Hyper Ige Syndrome (Job's Syndrome)

Beatriz Morillo-Gutierrez
Keywords: Hyper-IgE, Job’s syndrome, STAT3 deficiency, DOCK8 deficiency, TYK2 deficiency, PGM3 deficiency, primary immunodeficiencies.

Hyper IgE o Job’s syndrome (HIES) comprises a group of different primary immunodeficiencies (PIDs) with the common features of elevated IgE levels, severe eczema and recurrent skin and lung infections with increased susceptibility to pathogens such as S. aureus, fungus (Candida spp., Aspergillus spp.), and, in some cases, viruses.
Overall, it is a rare condition, with an estimated incidence of 1:100000, with no preference for sex.
Among the mutations found responsible for this syndrome we can find Signal transducer and activator of transcription 3 (STAT3) deficiency, causing autosomal dominant (AD)-HIES, Dedicator of cytokinesis 8 (DOCK8) deficiency, causing autosomal recessive (AR)-HIES, Tyrosine kinase 2 (TYK2) deficiency and Phosphoglucomutase 3(PGM3) deficiency.
Each of them are different clinical entities with different pathogenesis, manifestations, treatment and complications, and they will be discussed separately in the following sections.

This form of HIES is caused by AD mutations in the STAT3 gene. This gene codifies for a signal transduction protein –STAT3- that is expressed in many cellular lines, such as immune cells. It is involved in the signalling pathway of several cytokines, including IL6, IL10, IL11, IL17, IL21, IL22 and IL23 and of some growth factors; for that reason, AD-HIES is considered a multysistemic disease and its manifestations depends on the affected cell lines and pathways. Overall there is an unbalance between pro-inflammation and anti-inflammation; moreover, Il17 in particular is paramount in the development of Th17 lymphocytes, which are important for the clearance of S. aureus and Candida and in neutrophil proliferation and chemotaxis, leading to impaired neutrophil responses.
This form of HIES is caused by mutations in three proteins, DOCK8, TYK2 and PGM3; we will focus on DOCK8 here and discuss TYK2 and PGM3 later as they are very rare conditions.
DOCK8 is a protein member of the DOCK family, which takes part in some intracellular signalling networks, affecting proliferation, differentiation, cytoskeletal development, which involves migration, synapsis formation and adhesion processes, and survival of cells. It is expressed in several tissues such as placenta, kidney, lung and pancreas, but mostly within the immune system. Therefore, its deficiency leads to defective immune functions and decrease cell survival, affecting both the innate and the adaptative responses, and is considered a combined immune deficiency.

AD-HIES (STAT3 deficiency)
• Severe eczema with early onset, generally from the neonatal period, initially papular or pustular and later similar to atopic dermatitis, with S. aureus colonization.
• Increased susceptibility to infections:
Recurrent skin abscesses, characteristically with no inflammation signs –this is why they are called “cold”-, caused mostly by S. aureus.
Recurrent lung infections, with the same lack of inflammation signs and symptoms as in the skin abscesses, and caused mostly by S. aureus. The aberrant inflammation and healing process, and the delay in the diagnosis due to the lack of typical symptoms often lead to secondary bronchiectasis and cavitations, where other pathogens such as Aspergillus spp. can easily nest and establish secondary and protracted infections.
Increased incidence of chronic mucocutaneous candidiasis (CMC) and other systemic mycoses such as Cryptococcus spp., Histoplasma spp. and Coccidioides spp.
• Autoimmunity.
• Malignancy:
Increased risk as in other PIDs, developing particularly aggressive B cell lymphomas.
• Other non immunological abnormalities:
Characteristic facies with coarse facial appeareance, prominent forehead, high-arched palate.
Musculoskeletal abnormalities, with joint hyperextensibility, scoliosis and increased susceptibility to fractures and osteopenia.
Dentition disorders, with lack of exfoliation of primary dentition.
Vascular abnormalities involving broad range of vessels –brain, coronary- and including tortuosity and aneurysms. They can have significant morbi-mortality due to the secondary hypertension and risk of infarcts.
Parenchimal brain lesions
In spite of elevated IgE levels, there is no apparent correlation with increased allergic manifestations; however, gastrointestinal diseases manifestations has been described recently in some patients with endoscopic findings of eosinophilic esophagitis.
AR-HIES (DOCK8 deficiency)
• Increased susceptibility to infections:
Recurrent skin abscesses and Candida spp. as in AD-HIES; but more characteristic are the viral skin infections, generally caused by members of the herpes-virus family and molluscum contagiosum. These infections might be chronic, refractory to treatment and deforming.
Recurrent respiratory infections, mainly affecting the upper tract but also pneumonias with secondary bronchiectasis although not pneumatoceles as in AD-HIES.

• Atopy:
Wide range of atopic manifestations, from severe dermatitis with S. aureus colonization, allergy to food or environmental allergens, asthma, anaphylaxis or eosinophilic oesophagitis.
• Neurologic manifestations:
Facial paralysis, hemiplegia, cerebral aneurisms and CNS vasculitis.
• Autoimmunity:
Autommmune haemolytic anemia, hypothyroidism and vasculitis.
• Malignancies:
Early onset and frequent, being described in 10-36% of the patients, and predominantly associated with viruses: HPV-associated squamous cell carcinomas or EBV-associated Burkitt lymphoma and diffuse large B-cell lymphoma.

Hyper Ige Syndrome (Job's Syndrome) Hyper Ige Syndrome (Job's Syndrome) 09/05/2018
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