Hyperimmunoglobulin E syndrome is a primary immunodeficiency disorder, characterized by unusually high serum IgE levels, severe episodes of pneumonia, and skin boils and eczema like rashes. The most common form of this condition is the autosomal dominant form, also known as Job's syndrome. However, a rarer, distinct, autosomal recessive form has also been characterized. Patients affected with this autosomal recessive form of the disorder show the classical symptoms of Hyper IgE syndrome, including recurrent staphylococcal infections of the respiratory tract and skin, elevated serum IgE levels, and hypereosinophilia. In addition, patients also tend to be infected by fungi such as molluscum contagiosum, and viruses like herpes simplex and herpes zoster. Complications of the central nervous system, such as hemiplegia, and ischemic infarction are also fairly common. However, unlike in the autosomal dominant form of the disease, dental and skeletal abnormalities are not usually found in the recessive form.
Diagnosis of the condition is made based on the clinical as well as laboratory findings. Serum IgE level greater than 2000 IU/ml in adults, and 10 times the age appropriate level in infants is a diagnostic indicator. However, elevated IgE level, by itself, may not be enough for the diagnosis and needs to be correlated with the skin and respiratory condition. Antibiotics are usually administered to patients to counter the staphylococcal infections, while the eczema can be treated with high intravenous doses of gamma globulin. Prognosis for the disease is fairly good, if identified early and treated properly.
Autosomal recessive hyper-IgE recurrent infection syndrome is caused by homozygous or compound heterozygous mutation in the DOCK8 gene on chromosome 9p24. DOCK8 is a member of the DOCK180-related (DOCK1) protein family. In healthy individuals, DOCK8 is usually expressed in monocytes, B cells, and T cells.
El Noor et al. (1995) reported a two-year old boy who was diagnosed with hyper IgE syndrome after several admissions with repeated infections as he had pruritic dermatitis, growth retardation, osteopenia, immunoglobulin E levels greater than 20,000 IU/ml, positive staphylococcus aureus specific IgE antibodies, eosinophilia (ranging from 1715 X 109/L to 20700 X 109/L), along with positive family history in two of his siblings. He did not have any cardiac illness prior to his 13th admission when he presented with 10 days history of fever (38.7 degrees Celsius) and mild diarrhea. Examination revealed tachycardia (110/min), tender hepatomegaly, and a loud apical systolic murmur with a thrill. His hemoglobin was 9 g/dl, he had elevated white cell count (35% were polymorphonuclear leukocytes, 44% eosinophils, 12% monocytes, and 8% lymphocytes), and the ESR was 65 mm in the first hour. The remaining investigations (levels of immunoglobulin IgG, IgM, and IgA, complement levels, serum creatinine phosphokinase, liver function test, ASO titer, stool and urine analysis, blood culture, and serology for the following viruses: Coxsackie B, hepatitis A,B, and C, cytomegalovirus, Epstein Barr virus and human immunodeficiency virus) were either normal or negative. His cardiology evaluation revealed cardiomegaly with pulmonary congestion on chest X-ray, marked ST elevation with pathological Q waves on antero-lateral chest leads in an ECG, and an echocardiogram showed thickened ventricular walls and septum with shagginess of the left ventricular endocardium, dilated left atrium and ventricle, marked prolapse of the posterior leaflet of the mitral valve leading to severe mitral regurgitation (due to papillary muscle dysfunction) and moderate pericardial effusion. A repeat echo after one week of treatment with Frusemide, Flucloxacillin and Gentamicin revealed a sharply defined rounded bilocular thin-walled aneurysm at the left ventricular apex which on sequential echocardiograms showed healing (reduction of cavity size with thickening of its walls) along with gradual reduction of the left atrium and ventricle sizes, resolution of the pericardial effusion and mitral regurgitation with diminution of the its prolapse. Resolution of the acute focal injury (which had caused the papillary muscle instability and hence the mitral regurgitation in addition to the aneurysm) was also evident on repeated ECGs, and El Noor et al. (1995) had clinically diagnosed this patient with viral myocarditis with a ventricular aneurysm but definite diagnosis could only be made on basis of myocardial biopsy. The patient was doing well on long term Cloxacillin and intravenous immunoglobulin with less attacks of infection, and he had no cardiac symptoms.
Mahdi et al. (2002) reported the cases of two Saudi girls aged 8 years and 5 years with recurrent bilateral otitis media, repeated episodes of tonsillitis and chest infection. Cultures from the ears grew on numerous occasions Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeroginosa, Proteus species and Providencia species. The 8-year-old had a serum IgE level of 1431 iu/L, with normal levels of other immunoglobulin classes. The 5-year-old had an immunoglobulin E value of 1119 iu/L with normal values of other immunoglobulin classes. Both were human immuno-deficiency virus negative and no other causes for elevated immunoglobulin E were found. The mothers of both cases had elevated immunoglobulin E levels of 1216 iu/L and 1992 iu/L. Both fathers had normal IgE levels. A 13-year-old sibling of case one had a grossly elevated immunoglobulin E level of 2259 iu/L. She had diffuse lamellar icthyosis and recurrent episodes of chest infection and conjunctivitis. There was a good clinical response of patient one to monthly intravenous human immunoglobulin.
Samdani and Tania (2004) reported 9-year-old twin brothers with hyper IgE syndrome. They had repeated exacerbations of dermatitis and multiple skin abscesses over a period of five years. Both brothers had coarse facial appearance with prominent brow and deep-set eyes. Papulopustular lesions presented all over the body especially on the face and scalp to some degree at all times. They also had repeated attacks of conjunctivitis with purulent discharge, uni- or bi-lateral ear infections, episodes of skin infections, and a history of cough, fever and breathlessness due to chest infections. The serum IgE level was elevated in both brothers.
Alsum et al. (2013) described the clinical and molecular characteristics of Saudi patients diagnosed with AR-HIES. A total of 25 patients from 14 families were recruited to the study based on high serum IgE levels, eosinophilia, chronic eczema and recurrent infections. Upon investigation it was found that dermatitis, sinopulmonary infections, hepatic disorders, cutaneous and systemic bacterial, fungal and viral infections were the most common manifestations among the patients. Malignancies, neurological complications such as hemiparesis and seizures, and immune system conditions such as autoimmune hemolytic anemia were also noted in several patients. A statistical analysis unveiled cytomegalovirus (CMV) infections as the only significant indicator of a poor prognosis. Of the individuals in this study, 12 patients succumbed to pneumonia and/or sepsis. Their median age was 10-years. A genetic analysis was performed on 17 of the patients. While no STAT3 or TYK2 gene mutations were found, 13 patients carried DOCK8 mutations. All three DOCK8 mutations identified were found to be novel.
See: [Yemen> AlKhater, 2016]
AlKhater, 2016 described a 6-year-old Yemeni girl, born to consanguineous parents, who presented with eczema, skin abscesses, and recurrent bronchopneumonia. She also exhibited recurrences of Herpes zoster involving multiple dermatomes and persistent Molluscum contagiosum infections of the skin. Immunological analysis showed leukocytosis at 31 × 109/L, extreme peripheral eosinophilia as high as 18,000 × 109/L, an elevated IgG level of 2,530 mg/dl, and an elevated serum IgE level of 41,000 IU/ml. At 8 years of age, she had dysphasia, visual hallucinations, ipsilateral ptosis, acute left eye squinting, and fatigue. During three-week period she developed excessive sleepiness, dizziness, and unsteady gait. In addition, she had severe dermatitis on the back and buttocks and eczematous eruptions on the flexures of the arms and popliteal region. With steroids and mycophenolate mofetil (MMF) treatment, she remained symptom-free, and no vasculitis or infectious flare-ups have occurred. The patient made remarkable recover of most of her neurological deficits with effective treatments. By performing polymerase chain reaction (PCR) and multiplex ligation probe amplification (MLPA), a large homozygous deletion of the DOCK8 gene on chromosome 9 was identified.
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