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ORIGINAL ARTICLE
Year : 2018  |  Volume : 19  |  Issue : 1  |  Page : 31-36

Unusual presentations and associations of hyper IgE Syndrome: Retrospective analysis of ten cases at tertiary care institute – With review of indian published reports


1 Gujarat Cancer Society Medical College, Hospital and Research Centre, Ahmedabad, Gujarat, India
2 Department of Dermatology, Vernerology, Leprology, Gujarat Cancer Society Medical College, Hospital and Research Centre, Ahmedabad, Gujarat, India

Date of Web Publication28-Dec-2017

Correspondence Address:
Jigna K Padhiyar
Room No: 35, Department of Dermatology, Vernerology, Leprology, Gujarat Cancer Society Medical College, Hospital and Research Centre, Opp. D.R.M. Office, Near Chamunda Bridge, Naroda Road, Ahmedabad - 380 025, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_144_16

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  Abstract 

Background: Job syndrome also known as hyper IgE syndrome (HIES) is primary immunodeficiency syndrome. Autosomal dominant variant caused by mutation in signal transducer and activator of transcription-3 gene is characterized by recurrent staphylococcal skin infections, sinopulmonary infections, eczema, recurrent bone fractures, and coarse facial features. Autosomal recessive (AR) variant is because of mutation in DOCK8 gene which lacks the skeletal and dental involvement but manifest with severe viral infection and develop neurological complications. Aims: This study aims to evaluate variable presentations and associations of job syndrome. Methods: Analysis of ten cases, presented at our department between October 2015 and September 2016, with suspected HIES was done retrospectively. All cases were studied for their presentations and associations and were investigated accordingly for the same. Score for HIES was counted as per National Institutes of Health (NIH) scoring system. Indian published reports were found by internet search engine and were reviewed for unusual presentations. Results: NIH scoring was indeterminate in two patients and was highly likely for autosomal dominant-HIES in five patients. Three patients were diagnosed as AR-HIES. Two of our patients had multiple endocrinopathy, one had pyoderma gangrenosum and two patients had autoimmune disorders. Limitations: Genetic analysis was not done because of nonavailability of testing in our state and poor financial conditions of patients. It is a retrospective study. Conclusion: Our patients had unusual association in the form of multiple endocrinopathy, pyoderma gangrenosum, dermatomyositis, and all were diagnosed very much late in life. Hence, a vigilant eye for suspicion at a younger age might benefit patients.

Keywords: Autoimmune disorders, hyper IgE syndrome, molluscum contagiosum, multiple endocrinopathy, pyoderma gangrenosum


How to cite this article:
Patel NH, Padhiyar JK, Shah YB, Gajjar TP, Buch MD. Unusual presentations and associations of hyper IgE Syndrome: Retrospective analysis of ten cases at tertiary care institute – With review of indian published reports. Indian J Paediatr Dermatol 2018;19:31-6

How to cite this URL:
Patel NH, Padhiyar JK, Shah YB, Gajjar TP, Buch MD. Unusual presentations and associations of hyper IgE Syndrome: Retrospective analysis of ten cases at tertiary care institute – With review of indian published reports. Indian J Paediatr Dermatol [serial online] 2018 [cited 2019 Sep 19];19:31-6. Available from: http://www.ijpd.in/text.asp?2018/19/1/31/206073


  Introduction Top


Autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES) was first described in 1966 as Job syndrome [1] and included the triad of eosinophilia, eczema, and recurrent skin and pulmonary infections (named after the biblical character Job, who was “smote with sore boils”). Elevated IgE level was considered as a cardinal feature of same and the name HIES was subsequently proposed.[2] The phenotype was later expanded to include many abnormalities of connective tissue and bones. Later, autosomal dominant mutations in signal transducer and activator of transcription-3 (STAT3) gene were identified as the molecular cause of this disease.[3],[4],[5] Some patients with autosomal recessive hyperimmunoglobulin E syndrome (AR-HIES) have mutations in DOCK8[6] which has important role in T- and B-cell development and functions and its deficiency is now known to cause a combined immunodeficiency rendering the affected patients susceptible to viral, fungal, and bacterial infections.[7] AR-HIES with DOCK8 deficiency is particularly common in areas of the world with high consanguinity rates, where its occurrence sometimes may exceed that of AD-HIES. AR-HIES is distinguished by recurrent sinopulmonary infection, severe cutaneous viral infection often caused by herpes simplex virus, human papillomavirus, herpes zoster virus, and molluscum contagiosum virus in addition to elevated IgE and lack features involving the skeletal system. These patients are also known to be at high risk of malignancies including squamous cell carcinoma, cutaneous T-cell lymphoma/leukemia, and Burkitt lymphoma in late childhood and early adulthood.[8] Although the average age of diagnosis was 11.5 years, diagnosis can be made in infancy or adulthood. Being multisystem diseases elevated IgE levels alone can not be used a screening test for diagnosis, furthermore, overlap of clinical presentation with other childhood dermatosis such as atopic dermatitis and other type of primary immune deficiency in childhood diagnosis most of the time remain difficult to stamp. A scoring system was devised by researchers at the National Institutes of Health (NIH) to aid in the diagnosis of AD-HIES.[9] Age-adapted modification of NIH criteria too have been proposed.[10] Genetic tests revealing an STAT3 mutation confirms the diagnosis, but the absence of such mutation does not rule out the diagnosis of AD-HIES, and NIH scoring sensitively identifies patients with HIES.[11]

This analysis was done to evaluate the various clinical presentations and unusual associations of HIES. There are no prefixed criteria or studies for diagnosis of AR-HIES; high degree of suspicion is required for diagnosing same as neurological abnormalities are associated with it. HIES is considered as rare disorder, and its phenotype is still expanding with various studies and reports. Screening of patients for various abnormalities and associated disorders early in their life might help them to lead a productive life and expand their lifespan with various suggested preventions and therapy. Clearance from institutional Ethical committee was obtained.


  Methods Top


Analysis of ten cases, presented at our department between October 2015 to September 2016, with suspected HIES was done retrospectively. All cases were studied for their presentations and associations and were investigated accordingly for the same. The diagnosis of HIES was made using NIH scoring system in patients whom AD-HIES was suspected. Seven patients who had NIH scoring more than 20 falling in “indeterminate or highly likely” category were included for the analysis in the study. Three patients with elevated IgE levels with cutaneous and systemic features and history suggestive of HIES were presumptively diagnosed as AR-HIES, as the severe viral infection is feature of AR variant of disease in literature in reported cases, were included in the study. Indian published reports were found by internet search engine and were reviewed for unusual presentations. In all patients, informed written consents were obtained.


  Results Top


A total of 10 patients, 9 male and 1 female were included in the study with age ranging from 7 to 35 years. Age and sex distribution is compiled in [Table 1]. The average age of diagnosis in our study was 18.5 years. Two boys were first degree siblings, while rest of the patients did not have any significant family history. A history of consanguinity of parents was present in 4 patients out of which 2 patients had AR-HIES, and 2 patients had AD-HIES. Out of total 10, three male patients had AR-HIES and rest 7 (6 males, 1 female) had AD-HIES.
Table 1: Age, sex distribution

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Clinical features and laboratory investigations for AD-HIES and AR-HIES patients are summarized in [Table 2] and [Table 3], respectively.
Table 2: Clinical features, history and laboratory investigations in autosomal dominant hyper-immunoglobulin E syndrome patients

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Table 3: Clinical features, history and laboratory investigations in autosomal recessive hyper immunoglobulin E syndrome patients

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NIH scoring in 7 patients (patients 1–7) with suspected AD-HIES was indeterminate in two and highly likely in five patients. Age-adapted score also remained same.

Three male patients (patients 8–10) were suspected to have AR-HIES according to clinical and laboratory investigations. One patient had extensive molluscum contagiosum, one patient had disseminated herpes zoster, and one patient had suspected fulminant hepatitis or some autoimmune disorder that died due to systemic complications.

A 10-year-old male patient (patient 1) had multiple ulcers with punched out margins with pink granulation tissue on bilateral extensor aspect of foot, repeated culture from same was positive for pseudomonas aeruginosa; however, biopsy was confirmatory of pyoderma gangrenosum [Figure 1].
Figure 1: Patient 1 (a) high arched palate, (b and c) multiple ulcers with punched out ulcer over dorsal surface of feet, (d) epidermal ulceration with neutrophilic infiltration in upper dermis and perivascular area with karyorrhexis

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Two of our patients were found to have multiple endocrinopathy. A 17-year-old male patient (patient 3) also had short stature and low body weight for age and on further investigations, there was showed low Hb (9.9), reversed albumin/globulin ratio (0.59), low free testosterone (1.69 pg/ml), and low growth hormone (0.923 ng/ml). ECG showed right axis deviation. The same patient also had a history of pulmonary tuberculosis for which patient was treated in the past. Another 19-year-old male patient (patient 8) who had extensive molluscum contagiosum [Figure 2] and [Figure 3] had short stature (137 cm) and low body weight (34 kg) for his age and absence of secondary sexual characteristics. The same patient also had low testosterone (0.117 pg/ml), low follicle-stimulating hormone (0.18 mIU/ml), low lueienizing hormone (0.09 mIU/ml), increased human growth hormone (8.78 ng/ml), raised alkaline phosphates (159), calcium oxalate crystals in urine and intact epiphyseal growth plate of long bones.
Figure 2: Patient 8 (a) extensive molluscum with scars of healed pyoderma, (b) biopsy showing Henderson Patterson bodies

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Figure 3: Patient 8 (a) femur, (b) radius and ulna showing intact epiphyseal plats

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A 13-year-old male patient (patient 9) was a known case of juvenile dermatomyositis and patient was taking treatment for the same for last 4 years. The patient presented to us with multidermatomal herpes zoster involving right side L2 and L3 dermatome with few aberrant vesicular lesions over chest, generalized xerosis, and diffuse generalized hyperpigmentation which was marked over face sparing nose [Figure 4]. The patient also had cushingoid face which may be due to previous treatment with oral steroids. Patient's IgE was raised in multiple reports, and it was >2000 every time.
Figure 4: Patient 9 (a) cushingoid face with broad nasal bridge, diffuse hyperpigmentation, (b) xerosis with scar over hand, (c) multidermatomal zoster involving right L2 and L3 dermatome

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Patient number 10, a 35-year-old male patient, presented with multiple pyoderma in scalp, multiple scars of healed pyoderma occurred in the past, mild eczematization in flexures with oral ulcers and pedal edema. On further neurological examination, the patient had muscle weakness more in proximal muscles than distal muscle groups. The patient was advised biopsy for the same. On further investigations, patient had altered liver function test (LFT), antinuclear antibody (ANA) positive, raised IgE, raised total creatine phosphokinase (CPK), and normal ultrasonography of abdomen as mentioned in [Table 3]. Patient developed difficulty in deglutition and was transferred to Intensive Care Unit. Patient died of aspiration pneumonia before further investigation can be performed. Hence, patient's altered LFT and raised CPK was due to some autoimmune process or because of some infective condition or combination of both, could not be confirmed by further investigations.


  Discussion Top


In study group two cases, one of AD-HIES where NIH scoring was highly likely and one case of AR-HIES, are unique, perhaps the first to be reported with the absence of secondary sexual characteristics and delayed skeletal maturation and other hormonal abnormality. One of our AR-HIES patients who had extensive molluscum contagiosum had delayed skeletal maturation where X-ray long bones showed intact epiphyseal plats. Skeletal involvement is seen AD-HIES, and it's not considered a feature of AR-HIES. NIH criteria for Job syndrome are defined for AD-HIES so AR variant can be missed if detail clinical and investigational correlation is not made.

Extensive search of Indian published reports for unusual presentations and associations was done by using internet search engine. One case has been reported to have natal teeth, bilateral cervical ribs and conductive deafness and they also mentioned child was stunted and obese.[12] Another case reported by Sinha et al.[13] had her height and weight falling in the third percentile.

One case of AD-HIES where NIH scoring was highly likely had associated pyoderma gangrenosum. To the best of our knowledge, this type of associations is not reported till date.

One of our patients was a known case of juvenile dermatomyositis, and another one patient had proximal muscle weakness with raised CPK level, and ANA positivity was suggestive of some autoimmune disorders. Grimbacher et al., Brugnoni et al. and Tanji et al. have pointed out probable association of HIES with other autoimmune diseases such as lupus erythematosus, dermatomyositis, and nephrotic syndromes.[14],[15],[16] Due to impaired interleukin (IL)-6 and IL-23 signaling through STAT3, the crucial T-cell transcription factor retinoid-related orphan receptor gamma t is diminished, impairing IL-17 expression, and Th17 differentiation.[17] Recently, many of inflammatory and autoimmune disorders have been claimed to have a defect in IL-17 expression; this might be the reason for the association of autoimmune disorders with HIES.

Mycobacterial infections can also be seen in the spectrum of HIES-related infection [18] as one of our patient had pulmonary tuberculosis.

Characteristic face in HIES is described as thickened doughy skin, large follicular ostia, pitted scaring, a broad nasal bridge, a wide fleshy nasal tip, deep set eyes, a prominent forehead, and irregularly proportioned cheeks and jaw.[19] This is due to both bony defects and deforming effect of chronic facial abscesses. This was present in 4 of our AD-HIES patients; in others, because of younger age at presentation it may be absent. [Figure 5] shows one of our patients with characteristic face with multiple folliculitis and abscesses repeated culture from the same showed positivity for Staphylococcus aureus.
Figure 5: Patient 5 (a) characteristic face with broad nasal bridge, scaring over forehead, broad fleshy nasal tip, (b) abscess with little signs of inflammation and scars of healed previous lesions, (c) xerosis and follicuitis with little inflammation

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Elevated IgE levels, susceptibility to pyogenic infections and eczematous dermatitis have also been described in prolidase deficiency, an AR condition due to Peptidase D (PEPD) mutatios that also features chronic leg ulcers, facial dysmorphism, and mental retardation.[19] Our patient who had chronic leg ulcers over extensor aspect of bilateral feet also had recurrent sinusitis and retained primary teeth along with above-mentioned features and biopsy was confirmatory for pyoderma gangrenosum which responded to oral steroid therapy. Urine test was negative for imidodipeptiduria in the same patient. None of our patients had mental retardation.

Elevated IgE is also found in disorders such as atopic dermatitis, Wiskott–Aldrich syndrome, Netherton syndrome, Omenn syndrome, DiGeorge syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and graft versus host disease.[19] All these conditions were ruled out in our patients with appropriate history, physical examination, and investigations. Atopic dermatitis itself is a feature of HIES, but patients with HIES does not exhibit atopic diathesis in terms of allergic rhinitis or asthma and other cutaneous findings of atopy.[19]

All patients were treated symptomatically at the time of presentation according to clinical features and laboratory investigations. Patient with pyoderma gangrenosum was given oral prednisolone 20 mg/day with gradual tapering over 4-month period, and then it was stopped after complete healing of the lesions. The patient who had dermatomyositis with liver involvement was given treatment symptomatically after which patient improved for a day and then again deteriorated and died due to aspiration pneumonia.

Limitations

Genetic analysis was not done because of nonavailability of testing in our state and poor financial conditions of patients. It is a retrospective analysis, and a study with larger sample size is required.


  Conclusion Top


Our patients had an unusual association in the form of multiple endocrinopathy and pyoderma gangrenosum perhaps first to be reported in HIES. One of our patients had concomitant juvenile dermatomyositis, and other patient had suspected autoimmune disorder. Thus, a high degree of suspicion is required in early age to rule out other autoimmune disease in patients of HIES and patient should be followed up for the early diagnosis of same.

HIES is a primary immunodeficiency with complex and yet not very clear spectrum. Many other conditions present with recurrent bacterial and viral infections. Skeletal deformity, endocrinopathy take long time to present clinically. Presence of consanguinity, elevated IgE and multiple episodes of infections should raise suspicion to clinician. The use of NIH scoring system can aid in diagnosis. Early screening of endocrine system in such cases can help diagnosing endocrinopathy early. Further research is required for role of DOCK8 gene in endocrine system.

All of our patients were diagnosed very much late in life when they presented to us though most of them had a history of having complaints since childhood. The average age of diagnosis has been pointed out 11.5 years, though diagnosis can be made in infancy or adulthood, a vigilant eye and suspicion at a younger age might benefit patients and preventive and other suggested therapy can be started early which could decrease morbidity and mortality.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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