A Boy with Relentless Pruritus: Job's Syndrome.

BACKGROUND: Job's syndrome (hyper IgE syndrome) is a very rare primary immunodeficiency disease that has an annual approximate incidence of less than 1/1,000,000. This manuscript aims to provide education regarding diagnosis and management strategies of this syndrome worldwide. CASE REPORT: A 6-year-old boy was seen at the clinic secondary to persistent pruritus interfering with sleep. At the age of 2 months, the patient developed diffuse eczematous and desquamating skin lesions. He was subsequently diagnosed with atopic dermatitis and managed conservatively. From 2 months to 7 years of age, intermittent exacerbations of dermatitis persisted despite an aggressive treatment regimen. The serum IgE level increased exponentially over a period of 7 years, with a peak value of 57,400 IU/ml. Molecular genetic testing revealed a dominant negative mutation within the SH2 domain of the Signal Transducer and Activator of Transcription (STAT3) gene. The patient was subsequently diagnosed with Job's syndrome. Management included proper skin care, prophylactic antibiotics, immunomodulating agents, and psychotherapy.
CONCLUSIONS: Job's syndrome can often go unrecognized and masquerade as atopic dermatitis. Therefore, genetic testing for this condition should be obtained in all patients with treatment-refractory AD. Additionally, psychotherapy can be a successful management strategy for the grating psychological impact that can be imposed on children with excessive pruritus.

Background

Job’s syndrome is a very rare primary immunodeficiency disease that has an approximate annual incidence of less than 1/1,000,000 [1]. Fewer than 300 cases have been reported in the literature [1].

This report demonstrates how Job’s syndrome can often go unrecognized and masquerade as atopic dermatitis. We also demonstrate the refractoriness to treatment and subsequent psychosocial impact. The aim of this article is to provide education regarding management strategies of this syndrome worldwide.

Case Report

A 6-year-old Hispanic boy was seen at the clinic secondary to persistent pruritus interfering with sleep.

The patient was born at another hospital via an uncomplicated caesarean section, to a 32-year-old primigravid female. The mother received prenatal care and standard screening tests were reportedly normal throughout pregnancy. The birth weight was 3,600 grams and the length 54 cm. The patient progressed well and continued to receive appropriate perinatal care.

At age the age of 2 months, the patient developed diffuse, eczematous, and desquamating skin lesions. He was diagnosed with atopic dermatitis and managed conservatively. When skin lesions continued to worsen, topical fluticasone was attempted, yielding minimal relief. Ultimately, a combination of topical fluticasone, cyclosporine, acitretin, oral prednisone, and intramuscular methotrexate yielded mild to moderate improvement for periods of time. Despite this aggressive treatment regimen, the patient continued to experience intermittent exacerbations of pruritus and dermatitis. Of note, during this time he also developed 5 upper respiratory infections.

At 1 year of age, the patient was admitted to another hospital for pneumonia. On examination, the temperature was 38°C, the blood pressure 99/56 mm Hg, and the pulse was 140 beats per minute. Erythematous, eczematous lesions were present on the trunk and upper/lower extremities. There was mild leukocytosis (10.4 mm3) and eosinophilia (7%); other laboratory test results were reportedly negative (Table 1). A chest radiograph revealed patchy consolidation and a diagnosis of pneumonia was made. The patient was placed on appropriate antibiotics and shortly thereafter was discharged.

Table 1.

Laboratory data.

Variable	Reference Range	Hospital admission for pneumonia at 1 year of age	Presentation to an Immunology clinic at 3 years of age	Presentation to the emergency department at 6 years of age	Presentation to an Immunology clinic at 7 years of age
Hematocrit (%)	36.0–46.0	34	39.1	40.6	44.5
Hemoglobin (g/dl)	12.0–16.0	10.6	12	13	12.9
White-cell count (per mm3)	4,500–11,000	10.4	13.5	19.9	15.1
Differential count (%)
Neutrophils	40–70	36	45	42	37
Band forms	0.0–7.0		2	1
Lymphocytes	22–44	57	32	30	37
Monocytes	4.0–11		4	3
Eosinophils	0–8	7	17	33	44
Basophils	0–3
Platelet count (per mm3)	150,000–400,000	300,000	580,000	582,000	381,000
Erythrocyte sedimentation rate (mm/hr)	1.0–17	33	40
C-reactive protein (mg/l)	<5		17.87	3.9
Protein (mg/dl)
Total	6.4–8.2			7.5
Albumin	3.4–5.0			3.8
Lactate dehydrogenase (U/L)	81–234			407
Vitamin D (ng/ml)	13.0–47.8				2.1
Parathyroid hormone (pg/ml)	11.0–67				286
Calcium (mg/dl)	8.5–10.1				7.4
Phosphate (mg/dl)	2.4–4.9				3.9
Immunoglobulins
IgE (IU/mL)	Variable*	26	386	817	57,400
IgG (mg/dl)	Variable*			1,130.00	1240
IgA (mg/dl)	Variable*			104	119
IgM (mg/dl)	Variable*				154
IgD (mg/dl)	Variable*				1.9
Total T3 (ng/dl)	94–269		254
Total T4 (ug/dl)	4.5–12.5		9.13
TSH (µIU/mL)	0.5–4.7		4.93		2.49
Anti-nuclear antibody				Negative
Anti-smooth muscle antibody				Negative
Anti-transglutaminase antibody				Negative
Serum protein electrophoresis				Normal pattern
HIV-1/HIV-2		Negative			Negative
HTLV-1/HTLV-2					Negative
VDRL		Negative
EBV			Negative
Mycoplasma IgM			Negative
Chlamydia pneumoniae IgM			Negative

Intermittent exacerbations of dermatitis persisted, and at the age of 3 years he was referred to an immunologist for further workup. Allergen testing revealed severe allergies to eggs, peanuts, and soy. There was a serum IgE level of 386 IU/mL. The administration of topical fluticasone, cyclosporine, and oral methotrexate were continued, under the presumed diagnosis of atopic dermatitis. However, continued workup and varying treatment regimens remained unfruitful. At subsequent follow-up visits to the Immunology clinic, a continued upsurge in the serum IgE level was noted; laboratory findings are shown in Table 1.

The patient explained that the pruritus did not remit with sleep and interfered with daily activities. He would also frequently avoid bathing due to the pain associated with the lesions, and stopped going to school for the same reason. Further, given the exasperating nature of the lesions, the patient’s continued scratching only worsened the pruritic lesions into large, bloody, excoriations to oftentimes infected lesions. This unremitting exasperation caused insomnia, ultimately even giving way to suicidal ideation. With countless hospital admissions for pneumonia and infected skin lesions, the psychological impact was very severe.

The patient was born in Venezuela, and had resided there for the entirety of his life. The mother reported that there were no known sick contacts, pets in the household, or insect bites. He did not have a history of travelling outside of Venezuela. The patient did not smoke, drink alcohol, or use illicit drugs. His father had a history of asthma, allergic conjunctivitis, and allergic rhinitis.

During yet another exacerbating episode, he was admitted to another facility. On examination, the temperature was 39°C, the blood pressure 105/70 mm Hg, and the pulse 143 beats per minute. The patient appeared agitated and irritable. There were vesicular lesions forming pustules, with multiple white plaques on an erythematous base, covering approximately 80% of the skin surface (Figure 1). Dennie Morgan folds, allergic shiners, hyper-linear palms (Figure 2), and edema were noted. There was diffuse alopecia, madarosis, and clubbed fingers present. The patient had palpable, non-painful axillary and inguinal lymphadenopathy bilaterally; the remainder of the examination was normal.

Figure 1.

Clinical photographs of the patient: There are vesicular lesions forming pustules, with multiple white plaques on an erythematous base covering approximately 80% of the skin surface (A–F). Diffuse excoriations secondary to scratching are seen (A–C).

Figure 2.

Hyper-linear palms: A feature commonly present in atopic conditions.

There was leukocytosis (19,900 mm3), with a prominent left shift, and 44% eosinophilia; other laboratory results are shown in Table 1. Immunological workup included a serum IgE level that was 817 IU/mL; serum complement, natural killer cells, lymphocyte count, and other immunoglobulins were normal. Th17 cells were quantified via flow cytometry and revealed a markedly decreased level (0–0.20% of CD4 T cells). Skin biopsy revealed superficial perivascular dermatitis with psoriasiform changes, hypogranulosis/agranulosis with parakeratosis, and fragmented neutrophils, suggestive of atopic dermatitis versus psoriasis.

A pediatric hematologist was consulted and ruled out hematological malignancy. Upon review of these results and discussion with an infectious disease specialist, antimicrobial therapy was initiated. Over a period of 2 weeks, there was mild improvement of symptoms, with complete relapse at 3 weeks. The patient continued to experience persistent, fractious pruritus, despite the use of 1st and 2nd generation anti-histamines, triple doses of H2 receptor antagonists, and amitriptyline. Methotrexate (10 mg/m2, weekly) was administered for 4 months, with modest improvement of the skin lesions, but without alleviation of the pruritus. He was discharged on oral cefadroxil, chlorpheniramine, hydroxyzine, omalizumab, ranitidine, topical fluticasone/unibase, and moisturizers.

During the next year, there was modest improvement of the dermatitis, but the pruritus remained. A psychotherapist also became involved in the patients care at this time, perhaps providing some of the greatest relief.

At the age of 7 years, a second skin biopsy was obtained. Histopathological examination revealed superficial perivascular dermatitis with psoriasiform epidermal changes, compatible with atopic dermatitis versus lichen simplex chronicus. The serum IgE level was 57,400 IU/ml; laboratory values are shown in Table 1.

Upon reviewing the patient’s previous serum IgE levels, and recent spike, molecular genetic testing was obtained. This revealed a dominant negative mutation within the SH2 domain of the STAT3 gene, subsequently diagnosing the patient with Job’s syndrome.

The patient is presently doing well with improvement of the skin lesions over 80% of the skin surface. This was largely contributed to his refraining from scratching and daily showers after multiple sessions of psychotherapy; however, the pruritus has persisted. His current treatment includes monthly IVIG, deflazacort (9 mg orally), and hyperbaric oxygen therapy. The patient is also being considered for anti-interleukin 4 therapy (Dupilumab).

Discussion

Job’s faithfulness was tested when God permitted Satan to “smote Job with boils from the sole of his feet unto his crown.” In 1966, 2 females with recurrent skin abscesses, dermatitis, and pneumonia were described by Davis et al. [2]. These became the first 2 cases coined as Job’s syndrome. Six years later, 2 cases with similar symptoms, and the addition of eosinophilia and elevated serum IgE levels, were described by Buckley et al. [3].

Job’s syndrome (hyper IgE syndrome) is characterized by the triad of elevated serum IgE level (>2000 IU/ml), pneumonia with formation of pneumatoceles, and recurrent staphylococcal skin abscesses [4]. Characteristic facial features present in Job’s syndrome have a reported incidence of 83%, and 100% for patients older than 16 years [4]. These include a prominent forehead, deep-set eyes, mild prognathism, a broad nasal bridge, and increased inter-alar distance [4]. Delayed tooth eruption, bone fractures, hyperextensible joints, and scoliosis are also frequently present [4]. This patient’s facial features resembled those frequently present in Job’s syndrome (Figure 3).

Figure 3.

Characteristic facial features: Note the presence of a prominent forehead, broad nasal bridge, increased inter-alar distance, and mild prognathism.

In the majority of patients, heterozygous mutations of the STAT3 gene are found. Autosomal dominant forms of the disease are associated with mutations in the STAT3 gene, whereas autosomal recessive forms are associated with mutations and deletions in dedicator of cytokinesis 8 (DOCK8) and tyrosine kinase 2 (TYK2) genes [5]. There can be similarities to atopic dermatitis, Wiskott-Aldrich syndrome, Netherton syndrome, and severe combined immunodeficiency; therefore, these should be considered as a differential diagnosis.

Atopic dermatitis (AD) is a common condition of early childhood, affecting 15% to 30% of children; 85% develop the disease within 5 years of life [6]. The hallmark of the diagnosis is a relapsing-remitting pruritic dermatitis. Patients typically have elevated serum IgE levels, eosinophilia, and profound pruritus that can cause insomnia, analogous to this patient.

The diagnosis of AD seems likely. However, due to the presence of recurrent pneumonia, an exponentially rising serum IgE level, and early onset of symptoms, other differential diagnoses can be considered.

The second diagnostic consideration was if the patient had a mutation in the Wiskott-Aldrich syndrome protein (WASp) gene. Wiskott-Aldrich syndrome (WAS) is an X-linked immunological disease, characterized by the triad of eczema, recurrent infections, and microthrombocytopenia [7]. Patients generally have elevated levels of serum IgE, IgA, IgG, and variable levels of serum IgM [7].

In this case, the patient’s platelets were of normal quantity and quality, making WAS an improbable diagnosis. Thus, the patient did not undergo genetic testing for WAS.

In this case, recurrent pneumonia and cutaneous infections prompted the consideration of a severe combined immuno-deficiency (SCID). Etiologies of SCID include cytokine receptor defects, adenosine deaminase (ADA) deficiency, and multiple histocompatibility complex (MHC) II deficiency, which lead to a defect in cell-mediated and humoral immunity [8]. Classic features include recurrent bacterial, fungal, viral, and protozoal infections [8]. In the preponderance of cases, patient’s T cells are absent [8].

Findings in this case resembling SCID included elevated serum IgE level, skin rash, and recurrent infections. However, flow cytometry revealed the patient’s T cells to be of normal quantity, ruling out the disease.

In summary, we favored the diagnosis of Job’s syndrome. This was confirmed with the findings of elevated serum IgE (>2000 IU/mL), characteristic facial features, and a dominant negative mutation within the SH2 domain of the STAT3 gene.

In addition to conservative pharmacological therapy (steroids, vitamin A derivatives), it is imperative that these patients receive proper skin care to prevent the development of recurrent Staphylococcal skin infections. Effective treatments include immersion in bleach baths (1/2 cup of bleach in a tub of water for 15 minutes, 3 times a week), or chlorinated pools [9]. Prevention also involves the prompt administration of anti-Staphylococcal antibiotics at the first sign of infection. Prophylactic therapy with trimethoprim-sulfamethoxazole has been shown to be highly effective [4].

Intravenous immunoglobulin (IVIG) and Interferon (IFN)-gamma have been used anecdotally, with favorable results. There have been no randomized controlled trials described in the literature supporting the use of IVIG for Job’s syndrome. One study reported improvement of eczema in patients with Hyper IgE syndrome, after receiving IVIG (400 mg/day for 5 days) [10]. This study also exhibited diminished enhanced IgE production in vivo and in vitro [10]. The resolution of pneumonia after administration of IVIG in Job’s syndrome has been described [11]. However, 1 study concluded that IVIG was of no clear benefit, and did not significantly decrease serum IgE levels or IgE synthesis [12].

IFN-gamma has demonstrated effectiveness in decreasing serum IgE levels [13]. However, serum IgE levels returned to pre-treatment levels within 1–3 months after completion of treatment [13].

In addition to these treatments, psychotherapy was an integral part of the patient’s treatment regimen.

Dr. Maria Elena Abdulmassih: I initially met this patient after he experienced an episode of intense agitation that caused him to scratch himself until he bled.

During the course of family therapy sessions, I observed that this patient would use his constant state of pain and scratching to manipulate the parents into obeying him. The patient would use scratching and pain as a tool for social isolation. He did not want anyone to see him in his current state and also wished that he was dead. This led the parents to isolate the boy from normal social life.

During family therapy, I was able to demonstrate to the parents that this defense mechanism of isolation was detrimental to the patient’s mental health. I was able to explain to the patient that blaming others for his condition was not helpful, and that he had to cope and hopefully overcome it in life. Reinforcing the “ego” of the patient was an integral part of the treatment in an effort to control his anger.

The same mechanism of manipulating his parents was seen while bathing. Due to complaints of agonizing pain, he refused to bathe. This contributed enormously to the vicious cycle of his recurrent infections and secondary pruritus.

After multiple interventions during family therapy, this patient began to demonstrate an improved attitude towards his condition. We were then able to start an aggressive plan consisting of daily showers, wound care, and hyperbaric oxygen therapy.

Conclusions

We conclude that further research is necessary regarding treatment regimens for Hyper-IgE syndrome (Job’s syndrome). This condition can be identical in presentation to AD; therefore, genetic testing should be obtained in all children with treatment refractory AD. Psychotherapy can be a successful management strategy for the severe psychological impact that can be imposed on children with excessive pruritus, in addition to pharmacological therapy.