Update on Hyper IgE syndrome (HIES)

DOI: 10.7508/JPR-V2-N1-39-46 J Pediatr Rev. 2014;2(1):39-46 JPR Journal of Pediatrics Review Mazandaran University of Medical Sciences Update on Hyper IgE syndrome (HIES) Javad Ghaffari1 Hamid Ahanchian2* Fariborz Zandieh3 1 Antimicrobial Nosocomial Research Center, Mazandaran University of Medical Sciences, Sari, Iran Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 3 Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran 2 ARTICLE INFO ABSTRACT Article type: Review Article Hyper IgE Syndrome (HIES) is a rare primary immunodeficiency disease. Most of HIES cases are sporadic. Autosomal dominant HIES is caused by mutation in signal transducer and activator of transcription-3 (STAT-3). A Article history: number of mosaicism HIES has been reported that is associated with Received: 22 September 2013 intermediate phenotype. Autosomal recessive HIES is due to mutation in Revised: 21 October 2013 Dock-8 or cytokine sis 8 and TYK2 or tyrosine kinase 2. The common Accepted: 20 November 2013 manifestations are atopic eczema, staphylococcal dermatitis, cellulitis and folliculitis (cold dermal abscesses that are not warm, painful and without Key words: redness), recurrent pneumonia and pulmonary abscesses, osteopenia and Hyper IgE Syndrome, recurrent bone fracture. The diagnosis of standard HIES is based on clinical Infection, Immunodeficiency suspicion. There is no specific treatment for HIES. The treatment should be based on the prevention of developing infections. Prophylactic antibiotics such as cotrimoxazole and IVIG are administered. Hematopoietic stem cell transplantation was done for all types of HIES, but there is a little information and experience about the long term results of this therapy. http://jpr.mazums.ac.ir Introduction Hyper IgE Syndrome (HIES) was first described by Deiwis, Schuller and Wedgewood in 1966.1 HIES (Job syndrome or Buckley's syndrome) is a rare immune deficiency disease due to mutations in the signal transducer and activator of transcription-3 (STAT-3) (chromosome 17, MIM=147060), Dedicator of Cytokinesis 8 (Dock-8) (chromosome 9, MIM= 243700) and Tyrosine Kinase-2 (TYk2) (chromosome 19, MIM= 611521) genes.2 The incidence of the syndrome is about 1/100000 to 1/200000.2 HIES is characterized by high concentrations of the serum IgE level. It frequently occurs inheritance autosomal dominant, but autosomal recessive is also arisen. Both genders have been *Corresponding Author: Hamid Ahanchian MD, Assistant professor of allergy and clinical immunology Mailing Address: Allergy Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Tel: +98 511 8012469 Email: , Update on Hyper IgE syndrome affected by the two types of HIES equally.3 Up to now, about 200 cases of HIES were reported.4 HIES symptoms that usually appear in early childhood are characterized by atopic eczema, recurrent infections such as skin abscess, sinusitis, otitis, pneumonia. Skeletal abnormalities in female like fractures, and delay of shearing of primary teeth are other symptoms that have also been described in HIES. Kyphosis and scoliosis are developed. The diagnosis of HIES is based on symptoms, family history of HIES and determining of mutation. Treatment of the syndrome is included prophylactic drugs (Antibiotic and antifungal), management of infections, IVIG consumption and hematopoietic cell transplantation (HCT) is the last therapeutic method.5 Etiology and Pathogenesis Most of the HIES cases are sporadic. HIES type AD is due to mutation in STAT-3. A number of mosaicism HIES have been reported that are associated with intermediate phenotype.6 Defect in STATA-3 causes decrease in T cell differentiation and leads to decrease of CD8 cells and Th-17 and IL-17. In cases of somatic mosaicism STAT-3, the Th-17 and CD8 cells are in normal range and neutrophil chemotaxis is normal.6 In AD-HIES, sometimes mutation in IL-21R occurs that lead to the decline of CD8 T-cells. So that IL21R/STAT3 pathway has an important role in CD8-T cells functions.7 CD8 cells have an important role in control of infection and anti-tumor effects. Autosomal recessive HIES (AR-HIES) is due to mutation in Dock-8 or cytokine sis-8 and TYK2.8 Mutation in Dock-8 is the most type of ARHIES. In mutation TYK-2, there is a defect on Gama-interferon /IL-12.9 In most of HIES reported cases, parents are not related.10 40 Clinical manifestations AD-HIES Usually, Autosomal Dominant Hyper IgE Syndrome (AD-HIES) developed in the early months of life by presenting papular and pustular rash, eosinophilic dermatitis or eczema. The common manifestations are atopic eczema, staphylococcal dermatitis, cellulitis and folliculitis (cold dermal abscesses that are not warm, painful and without redness), recurrent pneumonia and pulmonary abscesses, osteopenia and recurrent bone fracture.1,11 The characteristics of patients with AD-HIES are included inflammation, infection, involvement of connective tissue and electrolyte imbalance. Mucocutaneous infections are developed due to bacterial and fungal agents. These pathogens include; Staphylococcus aureus, Streptococcus A and B, Haemophilus influenza and other Gram-negative microorganisms. Candida albicans is the most severe fungal infection. Chronic mucocutaneous candidiasis (CMC) is another fungal infection.1,8 Dermal abscesses were reported as furuncle and folliculitis.8 As a whole, viral infection is common infectious agent.11 Cutaneous manifestations of AD-HIES in somatic mosaicism STAT3 type with intermediate phenotype are manifested by infections such as mucocutaneous candidiasis.7 Dermatitis is seen in 81-100% of total HIES patients. Of course, the manifestation of dermatitis in AR-HIES with mutation in Duck 8 is more severe than AD-HIES.12 Eczematous rash occurs in 65-80% of neonates with STAT3 mutation.12 Pulmonary manifestations Bronchiectasis and pneumatocoeles usually occur due to recurrent pulmonary infections.13 The main causes of pneumonia include: Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenza.13,14 Pseudomonas Auroginosa and Aspergillus J Pediatr Rev.2014;2(1) Ghaffari J. et al fumigatus are also considered as the other causative agents. Pulmonary involvement is one of the main causes of mortality and morbidity and poor quality of life. Bronchiectasis and pneumatocoeles occur in 70% of the patients following pulmonary infection.14, 15 These patients are prone to pulmonary hemorrhage. Antiseptic mycobacterial infection is reported.16 Recurrent pneumonia (with purulent sputum but non-febrile) occurs in the early years of life.11 Renal infection such as pyelonephritis was reported due to Aspergillus fumigatus in patients with AD-HIES.17 Musculoskeletal manifestations Musculoskeletal abnormalities composed of hyper extensibility of joints, forehead protrusion, arthritis, macrocephaly, broad nasal bridge and delay shearing of primary teeth.18 k (...truncated)