Disease Markers 29 (2010) 123–130 123 DOI 10.3233/DMA-2010-0734 IOS Press Clinical manifestations of hyper IgE syndromes Alexandra F. Freeman∗ and Steven M. Holland Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA Abstract. Over the last 4 years, three genetic etiologies of hyper IgE syndromes have been identified: STAT3, DOCK8, and Tyk2. All of these hyper IgE syndromes are characterized by eczema, sinopulmonary infections, and greatly elevated serum IgE. However, each has distinct clinical manifestations. Mutations in STAT3 cause autosomal dominant HIES (Job’s syndrome), which is unique in its diversity of connective tissue, skeletal, and vascular abnormalities. DOCK8 deficiency is characterized by severe cutaneous viral infections such as warts, and a predisposition to malignancies at a young age. Only one individual has been identified with a hyper IgE phenotype associated with Tyk2 deficiency, which is characterized by nontuberculous mycobacterial infection. The identification of these genetic etiologies is leading to advances in understanding the pathogenesis of these syndromes with the goal of improving treatment. 1. Introduction syndrome). AD-HIES is a multi-system disorder with abnormalities of the immune system, skeleton, con- Until 2006, the Hyper IgE syndromes remained the nective tissues, and vasculature [6–8]. The diagnosis last of the major primary immunodeficiencies for which is suggested when both immunologic and connective no genetic etiologies were known. Then, in 2006, a ho- tissue/skeletal features are present. The pathogenesis mozygousdeletion in Tyk2 was identified in a boy with of the majority of these varied features remains poorly elevated IgE, eczema, and infections from Japan [1]. understood. This was followed in 2007 with the finding of dom- inant negative mutations in STAT3 as the etiology of autosomal dominant Hyper IgE (Job’s) syndrome [2, 2.1. Immunologic/infectious disease manifestations 3]. Subsequently,in 2009, homozygousand compound heterozygous mutations in DOCK8 were identified in In the great majority of cases, AD-HIES presents in a subset of individuals diagnosed with autosomal re- the newborn period with a rash, which may even be cessive Hyper IgE syndrome [4,5]. Each of these ge- present at birth [9,10]. This rash is typically pustu- netic etiologies leads to distinct clinical features, and lar, and on biopsy may be consistent with eosinophilic greater familiarity with these clinical presentations can pustulosis. This rash may resolve or persist, evolv- direct immunologic and genetic studies, and assist with ing into an eczematoid dermatitis that is typically driv- treatment and family counseling. en by Staphylococcus aureus infection. Control of S. aureus skin colonization typically leads to great im- 2. Autosomal dominant (AD) HIES provement in the rash. S. aureus skin abscesses oc- cur, and may be “cold”, lacking the usual warmth, Mutations in STAT3 have been found to be the cause redness, and pain; however, frank pus, often with in- of the majority, if not all, cases of AD-HIES (Job’s creased number of eosinophils, is found on aspiration. S.aureus skin colonization control with either antisep- tics (i.e. bleach baths) or maintenance antibiotics (such ∗Corresponding author: Alexandra Freeman, MD, NIH Building 10, Room 11N234 Bethesda, MD 20892, USA. Tel.: +1 301 594 as trimethoprim-sulfamethoxasole), makes these ab- 9045; Fax: +1 301 496 0773; E-mail: [email protected]. scesses very infrequent. ISSN 0278-0240/10/$27.50 2010 – IOS Press and the authors. All rights reserved 124 A.F. Freeman and S.M. Holland / Clinical manifestations of hyper IgE syndromes Fig. 1. Chest CT of a 48 year old with AD-HIES showing bronchiec- tasis, and a pneumatocoele with an Aspergilloma (arrow). Fig. 2. Patient with AD-HIES and chronic fungal infection of the nail (arrow). Recurrent bacterial sinus, ear, and lung infections infection localized in the gastrointestinal tract [16–19]. are classic findings in AD-HIES. S. aureus is the most Also, Coccidioides meningitis has been reported [20]. frequent etiology of the pneumonias, with Streptococ- Mucocutaneous candidiasis occurs frequently and may cus pneumoniae and Haemophilus species occurring require chronic suppressive antifungals (Fig. 2). frequently as well [7]. Purulence is found in the air- In general, viral infections are not especially severe, ways, but similar to the boils, systemic signs of in- chronicorrecurrentinAD-HIES,incontrastto DOCK8 fection may be minimal, which may lead to late di- deficiency (Table 1). Individuals with AD-HIES do agnosis of significant infections. Although these in- not have an increased incidence of warts or Molluscum fections can usually be treated adequately with antimi- contagiosum. However,there does appear to be a high- crobials directed against the infection organism, the er incidence of zoster, which tends to be limited to one healing of the lung is abnormal, and resultant pneuma- or contiguous dermatomes (unpublished data). tocoeles and bronchiectasis may occur (Fig. 1). The Asthma and allergies are uncommon in AD-HIES, parenchymal abnormalities of the lung are a source and anaphylaxisto foods is rare [21]. With the marked- of significant morbidity and mortality for these in- ly elevatedserum IgE,theremaybe IgEto specificanti- dividuals as more difficult-to-treat microbes, includ- gens present; however, the clinical significance needs ing molds (Aspergillus, Scedosporium species), Gram- to be interpreted carefully. Some patients do have ob- negative bacteria (typically Pseudomonas aeruginosa), structive lung disease that responds to beta agonist ther- and nontuberculous mycobacteria cause chronic infec- apy; however, this is much less common than in oth- tions (Fig. 1) [11–13]. Life threateninghemoptysisand er diseases with high IgE such as atopy and DOCK8 disseminated infections may result from these chronic deficiency. infections. Appropriate management of the pneuma- tocoeles is not well defined. Surgical resection should 2.2. Non-immunologic manifestations be undertaken with caution, as there appears to be a fairly high frequency of complications with prolonged AD-HIES can be differentiated from other etiolo- and often complicated bronchopleural fistulae leading gies of Hyper IgE by its distinctive connective tissue, to contaminated pleural space infections. skeletal, and dental abnormalities (Table 1). By late As opposed to certain other primary immunod- childhood or adolescence, a typical facial appearance eficiencies associated with fungal pneumonias (e.g. emerges characterized by asymmetry, deepset eyes, chronic granulomatous disease), fungi only seem to prominent forehead and chin, and a bulbous nose [6, cause infection in lungs in AD-HIES after parenchymal 7,22]. The palate is high, and there are often promi- damagehasoccurred[13]. However,otheropportunists nent ridges of the oral mucosa on the palate and central may cause infection. Pneumocystis jirovecii pneumo- depressions of the tongue [23]. These facial structural nia (PCP) may occur, typically during infancy, prior changes may result in the higher frequency of sinus to pyogenic pneumonias [14,15]. In addition, dissem- and ear infections that are typically encountered. Pri- inated dimorphic fungal infections occur occasionally, mary teeth usually fail to exfoliate, which may impair including Histoplasma and Cryptococcus, often with secondary dentition emergence [24]. A.F. Freeman and S.M. Holland / Clinical manifestations of hyper IgE syndromes 125 Table 1 Clinical features of hyper IgE syndromes STAT3 mutation HIES DOCK8 deficiency Newborn rash +++ + Eczema ++++ ++++ Skin abscesses +++ ++ Pneumonias ++++ +++ Lung parenchyma changes (bronchiectasis, cysts) +++ + Food Allergies + +++ Asthma + +++ Mucocutaneous viral infections + ++++ Mucocutaneous candidiasis +++ ++ Retained primary teeth ++++ + Minimal trauma fractures +++ + Scoliosis +++ Characteristic facial appearance +++ + Malignancy + +++ Skeletal abnormalities include osteoporosis, mini- mal trauma fractures, scoliosis, degenerative spine dis- ease, and craniosynostosis [6,7,25–27]. Although os- teoporosis is common, it is not predictive of who will have fractures,and minimal trauma fractures may occur without osteoporosis. Scoliosis curvature may progress to significant degreesrequiring therapeuticintervention including rod placement. Fractures and scoliosis that have required surgical correction have typically healed without incident. Significant spinal disease, most fre- quently observed in the cervical spine, often arises in the 4th and 5th decades of life, resulting in pain, neu- ropathy, and weakness (Fig. 3). Surgical stabilization hasbeen successfulin severalpatients. Varying degrees of craniosynostosis are common, but do not usually require surgical correction [25–27]. Hyperextensibility of joints is common, and as pa- tients age, joint pain may become more pronounced. Fig. 3. Cervical spine disease in a 55 year old with AD-HIES showing Physical therapy can help ameliorate these symptoms. angular kyphosis and retrolisthesis. Vascular abnormalities include arterial tortuosity, di- lation and aneurysm [28–31]. These findings have majority of Chiari malformations. Lacunar infarcts been reported predominantly in the coronary and cere- have occurred at relatively young ages in a few pa- bral arteries, the clinical significance of which remains tients. Whether the focal hyperintensities and lacunar unknown. With significant aneurysm, anticoagulation infarcts are related to vascular