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A twenty-three-year-old man with a chronic anterior chest wall wound, eosinophilia, and elevated IgE--Job's syndrome.

"So went Satan forth from the presence of the Lord, and smote Job with sore boils from the sole of his foot unto his crown" The Book of Job, chapter 2, verse 7. The Bible, King James Version, 1611

CASE REPORT

A 23-year-old man presented with a chronic anterior chest wall wound. Previously he had a split thickness skin graft in the area in where the wound bed had become infected, developing a thick purulent drainage. The infected skin graft was excised. Histologic examination of the failed graft revealed skin with surface ulceration, focal abscess formation, deep penetrating acute and chronic inflammation with numerous eosinophils, and granulomatous changes demonstrating a foreign body-type reaction to fungal hyphae (highlighted by periodic acid-Schiff staining, Figures 1A-E). The patient's past medical history included scoliosis, acute lower back pain, right shoulder degenerative joint disease, atopic dermatitis, lymphadenitis, rhonchi, insomnia, depression, and a long history of recurrent infections, particularly cutaneous staphylococcal and candida albicans infections, often accompanied by a purulent drainage. Review of the patient's laboratory studies revealed chronically elevated alkaline phosphatase, with highly elevated serum IgE (2,922 IU/ml) and eosinophilia (925/[micro]L3) since childhood. Other lab studies were unremarkable, except for episodic elevations of the white blood cell count. The patient's family history was largely unremarkable and the patient's parents and siblings had no histories of unusual infections.

DISCUSSION

A diagnosis of Job's Syndrome (JS) or hyper-IgE syndrome was rendered. JS is one of several primary rare immunodeficiencies characterized by elevated IgE and includes Omenn, Wiskott-Aldrich, and Netherton-Comel syndromes. (1,2) Although most cases of JS are sporadic, both autosomal-dominant and autosomal-recessive inheritance patterns occur. (1-4) The autosomal-dominant form is caused by dominant hypomorphic signal transducer and activator of transcription 3 (STAT3) mutations, often involving the DNA-binding and SRC homology 2 protein domains, while the recessive form is caused by null mutations of the dedicator of cytokinesis-8 (DOCK8) and tyrosine kinase-2 (Tyk2) genes. (3,5-11) Autosomal-dominant JS shows characteristic immunologic features including recurrent cutaneous and pulmonary staphylococcal infections often with abscess and pneumatocele formation, candidiasis and other fungal infections, eczema, and elevated IgE (>2,000 IU/ml) with eosinophilia. Additionally, nonimmunologic symptoms are seen, including characteristic facial features, scoliosis, recurrent bone fractures following minor trauma, retained primary dentition, joint hyperflexibility, and craniosynostosis (Table 1). (1,2,12) Autosomal-recessive JS has fewer extra-immune manifestations and presents with recurrent staphylococcal skin infections, viral infections, central nervous system abnormalities, vasculitis, lower pneumatocele incidence, and a higher mortality rate. (Table 1). (1,2,4)

The molecular pathogenesis of JS is poorly understood. Identified JS hypomorphic STAT3 mutations lower IFN-[gamma], TNF-[alpha], IL-6, IL17, MMP-3, and IL-22 secretion, inhibit Th17 T-cells differentiation, and increase MMP-8 and MMP-9 plasma levels, contributing to increased mucocutaneous fungal and extracellular bacterial infections, elevated IgE, and possibly contributing to JS abnormalities in bone formation and tissue remodeling. (13-17) DOCK8 loss results in defective dendritic cell migration and CD4+ T-cell priming, elevated IgE levels, and impaired B-cell responses with inhibited CD27+ memory B-cell formation. (17-19) Tyk2 gene mutation causes defects in IFN-[gamma], IL-6, IL-10, IL-12, and IL-23 signaling possibly accounting for the autosomal-recessive JS symptoms seen in some individuals with this gene mutation. (10,11)

The diagnosis of JS is based on clinical findings combined with a scoring system based on genetic linkage analysis. (20,21) Some of the clinical findings of JS employed in diagnosis are summarized in Table 1. Molecular genetic testing can be used in JS diagnosis, although currently such testing is not available at most medical centers. (1,2) JS is currently treated by antibiotic/antifungal therapy for recurrent bacterial and fungal infections (with careful susceptibility testing), careful skin care (bleach baths, hydrating measures for eczema, and topical antibiotics), antibiotic prophylaxis, and careful management of pulmonary infections and empyema. (1,2,4,20,22) One study suggests that intravenous IgG may help with some of the cutaneous manifestations of JS and also lower IgE levels. (23)

The case presented here reveals an eosinophil-rich, deeply penetrating inflammation, with ulceration, and granulomatous changes demonstrating a foreign body-type reaction to fungal hyphae, not further classified due to lack of fungal cultures. Such infections are common in JS and are further discussed in the references. (1-4,20,22,24) These histologic findings, combined with the patient's history and laboratory results are typical of JS.

Acknowledgments: We would like to thank Lisa LaChance, BA, for assistance in assembling and proof reading this manuscript.

R. Shackelford, DO; J. Abdulsattar, MD; J. Aufman, MD; E. Madrid, BS; J. Cotelingam, MD; K. Hookim, MD

REFERENCES

(1.) Grimbacher B, Holland SM, Puck JM. Hyper-IgE syndromes. Immunol Rev 2005;203:244-250.

(2.) Grimbacher B, Belohradsky BH, Holland SM. Immunoglobulin E in primary immunodeficiency diseases. Allergy 2002;57:995-1007.

(3.) Holland SM, DeLeo FR, Elloumi HZ, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 2007;357:1608-1619.

(4.) Renner ED, Puck JM, Holland SM, et al. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr 2004;144:93-99.

(5.) Engelhardt KR, McGhee S, Winkler S, et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper- IgE syndrome. J Allergy Clin Immunol 2009;124:1289-1302.

(6.) Sanal O, Jing H, Ozgur T, Ayvaz D, et al. Additional diverse findings expand the clinical presentation of DOCK8 deficiency. J Clin Immunol 2012;32:698-708.

(7.) Zhang Q, Davis JC, Lamborn IT, Freeman AF, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 2009;361:2046-2055.

(8.) Su HC. Dedicator of cytokinesis 8 (DOCK8) deficiency. Curr Opin Allergy Clin Immunol 2010;10:515-520.

(9.) Day-Williams AG, Sun C, Jelcic I, et al. Whole genome sequencing reveals a chromosome 9p deletion causing DOCK8 deficiency in an adult diagnosed with hyper IgE syndrome who developed progressive multifocal leukoencephalopathy J Clim Immunol, 2014 in press.

(10.) Minegishi Y, Saito M, Morio T, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 2006;25:745-755.

(11.) Minegishi Y, Karasuyama H. Hyperimmunoglobulin E syndrome and tyrosine kinase 2 deficiency. Curr Opin Allergy Clin Immunol 2007;7:506-509.

(12.) Borges WG, Hensley T, Carey JC, et al. The face of Job. J Pediatr 1998;133:303-305.

(13.) Del Prete G, Tiri A, Maggi E, et al. Defective in vitro production of gamma-interferon and tumor necrosis factor-alpha by circulating T cells from patients with the hyper-immunoglobulin E syndrome. J Clin Invest 1989;84:1830-1835.

(14.) Huang W, Na L, Fidel PL, et al. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 2004;190:624-631.

(15.) Aujla SJ, Chan YR, Zheng M, et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 2008;14:275-281.

(16.) Sekhsaria V, Dodd LE, Hsu AP, et al. Plasma metalloproteinase levels are dysregulated in signal transducer and activator of transcription 3 mutated hyper-IgE syndrome. J Allergy Clin Immunol 2011;128:1124-1127.

(17.) Yong PF, Freeman AF, Engelhardt KR, et al. An update on the hyper-IgE syndromes. Arthritis Res Ther 201;14:228.

(18.) Harada Y, Tanaka Y, Terasawa M, et al. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. Blood 2012;119:4451-4461.

(19.) Jabara HH, McDonald DR, Janssen E, et al. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nat Immunol 2012;13:612-620.

(20.) Grimbacher B, Schaffer AA, Holland SM, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet 1999;65:735-744. Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. N Engl J Med 1999;340:692-702.

(21.) O'Connell AC, Puck JM, Grimbacher B, et al. Delayed eruption of permanent teeth in hyperimmunoglobulinemia E recurrent infection syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:177-185.

(22.) Cruz-Portelles A, Estopinan-Zuniga D. A new case of Job's syndrome at the clinic: a diagnostic challenge. Rev Port Pneumol 2014;20:107-110.

(23.) Kimata H. High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome. J Allergy Clin Immunol 1995;95:771-774.

(24.) Dermatologic manifestations of Job syndrome. Accessed at: http:// emedicine.medscape.com/article/1050852-overview

Drs. Shackelford, Abdulsattar, Cotelingam, Aufman and Hookim are all associated with the Department of Pathology, LSU Health Shreveport, LA. Ms. Madrid is a medical student at the LSU Medical School Shreveport, LA.

Table 1. The more common clinical findings used in the diagnosis of
JS.

Clinical Finding                      Comment               References

Elevated IgE                 Usually >2,000 IU/ml or 2        1,2,20
                           standard deviations above the
                                    normal range

Characteristic facial       Prominent forehead, deep-set      12,20
features                     eyes, increase nose width,
                           nose and ear thickening, full
                                     lower lip

Eosinophilia                  Seen in 93% of patients        1,2,4,20

Recurrent infections,         Cutaneous and pulmonary        1,2,4,20
with abscess formation      candidiasis, Staphylococcus
common                          aureus, Haemophilus
                            influenzae, and pneumatocele
                                superinfection with
                            Pseudomonas aeruginosa, and
                             Aspergillus fumigatus, and
                                  other organisms

Scoliosis                    Seen in 67% of patients 16       1,2,20
                                  years and older

Retained primary             72-75% show problems with        20,21
dentition                   permanent tooth eruption due
                               to slow primary tooth
                           exfoliation secondary to poor
                                  root absorption

Recurrent bone fractures     57% of JS individuals show       1,2,20
                               three of more factures
                               following minor trauma

Hyperextensible joints       Seen 68% of JS individuals         20

Pneumatoceles               77% of JS individuals, very      1,2,4,20
                            rare in autosomal recessive
                                         JS

Central nervous system        Seen mainly in autosomal        1,2,4
abnormalities                       recessive JS

Hyperextensible joints     Seen in 68% of JS individuals     1,2,4,20

Low Memory B-cell and       Seen in most JS individuals       13-19
Th17 T-cell levels

Eczema                     Moderate-to-severe eczematoid      1,2,20
                           rashes are universal in early
                              life and often the first
                                manifestation of JS

Vasculitis                  Found in autosomal-recessive     1,2,4,20
                                         JS

Viral infections            Complications from molluscum       4.20
                               contagiosum and herpes
                               viruses are common in
                               autosomal-recessive JS
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Article Details
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Author:Shackelford, R.; Abdulsattar, J.; Aufman, J.; Madrid, E.; Cotelingam, J.; Hookim, K.
Publication:The Journal of the Louisiana State Medical Society
Article Type:Clinical report
Date:Jul 1, 2015
Words:1663
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