Autosomal dominant hyper IgE syndrome (AD-HIES) is a rare multisystem primary immunodeficiency disorder distinguished by the clinical triad of atopic dermatitis, recurrent skin staphylococcal infections, and recurrent pulmonary infections. The disorder is characterized by repeated bacterial infections of the skin and lungs (pneumonia), skeletal abnormalities, and characteristic facial features. The first symptom is often the development of a dry, red flaky skin rash (eczema) at birth or early during infancy. Researchers have discovered that mutations in the STAT3 gene cause AD-HIES in over 60% of the patients. Most cases of AD-HIES occur as the result of a new mutation in this gene. There are two main forms of hyper IgE syndrome – one inherited in an autosomal dominant pattern and one in an autosomal recessive pattern. Both involve defects of the immune system and elevated levels of immunoglobulin E (hyper IgE) in the blood. For years, researchers considered their different expressions of the same disorder, but now researchers consider them similar, yet distinct disorders.
Causes
Mutations in the STAT3 gene cause AD-HIES. The STAT3 gene is responsible for the production of one of the signal transducer and activator of transcription (STAT) proteins that are involved in signaling the immune system to respond to pathogens. The mutations associated with AD-HIES result in a normal amount of STAT3 protein produced but the function of the protein is affected resulting in defective host defense.
Mutations in other genes may also be associated with AD-HIES since STAT3 mutations are found in about 60% of patients.
AD-HIES is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Diagnosis
A diagnosis of AD-HIES is made based upon a thorough clinical evaluation, especially a detailed patient history and identification of characteristic findings by a physician with experience with the syndrome. Laboratory studies that may aid in a diagnosis include blood tests that demonstrate elevated levels of IgE in the blood and elevated levels of certain white blood cells known as eosinophils (eosinophilia). IgE levels may drop to normal or near-normal levels in adulthood and, therefore, normal IgE levels in an adult do not necessarily rule out a diagnosis of AD-HIES.
History
- Patients of hyper IgE syndrome are born with pustular or eczematoid rashes, or they may appear in the first month of life.[rx]
- Recurrent eczema, boils, and skin abscesses.
- Recurrent infections such as chronic otitis media, sinusitis, pneumonia, mucocutaneous infections, and neurological and systemic.
- Hyperextensible joints/recurrent bone fractures, and distinctive coarse faces( prominent forehead, deep-set eyes, broad nasal bridge, and wide internal distance) in early childhood.
- Eczema is complicated by mucocutaneous candidiasis involving the mouth and diaper areas.
- Skeletal abnormalities include scoliosis, osteopenia, minimal trauma fractures, hyperextensibility, and degenerative joint disease.
- Retained primary teeth past the age of normal dental exfoliation.
Physical Examination
- Coarse facial features( prominent forehead, deep-set eyes, broad nasal bridge, and wide internal distance).[22]
- Dental abnormalities- retained primary teeth.
- Facial pain (sinusitis), ear pain, and discharge (otitis media).
- Purulent sputum producing cough or dry cough due to recurrent pneumonia.
- Eczematous dermatitis and lichenification affect the face, trunk, and extremities.
- Boils and multiple skin abscesses.
- Purpura rash.
- Skeletal abnormalities include scoliosis, osteopenia, minimal trauma fractures, hyper-extensible, and degenerative joint disease.[rx]
Immunological Features
- These mainly include chronic eczematoid eruptions, recurrent skin and pulmonary bacterial infections, and mucocutaneous candidiasis. The skin manifestations usually appear very early, a few weeks after birth. They include a pruriginous eczematoid rash affecting the scalp and face, that is rapidly superinfected with Staphylococcus aureus, resulting in weeping, crusty, and follicular infectious lesions.
- Recurrent cold staphylococcal skin abscesses that are associated with little or no inflammation are seen in these patients. Candida infections are common; they affect the skin, mucous membranes, and nails.
- Recurrent pneumonia is typical, predominately due to S. aureus, and less frequently due to Streptococcus pneumoniae, and Haemophilus. It can get complicated with the development of recurrent lung abscesses, bronchiectasis, and pneumatoceles. These pneumatoceles can get colonized with Aspergillus and Pseudomonas. Superinfection with Pneumocystis carinii[rx] was also reported.
- Cryptococcosis and histoplasmosis can manifest outside the lung. Other infectious manifestations such as sinusitis, bronchitis, otitis externa, gingivitis, dental abscess, septic arthritis, and osteomyelitis can be seen.[rx][rx][rx][rx][rx]
Non-immunological Features
- Patients with Job syndrome have characteristic facial features that appear in early adolescence or earlier in late childhood, for example, facial asymmetry, prominent forehead, deep-set eyes, broad nasal bridge, wide fleshy nasal tip[rx], rough fascial skin, increased inter-alar distance, prognathism, and high-arched palate. Birth defects like craniosynostosis and Arnold Chiari type 1 malformation have been documented.
- Musculoskeletal abnormalities are common. They include hyperextensibility of the joints, scoliosis, and osteopenia. Hyperextensibility(noted in about 68% of the patients) may result in the early onset of degenerative joint disease. Bone density is decreased and is the source of multiple pathological fractures that occur in approximately 50% of patients (long bones and ribs). Scoliosis of variable severity is observed in approximately 60% of patients.
- Anomalies of dentinogenesis are possible manifestations. Decreased resorption of the roots of the deciduous teeth may result in prolonged retention of the deciduous teeth, preventing the appearance of definitive teeth. About 70% of the patients with Job syndrome have been reported to retain three or more primary teeth.
- Vascular manifestations include tortuosity or dilatation, coronary, cerebral and aortic aneurysms, and congenital coronary artery abnormalities. Ocular complications include xanthelasmas, chalazion, strabismus, and retinal detachment.
- The main diagnostic feature is an increase in serum IgE levels of more than 2000 U/mL, and often 500 U/mL. A clinical score has been developed to define the probability of diagnosis. A total IgE concentration greater than 1000 IU/mL and a weighted score of greater than 30 indicate an AD-HIES of the defect in STAT3, and a dominant-negative heterozygote mutation in STAT3 confirms the diagnosis.[rx][rx]
- Eosinophilia is observed in more than 90% of the patients. The WBC count can be normal, elevated, or reduced in number(neutropenia).[rx]
- X-ray studies such as computed tomography (CT scanning) may be used to detect lung infections and the development of pneumatoceles within the lungs. Pneumatoceles are an indicator of AD-HIES. During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.
A scoring system was devised by researchers at the National Institutes of Health (NIH) to aid in making a diagnosis of AD-HIES. Genetic tests revealing a STAT3 mutation confirm the diagnosis in some 60% of cases. Hence, the absence of such a mutation does not rule out the diagnosis of AD-HIES.
Treatment
The treatment of AD-HIES is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, internists for adults, dermatologists, dental specialists, immunologists, orthopedists, and other health care professionals may need to systematically and comprehensively plan treatment.
The mainstay for the treatment of individuals with AD-HIES is preventative (prophylactic) antibiotic therapy against bacterial infection. Common antibiotic medications (e.g., anti-staphylococcal agents) used to treat individuals with AD-HIES include dicloxacillin (flucloxacillin in many European countries) or cotrimoxazole. In severe infections, recombinant interferon-gamma subcutaneously may be given as an adjunctive treatment.
Treatment of hyper IgE syndrome includes prevention of infections, administering prohphylactic antibiotics, treating current infections and bone marrow transplant.
- Skin care with antiseptic wash prevents infection with bacteria and fungi.
- Eczematous dermatitis is treated with a topical corticosteroid, a moisturizing cream, and an antihistamine .
- Prophylactic administration of trimethoprim-sulfamethoxazole is useful in the prevention of cutaneous staphylococcal infections, including abscesses, as well as sinusitis, otitis media, and pneumonia.
- 5 to 8 mg/kg/day of the trimethoprim component administered orally in two divided daily doses, or from 0 to 6 months, 120 mg/day; 6 months to 5 years, 240 mg/day; 6 to 12 years, 480 mg/day; and >12 years, 960 mg/day.
- Treatment of active infections:
- Pneumonia and deep-seated abscesses caused by S aureus are treated intravenously with nafcillin and with vancomycin if it is methicillin-resistant.
- Lung abscesses superinfected with Aspergillus species require intravenous amphotericin B.
- P aeruginosa, requires an aminoglycoside and a third-generation cephalosporin or another synergistic antibiotic.
- Bone marrow transplantation (BMT) is also being studied to be used for treatment.
Surgery
Surgery is not recommended for the treatment of hyper IgE syndrome.
Some affected individuals may require therapy for mucocutaneous candidiasis such as fluconazole or itraconazole, which are anti-fungal drugs. Surgical drainage of existing skin lesions, followed by a regimen of antibiotic therapy may be required in some cases. Topical steroids and moisturizing creams may also be used to treat skin lesions.
Chronic lung infections may lead to the formation of air cavities (pneumatoceles), which can potentially become infected with Pseudomonas aeruginosa and Aspergillus fumigatus. The drug treatment of these infections can be difficult and management may require surgically opening the chest (thoracotomy) to allow for the removal or drainage of such infected pneumatoceles.
Affected individuals may have retained primary teeth removed, be regularly monitored for the development of scoliosis, and be evaluated for fractures following even minor trauma. Scoliosis and fractures may require treatment with various orthopedic procedures.
Genetic counseling is recommended for affected individuals and their families. Another treatment is symptomatic and supportive.
References
- https://www.ncbi.nlm.nih.gov/books/NBK525947/
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- https://www.fda.gov/medical-devices/
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- https://www.niams.nih.gov/health-topics/autoimmune-diseases
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