Hyper Ige Syndrome (job's Syndrome)

Introduction

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 is different clinical entities with different pathogenesis, manifestations, treatment, and complications, and they will be discussed separately in the following sections.

Pathogenesis

AD-HIES (STAT3)

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 signaling 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.

AR-HIES (DOCK8)

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 signaling 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 the 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.

Clinical Features and Complications

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 appearance, prominent forehead, high-arched palate.
  • Musculoskeletal abnormalities, with joint hyperextensibility, scoliosis, and increased susceptibility to fractures and osteopenia.
  • Dentition disorders, with a lack of exfoliation of primary dentition.
  • Vascular abnormalities involving a broad range of vessels -brain, coronary- and including tortuosity and aneurysms. They can have significant morbi-mortality due to secondary hypertension and the risk of infarcts.
  • Parenchymal brain lesions
  • In spite of elevated IgE levels, there is no apparent correlation with increased allergic manifestations; however, gastrointestinal disease manifestations have 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 is 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 pneumonia 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 aneurysms, and CNS vasculitis.
• Autoimmunity:
  Autoimmune hemolytic 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.

Investigations

When facing a patient with elevated IgE levels, rash, and infections, the differential diagnosis includes HIES but also other conditions such as:

• HIES: STAT3 deficiency and DOCK8 deficiency, and less often TYK2 deficiency or PGM3 deficiency
• Severe atopic dermatitis
• Netherton syndrome
• Wiskott-Aldrich syndrome
• Omenn’s syndrome
• Atypical DiGeorge syndrome

These other diseases are normally very characteristic and difficult to confuse; however, to simplify the clinical approach, the NIH developed a clinical score in 1999 for patients with elevated IgE, eczema, and infections, originally intended for the diagnosis of STAT3 deficiency but also useful for DOCK8 deficiency patients depending on the values and cut-offs used. Later in 2010, Woellner et all proposed another diagnostic guideline reviewing a cohort of 100 patients with HIES to establish the likelihood of AD-HIES with the following parameters:

• Possible: IgE >1000 IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate.
• Probable: These characteristics plus lack of TH17 cells or family history for definitive HIES.
• Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.

Ultimately, in the case of a patient presenting with clinical characteristics of HIES and suggestive score, genetic analysis directed to STAT3, DOCK8, TYK2, and PGM3 mutations or whole-exome sequencing is strongly recommended to achieve the confirmation diagnosis, as the management and treatment can vary. Other immunological tests that could help to differentiate the specific conditions are:

• AD-HIES (STAT3)

  Increased levels of IgE, often above 2000 IU/mL, and peripheral eosinophilia. Mild neutropenia. Generally, normal absolute lymphocyte counts, with a decreased number of CD4+ Th17 and T and B memory lymphocytes. Normal levels of IgG and IgM with variable levels of IgA and specific vaccine responses.

• AR-HIES (DOCK8)

  Increased levels of IgE levels above 1000 IU/mL and peripheral eosinophilia. It is a combined immunodeficiency, with decreased levels of CD8 and CD4 cells that worsens over time and impaired proliferation and activation of CD8 T cells, together with decreased memory B cells. Increased population of Th2. The variable decreased in the B and NK compartment. Elevation of IgG serum levels, decrease in IgM, and variable level on IgA, with poor antibody specific responses.

Treatment

AD-HIES (STAT3)

• Infection management:
  Aggressive and prompt treatment of infections, especially pneumonias, to avoid the establishment of complications. Prophylaxis if needed (eg., TMP-SMX).

  Anti-aspergillus prophylaxis (eg., itraconazole) in patients with pneumatoceles due to the increased risk of colonization or treatment in case of already established fungal lung infections; pulmonary surgery must be carefully considered in protracted aspergillus infections resistant to treatment.

  Anticandidal treatment, (eg., fluconazole) in cases of CMC.

  Consider immunoglobulin (IG) replacement in patients with impaired antibody responses.

• Skincare with intensive moisturizers, and eradication measures towards S. aureus, such as bleach baths or chlorhexidine washes; prophylactic topical antibiotics if needed.

• Consider hematopoietic stem cell transplant (HSCT) on an individual basis, for example, in case of malignancies, as there is a lack of consistent results with high risks of the procedure.

AR- HIES (DOCK8)

DOCK8 deficiency has worse prognosis than other forms of HIES with significant mortality in the 2^nd and 3^rd decades of life. Therefore, HSCT should be done as it is the only curative option available, and before the development of comorbidities that could hinder the outcome of the procedure.

These patients need as well

• Aggressive management of infections, with antimicrobial prophylaxis and IG replacement if needed.
• Atopic manifestations care asthma treatments if needed, skin moisturizers for dermatitis, etc.

Less Frequent Forms

PGM3 DEFICIENCY

Recently described, it is a glycosylation defect considered another multisystem disease, transmitted in an AR manner. The patients presented a variable phenotype, compatible with HIES for some of them, sharing the cutaneous rash, recurrent lung infections with secondary bronchiectasis, and increased levels of IgE; other features presented were enhanced allergic manifestations, vasculitis and skeletal abnormalities, neurocognitive deficits with developmental delay and psychomotor retardation and autoimmunity.Amongst the laboratory findings, there is leukopenia with lymphopenia and neutropenia, a decrease principally in the CD4 T compartment and low memory B cells, and increased Immunoglobulin levels.

The curative treatment is still to be elucidated and the patients need supportive care with infection management.

TYK2 MUTATIONS

TYK2 deficiency was the first mutation described in a patient with HIES, transmitted in an AR manner. TYK2 is a protein of the family of the Janus kinases (JAK) that signal through STAT, involved therefore in the cytokine pathway already mentioned for STAT3. But so far, the spectrum of the phenotype in the patients affected is very broad, with only a few patients carrying this mutation sharing the characteristics of HIES; other manifestations are increased susceptibility to disseminated atypical mycobacteria, Salmonella spp. and skin viral infections. The blood counts and lymphocyte subsets are generally normal, and the treatment is focused on the management of infections.