Hyper IgE syndrome

STAT3 deficiency is associated with heterozygous loss of function variants in the transcription factor STAT3. This is the more common form of HIES in the U.S. It commonly presents with skin findings, including newborn rash, eczema, and recurrent staphylococcal skin abscesses, as well as ear, sinus, and lung infections. The lung infections often result in cavitary lesions in the lungs (pneumatoceles). 

Other common infections in STAT3 deficiency include mucocutaneous candidiasis (Candida fungus on mucous membranes and/or skin), manifesting typically as thrush, vaginal candidiasis, or candidal nail infection (onychomycosis), and recurrent shingles outbreaks. Additional findings include connective tissue and skeletal abnormalities, such as a typical facial appearance, hyper-extensibility of joints, retained primary teeth, recurrent bone fractures with minimal trauma, and a propensity to aneurysm formation of brain and cardiac blood vessels. Severe allergic diseases, such as food allergies, are not common in individuals with STAT3 deficiency. However, they often have positive skin prick tests making it appear that they have significant allergies.

A newborn rash or eczema is frequently the first manifestation of STAT3 deficiency. Pustular and eczema-like rashes usually begin within the first month of life, first affecting the face and scalp. Skin abscesses are a classic finding in this disorder, caused by a particular susceptibility to infections with Staphylococcus aureus. The degree of inflammatory symptoms, such as tenderness and warmth, often is quite variable. The term 'cold abscesses' is applied to those lesions that lack external signs of inflammation despite the presence of pus. The occurrence and severity of these abscesses substantially decrease with prophylactic therapy with antibiotics against Staphylococcus aureus. Deep tissue abscesses, such as liver or bone infections, are much less common in AD-HIES.

Recurrent bacterial cases of pneumonia are often encountered in individuals with AD-HIES. Pneumonias typically start in childhood and are most frequently caused by Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Similar to the occurrence of cold skin abscesses, these types of pneumonia may present with fewer symptoms than would be expected in a person with intact immunity. This relative lack of symptoms and subsequent delay in clinical presentation may contribute to advanced disease and significant tissue damage before identification and initiation of appropriate therapy. 

Infection-induced tissue destruction in individuals with AD-HIES may give rise to pneumatocele formation, and large cavities in the lung, which is a distinguishing feature of AD-HIES due to STAT3 deficiency. When pneumatoceles or bronchiectasis are present in the lungs, the individuals are more susceptible to lung infections with other bacteria, such as Pseudomonas, and molds, such as Aspergillus.

The involvement of both the connective and skeletal tissues is an important feature of STAT3 deficiency. An asymmetrical facial appearance with a prominent forehead and chin, deep-set eyes, broad nose, thickened facial skin, and a high-arched palate are typical of this disorder. These features evolve during childhood and become more established by adolescence. 

Individuals with AD-HIES also exhibit hyperextensibility of the joints. They frequently suffer bone fractures from seemingly insignificant trauma and bone density may be reduced. Scoliosis is common and typically emerges during adolescence or later in life. Craniosynostosis (fused skull bones) and extra or abnormally formed ribs or vertebrae are also found more often in those with AD-HIES than in the general population. These skeletal abnormalities are not usually seen in individuals with DOCK8 deficiency.

Abnormalities affecting the teeth are another common feature of AD-HIES with STAT3 mutations. Retention of primary teeth, even after the permanent teeth have erupted, is a consistent finding. This abnormality is revealed on panoramic x-ray views as double rows of retained primary teeth overlaying the permanent ones. Surgical extraction of the retained primary teeth is often necessary for healthy dentition. Children who have had their retained primary teeth extracted will have a normal eruption of their permanent teeth. 

Individuals with AR-HIES due to DOCK8 deficiency have characteristics similar to STAT3 deficiency such as eczema, skin abscesses caused by Staphylococcus aureus, recurrent respiratory infections, mucocutaneous candidiasis, and other fungal infections. However, those with DOCK8 deficiency are distinguished from those with AD-HIES by the lack of joint, bone, and teeth changes. They tend to have frequent occurrences of severe, recurrent viral infections not seen in those individuals with STAT3-LOF. Individuals with DOCK8 deficiency often have frequent outbreaks caused by herpes simplex virus (cold sores or other skin lesions), herpes zoster virus (shingles), human papillomavirus (HPV; difficult-to-treat warts), and molluscum contagiosum, a viral skin infection that causes round, firm, painless bumps that can occur on any part of the body.

Recurrent lung infections are common in DOCK8 deficiency, and they may also lead to chronic lung disease with damage to the airways (bronchiectasis) and lung tissues. However, cavitary lesions are not commonly seen in DOCK8 deficiency. DOCK8 deficiency is also associated with a higher incidence of pneumonia caused by the fungus Pneumocystis jirovecii. Liver disease can result from chronic infection with the parasite Cryptosporidia.

Asthma and allergies can be more severe in DOCK8 deficiency, including food allergies manifesting with anaphylaxis.

Vasculitis (inflammation within blood vessels) may occur in the brain blood vessels and in the main body vessels, such as the aorta. This may lead to a stroke, resulting in neurologic impairments.