History
Infants in families with HIE syndrome often exhibit severe eczema complicated by mucocutaneous candidiasis involving the mouth and diaper areas in the first few weeks of life. Lichenification quickly follows; then recurrent otitis media soon develops. Wheezing is not common; a persistent cough beginning in infancy is common. Chronic, disfiguring M contagiosum infection has also been reported in patients with AR HIES but not in those with AD HIES.
Recurrent or chronic otitis media and sinusitis persist into adulthood. Although surgical intervention has been recommended in these patients, in the author's experience, sinus surgery seldom has favorable outcomes, and persistent otorrhagia may result after the surgery.
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Food and respiratory allergens can be identified using routine allergy testing; however, avoiding known allergens has minimal influence on patient's dermatitis or other atopic features of HIE syndrome.
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In patients with AD HIE syndrome, fractures can result from minimal trauma (pathological fractures). Long bones, ribs, vertebrae, and pelvic bones are those most commonly affected.
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Pneumatoceles often develop occultly following pneumonia in people with AD HIE syndrome. Chronic coughing with purulent sputum accompanies pneumatocele formation. In AR HIE syndrome, pneumatoceles rarely develop.
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Susceptibility to malignancies, including squamous cell carcinoma, cutaneous T-cell lymphoma/leukemia, and Burkitt lymphoma, was reported in patients with AR HIES. [23] DOCK8 mutation is a known cause of AR HIES and has a role in T-cell development and function, which helps explain these clinical features.
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In patients with AR HIES, neurological symptoms are frequently seen, and these appear to be highly associated with vascular abnormalities including stenosis, occlusion, and aneurysm formation. Etiology of vascular abnormalities are implicated with CNS vasculitis and infection.
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Coronary artery aneurysms were reported in 2 patients with AD HIES who were in their fifth decade of life. In contrast, fatal aneurysmal dilatation of the thoracic aorta has been reported in 2 adolescents with AR HIES.
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Family members without HIES are not reported to have increased incidences of isolated fractures, facial anomalies, vasculitis, or malignancy. They also have normal IgE levels.
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When atopic predisposition is significant in the family, patients with HIES seem to have more severe skin and pulmonary symptoms.
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Patients with tyk2 deficiency exhibit more severe clinical features characterized by extreme vulnerability to intracellular bacteria as well as extracellular bacteria. This is attributed to impaired signaling mediated by interleukin (IL)-6, IL-10, IL-12, and IL-23. [5]
Physical
Facial abnormalities and eczema varies with age. Infants and toddlers with AD HIES often do not demonstrate the distinctive facial features found in older patients with AD HIES. By mid childhood, however, most patients with AD HIES have coarse faces, a prominent forehead, a broad nasal bridge, and a bulbous nose. Midline facial anomalies such as cleft lip and palatal abnormalities may be present. Craniosynostosis has been reported in a few patients. Such skeletal abnormalities do not appear to be present in patients with AR HIES.
Eczematous dermatitis and lichenification affect the face, trunk, and extremities in a distribution similar to that found in people without HIE syndrome who have atopic dermatitis. Dermatitis is pruritic, leading to excoriation. It differs from typical eczema in that the weeping, superinfected severe eczematous skin lesions are less frequent; patients with HIES instead develop boils, deep-seated cold abscesses, and even pyomyositis. Multiple guidelines have been established for the diagnosis and management of atopic dermatitis. [32, 33]
In patients with AD HIES fractures may lead to asymmetry in the extremities or the chest wall. Scoliosis develops during adolescence and vertebral abnormalities cause spinal deformity. One recent study reported hyperextensible joints in approximately 70% of AD HIES patients. Dental abnormalities are also frequently seen in people with AD HIES. Some patients with AD HIES reportedly fail to shed their primary teeth. They may retain these teeth even as permanent teeth erupt.
Chronic sinusitis, chronic bronchitis, and lung abscesses (for patients with AD HIES) are common sinopulmonary findings. A purulent sputum-producing cough is common in patients who develop pneumatoceles, although some individuals have a dry cough associated with sinopulmonary infection. Wheezing is highly unusual in people with HIES and is more suggestive of atopy asthma with elevated IgE levels. The common manifestation in patients with AD HIES includes a chronic cough and pneumatoceles in the second decade of life.
Because HIES affects multiple organ systems and clinical features may change with age, the National Institutes of Health (NIH) developed a scoring system for clinical diagnosis for HIES. A clinical point score of more than 40 is reported to be highly likely to have AD HIES. [26] Clinical findings listed in this scoring system include highest serum IgE level, skin abscesses, pneumonia, parenchymal lung anomalies, retained primary teeth, scoliosis (maximum curvature), fractures with minor trauma, highest eosinophil count, characteristic coarse facial features, midline anomaly, newborn rash, eczema (worst stage), frequency of upper respiratory tract infection, candidiasis, other serious infections, fetal infection, hyperextensibility, lymphoma, increased nasal width, and high palate. Scores are corrected with young age.
Causes
Studies have revealed that many cases of AD HIES are associated with STAT3 mutations and most AR HIES cases are associated with DOCK8 mutations. In patients without STAT3 or DOCK8 mutations, mutations of other genes such as tyk2 or PGM3 can be associated. Also clinical features even in patients with one specific gene can vary significantly.
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Chest radiograph of a patient with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES) and a lung abscess following multiple staphylococcal pneumonias. Aspergillus fumigatus was isolated from the abscess.
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Father and daughter with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES). Note the father's distinctive facies with prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance.
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Mother and son with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES). Note the mother's distinctive facies. She had a history of multiple deep-seated abscesses that took months to heal after incision and drainage.
