The Hyperimmunoglobulinemia E Syndromes: A Literature Review

This article has been published in whole in Maced J Med Sci. 2013 Dec 15; 6(4):455-464. Open Access Macedonian Journal of Medical Sciences. 2013 Dec 15; 1(1):117-126. http://dx.doi.org/10.3889/oamjms.2013.024 Review Paper The Hyperimmunoglobulinemia E Syndromes: A Literature Review Slavica Hristomanova*, Mirko Spiroski Institute of Immunobiology and Human Genetics, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Republic of Macedonia Abstract Citation: Hristomanova S, Spiroski M. The Hyperimmunoglobulinemia E Syndromes: A Literature Review. OA Maced J Med Sci. 2013 Dec 15; 1(1):117-126. http://dx.doi.org/10.3889/oamjms.2013.024 Key words: hyper-immunoglobulin E syndromes (HIES); dominant form (AD-HIES); recessive form (AR-HIES); STAT3; review article. * Correspondence: Slavica Hristomanova, MD, PhD candidate. Institute of Immunobiology and Human Genetics, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, 50. Divizija No 16, PO Box 60, 1109 Skopje, Republic of Macedonia. E-mail: The hyper-immunoglobulin E (IgE) syndromes (HIES) are primary immunodeficiencies characterized by the recurrent staphylococcal abscesses, recurrent pneumonia and highly elevated serum IgE levels. There are two forms of HIES: a dominant form (AD-HIES) and a recessive form (AR-HIES). AD form of HIES is caused by mutations in STAT3 and the AR form is caused by mutations in DOCK8 and TYK2. These syndromes have different clinical presentations and outcomes. AD-HIES is a multisystem disorder that includes abnormalities of the skin, lungs, musculo-skeletal system and dental system. In contrast, these symptoms in patients with AR-HIES are missing. AR-HIES patients have severe viral infections and may develop neurological complications. This review article discusses the clinical presentation and laboratory findings in both forms of HIES, as well as the establishment of diagnose, inheritance, molecular genetics and immunological abnormalities of HIES. Received: 06-Apr-2013; Revised: 10-Sep2013; Accepted: 11-Sep-2013; Online first: 20-Sep-2013 Copyright: © 2013 Hristomanova S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Competing Interests: The authors have declared that no competing interests exist. Introduction The hyper-immunoglobulin E syndromes (HIES) 147060 and 243700 (Mendelian Inheritance in Man, a catalogue of inherited diseases) refer to two related immunodeficiency disorders that can manifest in a variety of ways [1]. Initially, HIES was described in 1966 by Davis and Wedgwood, who associated staphylococcal skin infections in newborns with what they termed the “Job’s syndrome”, along with skin lesions lacking typical signs of inflammation (cold abscesses) [2, 3]. Buckley and colleagues (1972) then further characterized the condition by associating severe dermatitis, joint hyperextensibility, asymmetric facies and especially the highly elevated serum IgE levels with it, which lead them to phrase the term “Hyper IgE syndrome” [4]. In the following years, an ever-increasing effort was devoted to identify describe different HIES cases [5-8], which revealed additional characteristic clinical symptoms and motivated further research into the causative mechanisms thereof [9-17], while others suggested a genetic inheritance pattern [18]. In 2004, Renner et al. distinguished between the autosomal recessive (AR) and autosomal dominant (AD) HIES forms, based on their clinical appearance [19]. Minegishi and colleagues [20] described the potential cause for the AR-HIES form, a homozygous deletion within the TYK2 gene, in 2006. In continued investigations, Minegishi and colleagues identified the mechanism underlying AD-HIES by revealing heterozygous STAT3 mutations in patients with ADHIES [21]. In 2007, Holland et al. found missense mutations and in-frame single-codon deletions within STAT3 in AD-HIES patients and their families, thereby further underscoring the importance of STAT3. They concluded that STAT3 mutations are present in sporadic and dominant forms of the hyper-IgE syndrome [22]. _______________________________________________________________________________________________________________________________ OA Maced J Med Sci. 2013 Dec 15; 1(1):117-126. 117 Review Article _______________________________________________________________________________________________________________________________ While several studies had identified mutations responsible for the AD form of HIES, apart from one possible exception, no mutations had been linked to the AR-HIES form until 2009. Then, in 2009, Zhang et al. reported on a group of AR-HIES patients exhibiting homozygosity or compound heterozygosity for DOCK8 gene deletions or mutations [23]. Alsum et al. identified novel DOCK8 mutations in continued investigations of AR-HIES patients [24]. The consensus involves the acknowledgment of two HIES forms: a dominant and a recessive form caused by mutations in either STAT3 or DOCK8 and TYK2, respectively. These two different syndromes have distinct presentations and outcomes with only elevated IgE serum levels in common. In this review we will address the differences between the two HIES forms in terms of clinical features, laboratory abnormalities, diagnosis, inheritance, molecular genetics and immunological abnormalities. Clinical characteristics of HIES HIES is a multisystem disorder affecting the skin, lungs, musculoskeletal system, the face, central nervous system, dentition and the vascular system. All of the clinical findings in HIES vary with age and among individuals, with further differences arising due to the different mutations characteristic of either the autosomal dominant HIES (AD-HIES) or the autosomal recessive HIES (AR-HIES) form. AD-HIES (STAT3 mutations) Skin. A newborn rash is usually the first manifestation of AD-HIES. The rash is pustular and eczematoid and usually begins within the first month of life. It typically affects the scalp and the face first [25, 26]. In a group of 43 patients, 19% (8 babies) were born with the rash, while in 53% (23 babies) the rash appeared within the first week of life [27]. The biopsies reveal eosinophilic infiltrates and bacterial cultures. Staphylococcus aureus is the most common bacteria. The rash often persists throughout childhood, but it can be well controlled with appropriate therapy. Furuncles are characteristic for the diagnosis and are classical findings typical of the disease. The severity of inflammatory symptoms is often quite variable. The “cold” abscesses are also common and even with the absence of the external inflammation signs there is apparent pus and again Staphylococcus aureus is the most common bacteria. Lung. Recurrent pyogenic pneumonias are typical. They usually start in early childhood. The most (...truncated)