene provides instructions for making a protein that plays an important role in several body systems. The STAT3 protein is involved in controlling the activity of particular genes, including genes involved in the immune system, especially the T cells.

Changes in the STAT3 gene alter the structure and function of the STAT3 protein, impairing its ability to control the activity of other genes. The defective protein disrupts cellular functions such as immune system regulation. The resulting immune system abnormalities make people with AD-HIES highly susceptible to infections. The STAT3 protein is also involved in the formation of cells that build and break down bone tissue, which could explain why STAT3 gene mutations lead to the skeletal and dental abnormalities characteristic of AD-HIES. It remains unclear how STAT3 gene mutations lead to increased IgE levels. 

When AD-HIES syndrome is not caused by STAT3 gene mutations, the genetic cause of is unknown.[1]

Diagnosis

The diagnosis of autosomal dominant hyper IgE syndrome (AD-HIES) is most often made based on a combination of clinical and laboratory findings. Diagnostic guidelines have been developed that include both immunologic /infectious manifestations and skeletal/connective tissue abnormalities. Molecular genetic testing of the STAT3 gene confirms the diagnosis.[2]

GeneReviews provides more detailed information about the diagnosis of AD-HIES.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Organizations Providing General Support

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • DermNet NZ is an online resource about skin diseases developed by the New Zealand Dermatological Society Incorporated. DermNet NZ provides information about this condition.
        • MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
        • Genetics Home Reference (GHR) contains information on Autosomal dominant hyper IgE syndrome. This website is maintained by the National Library of Medicine.
        • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

          In-Depth Information

          • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
          • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Autosomal dominant hyper IgE syndrome. Click on the link to view a sample search on this topic.

            References

            1. Autosomal dominant hyper-IgE syndrome. Genetics Home Reference (GHR). October 2015; https://ghr.nlm.nih.gov/condition/autosomal-dominant-hyper-ige-syndrome.
            2. Hsu AP, Davis J, Puck JM, Holland SM, Freeman AF. Autosomal Dominant Hyper IgE Syndrome. GeneReviews. June 2012; https://www.ncbi.nlm.nih.gov/books/NBK25507/. Accessed 12/3/2015.

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