The immune system is affected by a rare genetic condition called Job syndrome, often known as hyper-IgE syndrome. It was first described by Dr. Robert Good and colleagues in 1966, based on their observations of two patients with recurrent infections, eczema, and elevated levels of immunoglobulin E (IgE) in their blood. The syndrome is named after the biblical character Job, who is afflicted with boils and sores.
The underlying cause of Job syndrome is a mutation in the signal transducer and activator of the transcription 3 (STAT3) gene, which leads to impaired function of immune cells called T-helper 17 (Th17) cells. Th17 cells are responsible for defending the body against fungal and bacterial infections, and their dysfunction results in recurrent infections and an inability to clear infections effectively. Additionally, the syndrome is characterized by a range of other symptoms, including eczema, recurrent skin abscesses, osteoporosis, and dental abnormalities.
Job syndrome is an autosomal dominant disorder, meaning an affected person has a 50% chance of passing the mutated gene on to their offspring. The syndrome can also arise spontaneously in individuals with no family history of the disorder due to a new mutation in the STAT3 gene.
Epidemiology
Mortality/Morbidity
AD-HIES(Autosomal Dominant Hyper IgE Syndrome) is associated with a high morbidity rate, and patients have an increased risk of mortality from severe infections. However, the life expectancy of patients with AD-HIES is not well established, and a wide range of outcomes is reported in the literature. Some patients have died in infancy or childhood, while others have survived into adulthood.
Race
AR-HIES has been reported in individuals from various racial and ethnic backgrounds.
Sex
Regarding disease incidence or severity, no gender-based differences are reported.
Age
AD-HIES is typically diagnosed in infancy or early childhood, and affected individuals may have a history of recurrent infections and failure to thrive. However, patients’ age at diagnosis and clinical presentation can vary widely.
PATHOPHYSIOLOGY
Job syndrome, also known as autosomal dominant hyper-IgE syndrome (AD-HIES), is brought on by heterozygous mutations in the STAT3 (signal transducer and activator of transcription) gene. Interleukin (IL)-6 and IL-23 are cytokines that control immunological responses, particularly the differentiation and survival of T-helper 17 (Th17) cells, and STAT3 is an essential transcription factor to these processes.
Due to reduced Th17 cells, AD-HIES patients generate fewer cytokines, IL-17 and IL-22, which are crucial for the host’s defense against extracellular bacteria and fungi. This deficiency results in impaired neutrophil recruitment, decreased opsonization, and poor microbial killing, increasing susceptibility to bacterial and fungal infections.
Furthermore, AD-HIES patients have an abnormal immune response to Staphylococcus aureus (S. aureus) due to the production of excess IgE antibodies, leading to the activation of eosinophils and basophils and the release of proinflammatory cytokines, such as IL-4, IL-13, and IL-31, that contribute to the pathogenesis of atopic dermatitis.
AD-HIES patients also have a defect in the function of natural killer (NK) cells, which are essential in the defense against viral infections and tumors. The defect is caused by decreased IL-12 and interferon-gamma (IFN-γ) production by dendritic cells and macrophages, leading to impaired NK cell activation and function.
The bone abnormalities observed in AD-HIES patients, including osteopenia and osteoporosis, are thought to be related to the effect of STAT3 mutations on osteoblast differentiation and function. Additionally, the increased incidence of scoliosis is thought to be due to a defect in the formation of connective tissue and muscle in the spine.
Anatomy
Pathophysiology
Etiology
The etiology of AD-HIES is a genetic mutation in the signal transducer and activator of the transcription 3 (STAT3) gene. Th17 cells, which mediate immune responses against extracellular bacteria and fungi, depend on this gene for proper development and function.
STAT3 mutations impair Th17 differentiation, leading to reduced IL-17 production and decreased neutrophil recruitment and activity. This defective immune response results in susceptibility to recurrent skin and pulmonary infections and other clinical manifestations of AD-HIES. Most cases are sporadic, but autosomal dominant inheritance with variable expressivity has been documented.
Genetics
Prognostic Factors
The prognosis of AD-HIES is guarded. Patients with AD-HIES are at risk of developing severe and life-threatening infections. The mortality rate in AD-HIES patients is high due to the consequences of chronic infections, with infection-related deaths occurring at an average age of 29.
Patients with AD-HIES are also at increased risk of developing malignancies, particularly lymphoma. However, with proper medical management, patients may survive into adulthood and have children. Early diagnosis, prompt treatment of infections, and appropriate prevention can reduce morbidity and mortality in patients with AD-HIES.
Clinical History
Age group:
Job syndrome can present in infancy, childhood, or adulthood. The age of onset can vary widely, but most patients are diagnosed in childhood.
Physical Examination
Eczema: Nearly all patients with Job syndrome have eczema or other skin lesions, which may occur at birth or develop during infancy.
Recurrent skin abscesses: Patients with Job syndrome often have recurrent skin abscesses, typically caused by Staphylococcus aureus.
Recurrent pneumonia: Patients with Job syndrome are susceptible to recurrent bacterial infections, particularly of the respiratory tract. Pneumonia may be severe and difficult to treat.
Facial features: Patients with Job syndrome may have characteristic facial features, including a prominent forehead, broad nasal bridge, deep-set eyes, and a wide, thin upper lip.
Dental abnormalities: Dental abnormalities are common in patients with Job syndrome, including retained primary teeth, delayed eruption of permanent teeth, and frequent dental caries.
Skeletal abnormalities: Patients with Job syndrome may have skeletal abnormalities, including scoliosis, hyperextensible joints, and fractures.
Lymphadenopathy: Patients with Job syndrome may have enlarged lymph nodes, particularly in the cervical region.
Delayed wound healing: Patients with Job syndrome may have delayed wound healing, which can develop chronic wounds and skin ulcers.
Age group
Associated comorbidity
Job syndrome is associated with many comorbidities, including atopic dermatitis, recurrent skin infections (particularly staphylococcal infections), and recurrent pulmonary infections (such as pneumonia).
Patients may also have dental, skeletal, and connective tissue abnormalities. In addition, some patients may have cognitive impairment and developmental delays.
Associated activity
Acuity of presentation
The presentation of Job syndrome can be acute or chronic, depending on the severity of the symptoms. In some cases, patients may present with life-threatening infections, such as sepsis or meningitis, that require immediate medical attention.
In other cases, patients may have a chronic history of recurrent infections and other symptoms from childhood.
Differential Diagnoses
The differential diagnosis for hyper-IgE syndrome (HIES), also known as Job syndrome, includes:
Other primary immunodeficiency disorders, such as severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), and common variable immunodeficiency (CVID).
Additional atopic conditions, including allergic rhinitis, asthma, and eczema.
Recurrent infections of the skin and mucous membranes by candida characterize chronic mucocutaneous candidiasis.
This syndrome is characterized by high levels of immunoglobulin M (IgM) and low levels of other immunoglobulins.
Autoimmune Poly endocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is characterized by multiple endocrine gland deficiencies, chronic mucocutaneous candidiasis, and other autoimmune disorders.
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
Management of Job syndrome involves a combination of approaches, including environmental modification, pharmaceutical agents, and procedures.
by Stage
by Modality
Chemotherapy
Radiation Therapy
Surgical Interventions
Hormone Therapy
Immunotherapy
Hyperthermia
Photodynamic Therapy
Stem Cell Transplant
Targeted Therapy
Palliative Care
Patients with Job syndrome should avoid exposure to potential allergens and irritants. Practicing excellent personal hygiene, including frequent hand cleansing, is essential to prevent skin infections.
Avoiding congested areas and infected individuals is also crucial to prevent the spreading of contagious diseases.
Antibiotics are usually prescribed for skin and respiratory infections, and antifungal agents may be necessary for fungal infections. Immunoglobulin replacement therapy (IVIG) may also be required to help prevent infections.
Some patients may benefit from medications that reduce inflammation, such as corticosteroids.
Pneumatoceles or lung abscesses in Job syndrome may require surgical intervention to remove the damaged tissue. Dermatologic procedures may also be necessary, such as drainage of abscesses or removal of excess tissue.
The management of Job syndrome involves both acute and long-term management. Acute management involves treating infections and complications as they arise. Long-term management involves preventative measures to reduce the risk of infection and disease complications.
It is critical to have frequent contact with a healthcare practitioner to evaluate illness development and treat new symptoms.
The immune system is affected by a rare genetic condition called Job syndrome, often known as hyper-IgE syndrome. It was first described by Dr. Robert Good and colleagues in 1966, based on their observations of two patients with recurrent infections, eczema, and elevated levels of immunoglobulin E (IgE) in their blood. The syndrome is named after the biblical character Job, who is afflicted with boils and sores.
The underlying cause of Job syndrome is a mutation in the signal transducer and activator of the transcription 3 (STAT3) gene, which leads to impaired function of immune cells called T-helper 17 (Th17) cells. Th17 cells are responsible for defending the body against fungal and bacterial infections, and their dysfunction results in recurrent infections and an inability to clear infections effectively. Additionally, the syndrome is characterized by a range of other symptoms, including eczema, recurrent skin abscesses, osteoporosis, and dental abnormalities.
Job syndrome is an autosomal dominant disorder, meaning an affected person has a 50% chance of passing the mutated gene on to their offspring. The syndrome can also arise spontaneously in individuals with no family history of the disorder due to a new mutation in the STAT3 gene.
Mortality/Morbidity
AD-HIES(Autosomal Dominant Hyper IgE Syndrome) is associated with a high morbidity rate, and patients have an increased risk of mortality from severe infections. However, the life expectancy of patients with AD-HIES is not well established, and a wide range of outcomes is reported in the literature. Some patients have died in infancy or childhood, while others have survived into adulthood.
Race
AR-HIES has been reported in individuals from various racial and ethnic backgrounds.
Sex
Regarding disease incidence or severity, no gender-based differences are reported.
Age
AD-HIES is typically diagnosed in infancy or early childhood, and affected individuals may have a history of recurrent infections and failure to thrive. However, patients’ age at diagnosis and clinical presentation can vary widely.
PATHOPHYSIOLOGY
Job syndrome, also known as autosomal dominant hyper-IgE syndrome (AD-HIES), is brought on by heterozygous mutations in the STAT3 (signal transducer and activator of transcription) gene. Interleukin (IL)-6 and IL-23 are cytokines that control immunological responses, particularly the differentiation and survival of T-helper 17 (Th17) cells, and STAT3 is an essential transcription factor to these processes.
Due to reduced Th17 cells, AD-HIES patients generate fewer cytokines, IL-17 and IL-22, which are crucial for the host’s defense against extracellular bacteria and fungi. This deficiency results in impaired neutrophil recruitment, decreased opsonization, and poor microbial killing, increasing susceptibility to bacterial and fungal infections.
Furthermore, AD-HIES patients have an abnormal immune response to Staphylococcus aureus (S. aureus) due to the production of excess IgE antibodies, leading to the activation of eosinophils and basophils and the release of proinflammatory cytokines, such as IL-4, IL-13, and IL-31, that contribute to the pathogenesis of atopic dermatitis.
AD-HIES patients also have a defect in the function of natural killer (NK) cells, which are essential in the defense against viral infections and tumors. The defect is caused by decreased IL-12 and interferon-gamma (IFN-γ) production by dendritic cells and macrophages, leading to impaired NK cell activation and function.
The bone abnormalities observed in AD-HIES patients, including osteopenia and osteoporosis, are thought to be related to the effect of STAT3 mutations on osteoblast differentiation and function. Additionally, the increased incidence of scoliosis is thought to be due to a defect in the formation of connective tissue and muscle in the spine.
The etiology of AD-HIES is a genetic mutation in the signal transducer and activator of the transcription 3 (STAT3) gene. Th17 cells, which mediate immune responses against extracellular bacteria and fungi, depend on this gene for proper development and function.
STAT3 mutations impair Th17 differentiation, leading to reduced IL-17 production and decreased neutrophil recruitment and activity. This defective immune response results in susceptibility to recurrent skin and pulmonary infections and other clinical manifestations of AD-HIES. Most cases are sporadic, but autosomal dominant inheritance with variable expressivity has been documented.
The prognosis of AD-HIES is guarded. Patients with AD-HIES are at risk of developing severe and life-threatening infections. The mortality rate in AD-HIES patients is high due to the consequences of chronic infections, with infection-related deaths occurring at an average age of 29.
Patients with AD-HIES are also at increased risk of developing malignancies, particularly lymphoma. However, with proper medical management, patients may survive into adulthood and have children. Early diagnosis, prompt treatment of infections, and appropriate prevention can reduce morbidity and mortality in patients with AD-HIES.
Age group:
Job syndrome can present in infancy, childhood, or adulthood. The age of onset can vary widely, but most patients are diagnosed in childhood.
Eczema: Nearly all patients with Job syndrome have eczema or other skin lesions, which may occur at birth or develop during infancy.
Recurrent skin abscesses: Patients with Job syndrome often have recurrent skin abscesses, typically caused by Staphylococcus aureus.
Recurrent pneumonia: Patients with Job syndrome are susceptible to recurrent bacterial infections, particularly of the respiratory tract. Pneumonia may be severe and difficult to treat.
Facial features: Patients with Job syndrome may have characteristic facial features, including a prominent forehead, broad nasal bridge, deep-set eyes, and a wide, thin upper lip.
Dental abnormalities: Dental abnormalities are common in patients with Job syndrome, including retained primary teeth, delayed eruption of permanent teeth, and frequent dental caries.
Skeletal abnormalities: Patients with Job syndrome may have skeletal abnormalities, including scoliosis, hyperextensible joints, and fractures.
Lymphadenopathy: Patients with Job syndrome may have enlarged lymph nodes, particularly in the cervical region.
Delayed wound healing: Patients with Job syndrome may have delayed wound healing, which can develop chronic wounds and skin ulcers.
Job syndrome is associated with many comorbidities, including atopic dermatitis, recurrent skin infections (particularly staphylococcal infections), and recurrent pulmonary infections (such as pneumonia).
Patients may also have dental, skeletal, and connective tissue abnormalities. In addition, some patients may have cognitive impairment and developmental delays.
The presentation of Job syndrome can be acute or chronic, depending on the severity of the symptoms. In some cases, patients may present with life-threatening infections, such as sepsis or meningitis, that require immediate medical attention.
In other cases, patients may have a chronic history of recurrent infections and other symptoms from childhood.
The differential diagnosis for hyper-IgE syndrome (HIES), also known as Job syndrome, includes:
Other primary immunodeficiency disorders, such as severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), and common variable immunodeficiency (CVID).
Additional atopic conditions, including allergic rhinitis, asthma, and eczema.
Recurrent infections of the skin and mucous membranes by candida characterize chronic mucocutaneous candidiasis.
This syndrome is characterized by high levels of immunoglobulin M (IgM) and low levels of other immunoglobulins.
Autoimmune Poly endocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is characterized by multiple endocrine gland deficiencies, chronic mucocutaneous candidiasis, and other autoimmune disorders.
Management of Job syndrome involves a combination of approaches, including environmental modification, pharmaceutical agents, and procedures.
The immune system is affected by a rare genetic condition called Job syndrome, often known as hyper-IgE syndrome. It was first described by Dr. Robert Good and colleagues in 1966, based on their observations of two patients with recurrent infections, eczema, and elevated levels of immunoglobulin E (IgE) in their blood. The syndrome is named after the biblical character Job, who is afflicted with boils and sores.
The underlying cause of Job syndrome is a mutation in the signal transducer and activator of the transcription 3 (STAT3) gene, which leads to impaired function of immune cells called T-helper 17 (Th17) cells. Th17 cells are responsible for defending the body against fungal and bacterial infections, and their dysfunction results in recurrent infections and an inability to clear infections effectively. Additionally, the syndrome is characterized by a range of other symptoms, including eczema, recurrent skin abscesses, osteoporosis, and dental abnormalities.
Job syndrome is an autosomal dominant disorder, meaning an affected person has a 50% chance of passing the mutated gene on to their offspring. The syndrome can also arise spontaneously in individuals with no family history of the disorder due to a new mutation in the STAT3 gene.
Mortality/Morbidity
AD-HIES(Autosomal Dominant Hyper IgE Syndrome) is associated with a high morbidity rate, and patients have an increased risk of mortality from severe infections. However, the life expectancy of patients with AD-HIES is not well established, and a wide range of outcomes is reported in the literature. Some patients have died in infancy or childhood, while others have survived into adulthood.
Race
AR-HIES has been reported in individuals from various racial and ethnic backgrounds.
Sex
Regarding disease incidence or severity, no gender-based differences are reported.
Age
AD-HIES is typically diagnosed in infancy or early childhood, and affected individuals may have a history of recurrent infections and failure to thrive. However, patients’ age at diagnosis and clinical presentation can vary widely.
PATHOPHYSIOLOGY
Job syndrome, also known as autosomal dominant hyper-IgE syndrome (AD-HIES), is brought on by heterozygous mutations in the STAT3 (signal transducer and activator of transcription) gene. Interleukin (IL)-6 and IL-23 are cytokines that control immunological responses, particularly the differentiation and survival of T-helper 17 (Th17) cells, and STAT3 is an essential transcription factor to these processes.
Due to reduced Th17 cells, AD-HIES patients generate fewer cytokines, IL-17 and IL-22, which are crucial for the host’s defense against extracellular bacteria and fungi. This deficiency results in impaired neutrophil recruitment, decreased opsonization, and poor microbial killing, increasing susceptibility to bacterial and fungal infections.
Furthermore, AD-HIES patients have an abnormal immune response to Staphylococcus aureus (S. aureus) due to the production of excess IgE antibodies, leading to the activation of eosinophils and basophils and the release of proinflammatory cytokines, such as IL-4, IL-13, and IL-31, that contribute to the pathogenesis of atopic dermatitis.
AD-HIES patients also have a defect in the function of natural killer (NK) cells, which are essential in the defense against viral infections and tumors. The defect is caused by decreased IL-12 and interferon-gamma (IFN-γ) production by dendritic cells and macrophages, leading to impaired NK cell activation and function.
The bone abnormalities observed in AD-HIES patients, including osteopenia and osteoporosis, are thought to be related to the effect of STAT3 mutations on osteoblast differentiation and function. Additionally, the increased incidence of scoliosis is thought to be due to a defect in the formation of connective tissue and muscle in the spine.
The etiology of AD-HIES is a genetic mutation in the signal transducer and activator of the transcription 3 (STAT3) gene. Th17 cells, which mediate immune responses against extracellular bacteria and fungi, depend on this gene for proper development and function.
STAT3 mutations impair Th17 differentiation, leading to reduced IL-17 production and decreased neutrophil recruitment and activity. This defective immune response results in susceptibility to recurrent skin and pulmonary infections and other clinical manifestations of AD-HIES. Most cases are sporadic, but autosomal dominant inheritance with variable expressivity has been documented.
The prognosis of AD-HIES is guarded. Patients with AD-HIES are at risk of developing severe and life-threatening infections. The mortality rate in AD-HIES patients is high due to the consequences of chronic infections, with infection-related deaths occurring at an average age of 29.
Patients with AD-HIES are also at increased risk of developing malignancies, particularly lymphoma. However, with proper medical management, patients may survive into adulthood and have children. Early diagnosis, prompt treatment of infections, and appropriate prevention can reduce morbidity and mortality in patients with AD-HIES.
Age group:
Job syndrome can present in infancy, childhood, or adulthood. The age of onset can vary widely, but most patients are diagnosed in childhood.
Eczema: Nearly all patients with Job syndrome have eczema or other skin lesions, which may occur at birth or develop during infancy.
Recurrent skin abscesses: Patients with Job syndrome often have recurrent skin abscesses, typically caused by Staphylococcus aureus.
Recurrent pneumonia: Patients with Job syndrome are susceptible to recurrent bacterial infections, particularly of the respiratory tract. Pneumonia may be severe and difficult to treat.
Facial features: Patients with Job syndrome may have characteristic facial features, including a prominent forehead, broad nasal bridge, deep-set eyes, and a wide, thin upper lip.
Dental abnormalities: Dental abnormalities are common in patients with Job syndrome, including retained primary teeth, delayed eruption of permanent teeth, and frequent dental caries.
Skeletal abnormalities: Patients with Job syndrome may have skeletal abnormalities, including scoliosis, hyperextensible joints, and fractures.
Lymphadenopathy: Patients with Job syndrome may have enlarged lymph nodes, particularly in the cervical region.
Delayed wound healing: Patients with Job syndrome may have delayed wound healing, which can develop chronic wounds and skin ulcers.
Job syndrome is associated with many comorbidities, including atopic dermatitis, recurrent skin infections (particularly staphylococcal infections), and recurrent pulmonary infections (such as pneumonia).
Patients may also have dental, skeletal, and connective tissue abnormalities. In addition, some patients may have cognitive impairment and developmental delays.
The presentation of Job syndrome can be acute or chronic, depending on the severity of the symptoms. In some cases, patients may present with life-threatening infections, such as sepsis or meningitis, that require immediate medical attention.
In other cases, patients may have a chronic history of recurrent infections and other symptoms from childhood.
The differential diagnosis for hyper-IgE syndrome (HIES), also known as Job syndrome, includes:
Other primary immunodeficiency disorders, such as severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), and common variable immunodeficiency (CVID).
Additional atopic conditions, including allergic rhinitis, asthma, and eczema.
Recurrent infections of the skin and mucous membranes by candida characterize chronic mucocutaneous candidiasis.
This syndrome is characterized by high levels of immunoglobulin M (IgM) and low levels of other immunoglobulins.
Autoimmune Poly endocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is characterized by multiple endocrine gland deficiencies, chronic mucocutaneous candidiasis, and other autoimmune disorders.
Management of Job syndrome involves a combination of approaches, including environmental modification, pharmaceutical agents, and procedures.
Patients with Job syndrome should avoid exposure to potential allergens and irritants. Practicing excellent personal hygiene, including frequent hand cleansing, is essential to prevent skin infections.
Avoiding congested areas and infected individuals is also crucial to prevent the spreading of contagious diseases.
Antibiotics are usually prescribed for skin and respiratory infections, and antifungal agents may be necessary for fungal infections. Immunoglobulin replacement therapy (IVIG) may also be required to help prevent infections.
Some patients may benefit from medications that reduce inflammation, such as corticosteroids.
Pneumatoceles or lung abscesses in Job syndrome may require surgical intervention to remove the damaged tissue. Dermatologic procedures may also be necessary, such as drainage of abscesses or removal of excess tissue.
The management of Job syndrome involves both acute and long-term management. Acute management involves treating infections and complications as they arise. Long-term management involves preventative measures to reduce the risk of infection and disease complications.
It is critical to have frequent contact with a healthcare practitioner to evaluate illness development and treat new symptoms.
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