Indian Pediatrics 2001; 38: 1029-1034
Hyperimmunoglobulin E Syndrome
A.V. Pherwani, N.A. Madnani
Davis in 1966 reported the association of infected eczematous dermatitis with sinusitis, acute pulmonary infections and recurrent "cold" staphylococcal abscesses in two caucasian red haired girls and named it "The Job’s Syndrome", after the Biblical character Job(1). Though the initial case of Job’s syndrome was reported in a boy who had red hair, these two features are not seen in many cases. Later renamed as the ‘Hyperimmuno-globulin E syndrome (HIE)’, it is a rare immunodeficiency disorder, characterized by recurrent skin and pulmonary abscesses and markedly elevated levels of serum IgE(2). Reports of more than 200 cases have been published(3). As children with HIE are living longer, a wide spectrum of new phenotypes are being unfolded which will aid in the diagnosis, management and genetic linkage studies(4). Findings unrelated to the immune system have been reported(5). We reported our first case in 1994(6). This manuscript reports our experience with six cases.
Table I elaborates the clinical symptoms of the cases. One of the cases is shown in Fig. 1. All patients became symptomatic within few months of birth, having severe itching, urticaria, and skin abscesses. Respiratory symptoms (severe cough, wheezing, otitis media, pneumonia were documented in 5 subjects (83,3%) and chronic diarrhea in 2 patients (33.3%). Coarse features (Fig. 1) were seen in 4/5 (80%), prognathia in 1/5 (20%) and short stature in 4/5(80%). One patient was of 2 months age and no particular phenotype could be discerned. Grimbacher(4) reported an autosomal dominant inheritance with variable expression for specific groups of dental, facial, skeletal or immunological abnormalities in 11/30 (36%) in HIE having more than one affected family member. Only Case 1 was born of
consanguineous marriage. In our series, only one subject had 3 involved relatives; a great grand father, father and an aunt indicating the carriage of the gene in three generations. The child also had skeletal anomalies. Two cases were loosing grades in their school but one is doing well in school and another is studying commerce.
The infecting organisms isolated from various organs, during multiple episodes of infections were mainly, Staphylococcus aureus (5/6, 83.3%) (including the methicillin resistant), Streptococcus pneumoniae, and Gram negative bacilli (2/6, 33.3%). Muco-cutaneous candidiasis involving nail beds was seen in 3/6 (50%) and of esophagus and vagina in 1/5 (20%). Osteoporosis was seen in 3/5 (60%) studied with one of them showing evidence of old fracture of the humerus, metaphysial hyperluscencies of both humeri and osteochondroma of the 4th rib. None of our patients had scoliosis. Only two were older than 16 years and scoliosis usually manifests as the age advances. We could do oral polygram (OPG) in two cases. One child had a visible cavity in his retained deciduous tooth. Retention of deciduous teeth was seen in two cases.
All our patients had whole body skin involvement, high IgE and absolute eosinophil counts. Table II gives the details of investigations. Though IgE levels do fluctuate, we could not document normal levels even during relatively quiet periods and neither did the clinical severity of the disease correspond with serum IgE levels. Only 80% children below the age of 8 years show high IgE levels(4). Five of our patients were seen before this age and had raised levels. Three cases in whom skin biopsy was done showed tissue eosinophilia. Chemotaxis was defective in all the 4 cases studied by us.
Table I - Details of Symptoms
In HIE, the host defence suffers from a T-suppresser cell abnormality thereby allowing unregulated T-helper activity which augments IgE production(7). Though there is no struc-tural defect in the IgE molecule, nevertheless, it is ineffective. B-cell abnormality is shown by defective immunoglobulin synthesis in vitro. Mononuclear cells from HIE patients have been shown to produce an inhibitor of leukocyte chemotaxis, but this defect of neutrophil chemotaxis is fluctuating(8). There is usually a normal E-resetting count and the CD4+ cell count is also usually normal, but CD3+ and CD8+ lymphocytes are usually
depressed(5). A recent study suggests that CD45RO expressed on the memorty T cells of CD4 and CD8 are deficient in number though normal in function(9).
Defective immunity may be the reason for prolonged Varicella infection in one case and 3 attacks of the same in another child and prolonged herpes infection and tuberculosis in two more subjects. The anamnestic response to vaccines and recall antigens is usually poor, but immediate reaction to inhaled or ingested allergens are frequent even though skin tests for the same may show no response. Skin prick tests performed on four patients with a battery of allergens consisting of house dust, house dust mites, cockroaches, alternaria, wheat, eggs, Bengal gram, grass pollen and tetanus toxoid were negative.
Several reports(5) have pointed out findings apparently unrelated to the immune system, namely hyper-extensible joints, multi-ple fractures, craniosynostosis, high arched palate, cleft lip and palate and clefts in the tongue. In our study one child had evidence of old fractures.
Complications in HIE mainly involve the respiratory system, and include chronic bronchitis, bronchiectasis, empyema, pneumo-thorax and bronchopleural fistulae. Pneumato-coeles are common and may need surgical excision. All these pulmonary complications were seen in one child.
Several diseases like systemic mastocytosis and systemic lupus erythematosis have been associated with HIE but so far only 3 reports of malignancies have been reported (Hodgkin’s disease, Histiocytic lymphoma of the brain and Burkitts lymphoma). One of our cases developed Burkitts lymphoma, which is probably the second case reported in the world literature. Our patients needed continuous treatment and prophylaxis.
Treatment involves giving appropriate antibiotics for specific infections. Prophylaxis is advised with dicloxacillin. In our cases we gave cloxacillin and cephalosporins. As remissions and exacerbations are known in HIE we are not sure whether the relatively symptom free intervals were due to prophylaxis per se. A trial of intravenous immunogloulins (IVIG) and plasmapheresis produced only temporary relief(10). We gave IVIG (400 mg/kg/day) for 5 days in 3 patients, but the effect was temporary lasting for about two months. Methotrexate (Mx) was very effective in controlling the skin symptoms in two children; one of them had taken Mx for 4 months and the other irregularly for one year, at a low dose of 7.5-2.5 mg/week. We can not comment on the long term use of this drug in our series since one child died of Burkitts lym-phoma and another expired of severe bleeding following lobectomy for lung abscess.
Recently, studies have shown that the over production of IgE can be regulated by a number of cytokines affecting the IL-4 dependent pathways in HIE and this suggests possibilities for exploring novel avenues for therapeutic interventions(11). Treatment with anti-IgE has recently been tried for asthma cases but has not yet been tried in HIE.
Contributors: AP co-ordinated the study (diagnosis and treatment) and NAM was responsible for diagnosing skin conditions and performing skin biopsies. AP will act as the guarantor for the manuscript.
Table II - Details of Investigations