A Case of Hyper Immunoglobulin-E Syndrome Associated with Scrotal Tongue and Intraoral Hyperpigmentation.

Sir,

Hyper IgE syndrome (HIES), a complex of primary immunodeficiencies manifesting during childhood, was named in 1966 by Davis et al., as Job's syndrome after the Biblical prophet Job who was “smote with sore boils.[1] Besides characteristic triad of high serum IgE (>2000 IU/ml), recurrent skin abscesses and pneumonia with pneumatocele formation, other common features are atopic dermatitis, scoliosis, fractures and dental abnormalities.[2] Sporadic as well as familial cases occur.[3] While multisystem involvement is the rule in sporadic and autosomal dominant (AD-HIES) types, autosomal recessive (AR-HIES) cases have severe viral infections and potentially lethal neurologic complications but lack skeletal and dental involvement.[3]

A 7-year-old female patient born of non-consanguineous marriage brought with severe impetiginized skin lesions, intertrigo and lymphadenopathy. History of recurrent skin/respiratory tract infections and three hospitalizations for ’pneumonia’ since infancy, was reported. The patient was treated for pulmonary tuberculosis at the age of two years. The parents and siblings were unaffected.

General examination showed a pale poorly built/nourished child with coarse facies [Figure 1] and significant bilateral axillary and left inguinal lymphadenopathy [Figure 2]. Dermatological examination revealed generalized xerosis, lichenification, excoriations, angular cheilitis, perioral/pubic encrusted papuloplaques, axillary/inguinal intertrigo [Figures 1 and 2], non-exfoliation of the primary teeth, scrotal tongue and hyperpigmentation of gingiva and buccal/hard palatine mucosae [Figure 3].

Figure 1

Coarse facies, broad nose, angular cheilitis, rough and encrusted skin

Figure 2

(a) Vegetative plaque left axilla (b) Encrusted papuloplaques and left inguinal lymphadenopathy

Figure 3

(a) Scrotal tongue (b) Hyperpigmention of gingivae and buccal mucosa

Investigation revealed increased eosinophilia (735/μL) and serum IgE (≥ 2500 IU/ml). Hemogloblin was 9.6 gm %. The chest X-ray showed pleural thickening and patchy consolidation of upper lung zones. Brain CT scan and magnetic resonance imaging were normal. Fine needle aspiration cytology of lymph nodes was non contributory. Skin biopsy revealed eosinophilic spongiotic dermatitis [Figure 4]. C3 and C4 levels were normal and nitroblue tetrazolium test negative. Absolute CD4 and CD8 T cells were 622 and 240/mm3 respectively. The patient's score as per National Health Scoring was 32.[4]

Figure 4

(a) Spongiosis, basal cell vacuolization (H and E, ×100) (b) Eosinophilic exocytosis (H and E, ×400)

Based on the above, diagnosis of AD-HIES was made and the patient gradually improved with treatment consisting of antibiotics, antifungals, emollients and oral vitamin C.

After the initial description by Davis et al., of two patients with red hair, severe chronic dermatitis, cold abscesses and recurrent pneumonia, Buckley et al. in 1972 defined the classical triad of Job's syndrome comprising of extremely high IgE levels, eczema and recurrent skin and lung infections; hence the eponym of Buckley's syndrome for this entity.[2] Over 250 cases, occurring one in a million population, have since been reported in the world literature[1] Whereas, 10 (5 sporadic, 4 dominant and one recessive) have been from India after the first case report by Pherwani et al. in 1994.[567]

The pathophysiology of this diverse syndrome is not completely understood.[8] Three different gene defects have been related to lack of response/absence of Th17 cells and the resultant cytokine abnormalities.[3] AD-HIES is a result of mutations in the signal transducer and the activator of transcription 3 gene leading to neutrophil chemotactic defect or Th1/Th2 cytokine imbalance as a result Ig class switching towards IgE.[12] AR-HIES results from mutation in TYK2 and defective dedicator of cytokinesis leading to disruptive production of a protein involved in the regulation of the actin skeleton.[8]

After the neonatal onset of pustular and eczematoid rash affecting the face and the scalp, the patient's infancy is characterized by recurrent staphylococcal infections of the skin, ear, sinuses, mastoid and lungs.[3] Characteristic facies include greater interalar width, longer outer canthal distance and prominent brows/supraorbital ridge with deep-seated eyes.[6] Intraorally, retention of primary dentition, high arched palate, central tongue depressions and recurrent oral candidiasis occur.[38] Skeletal abnormalities include hyperextensibility of joints, scoliosis and osteoporosis.[3] Pneumonias are typically complicated by lung abscesses, bronchiectasis, bronchopleural fistulas and pneumatocele which predispose to opportunistic infections leading invariably to the development of chronic respiratory insufficiency. The main cause of mortality in HIES; hemoptysis complicating lung abscess and cystic lung disease being next common.[19] Cranial abnormalities include Chiari 1 malformations and craniosynostosis. There is increased risk of Hodgkin's and non-Hodgkin's lymphoma.[1]

The more severe autosomal recessive form of the disease is often fatal in childhood due to sepsis. CNS vasculitic sequelae (facial paralysis, hemiplegia, ischemic infarction, and subarachnoid hemorrhages, etc.) are next common causes of its high mortality.[12]

AD-HIES has serum IgE concentrations >2000 IU/ml and eosinophilia >700 cells/μL. In AR-HIES other immunoglobulin isotypes are also raised and there is severe eosinophilia (up to 17,500/μL).[2]

Prompt treatment of infections and drainage of abscesses is paramount.[2] In addition to topical antibacterials, emollients and corticosteroids, long term systemic antibiotics/antifungals can prevent infections and lung parenchymal damage.[8] Interferons, immunoglobulin supplementation, cyclosporine A, methotrexate, levamisole, cimetidine, ascorbic acid and transfer factor have occasionally been used.[67]

Despite a diligent search of the literature, we have failed to find any previously reported association of scrotal tongue and intraoral hyperpigmentation in any case of AD-HIES which is present in our typical case of this entity.