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Hyper Ige Syndromes and DOCK8 Forms of HIES Table 20:1 Immune Deficiency Foundation Patient & Family Handbook For Primary Immunodeficiency Diseases Chapter 20 Immune Deficiency Foundation Patient & Family Handbook For Primary Immunodeficiency Diseases 6th Edition The development of this publication was supported by Shire, now Takeda. 110 West Road, Suite 300 Towson, MD 21204 800.296.4433 www.primaryimmune.org [email protected] Chapter 20 Hyper IgE Syndromes (HIES): STAT3 Loss of Function, DOCK8 Deficiency and Others Alexandra Freeman, MD, National Institutes of Health, Bethesda, Maryland, USA Jennifer Heimall, MD, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Hyper IgE Syndromes (HIES) are rare forms of primary immunodeficiency diseases (PI) characterized by recurrent eczema, skin abscesses, lung infections, eosinophilia (high numbers of eosinophils in the blood), and high serum levels of immunoglobulin E (IgE). Although initially described as two forms, with autosomal dominant (AD) and autosomal recessive (AR) inheritance, we now recognize that these are two distinct diseases caused by different genetic causes, with the two most common being from harmful mutations in STAT3 causing loss of function (STAT3-LOF) and DOCK8. These diseases share overlapping clinical and laboratory features; however, they also exhibit distinct clinical symptoms, disease courses, and outcomes. In addition, several other genetic variants have since been described to present with similar symptoms. History Clinical Presentation STAT3-LOF was described first as Job Syndrome STAT3 Deficiency in 1966 in two girls with many episodes of STAT3 Deficiency, is associated with heterozygous pneumonia, eczema-like rashes, and recurrent skin loss of function mutations in the transcription factor boils. These boils were remarkable for their lack STAT3. This is the more common form of HIES in of surrounding warmth, redness or tenderness, the U.S. It commonly presents with skin findings and were so called cold abscesses. In 1972, including newborn rash, eczema, and recurrent the syndrome was refined and clarified upon. It staphylococcal skin abscesses as well as ear, sinus, found similar infectious problems in two boys and lung infections. The lung infections often result who also had a distinctive facial appearance and in cavitary lesions in the lungs (pneumatoceles). extremely elevated IgE levels. Following this Other common infections in STAT3 deficiency report, elevated IgE was found in the two girls include mucocutaneous candidiasis (Candida from the initial report, showing that Job Syndrome fungus on mucous membranes and/or skin), and Buckley Syndrome represented the same manifesting typically as thrush, vaginal candidiasis condition. In 2007, a heterozygous mutation in or candidal nail infection (onychomycosis), the gene encoding the transcription factor STAT3 and recurrent shingles outbreaks. Additional was found to underlie most cases of AD-HIES. In findings include connective tissue and skeletal 2009 mutations and deletions in the DOCK8 gene abnormalities, such as a typical facial appearance, were found to underlie many patients with similar hyper-extensibility of joints, retained primary teeth, symptoms inherited in an AR fashion. recurrent bone fractures with minimal trauma, and 96 Chapter 20: Hyper IgE Syndromes and DOCK8 Forms of HIES Table 20:1 Causative Syndrome Symptoms Gene High IgE, High Eosinophils, Severe Eczema, Skin “Autosomal dominant HIES” infections (boils). Mucocutaneous Candidiasis. STAT3 Deficiency (Job’s Syndrome) Minimal Trauma Fractures, Retained Primary Teeth, Scoliosis High IgE, High Eosinophils, Severe Eczema, Skin infections (boils). Mucocutaneous Candidiasis. ZNF341 Deficiency ZNF341 Minimal Trauma Fractures, Retained Primary Teeth, Scoliosis High IgE, High Eosinophils, Severe Eczema, Skin Autosomal recessive infections (boils). Mucocutaneous Candidiasis. IL6ST GP130 deficiency Minimal Trauma Fractures, Retained Primary Teeth, Scoliosis High IgE, High Eosinophils, Severe Eczema, Skin Autosomal recessive IL-6 infections (boils). Mucocutaneous Candidiasis. IL6R receptor deficiency Minimal Trauma Fractures, Retained Primary Teeth, Scoliosis High IgE, High Eosinophils, Severe Eczema, Skin Autosomal recessive HIES infections (boils), Mucocutaneous Candidiasis, DOCK8 DOCK8 deficiency Warts, Herpes Viridae infections, Malignancy, Severe Food Allergies High IgE, Severe Eczema, Sinopulmonary Autosomal recessive Infections, Herpes Viridae infections, Malignancy, PGM3 PGM3 deficiency Severe Food Allergies, Asthma, Neurocognitive Delays, Scoliosis High IgE, High Eosinophils, Severe Eczema, Dominant negative CARD11 Pulmonary Infections, Molluscum, Food allergies CARD11 deficiency and Asthma High IgE, High Eosinophils, Severe Eczema, “Bamboo Hair”, Recurrent sinopulmonary Comel-Netherton Syndrome SPINK5 infections, Enteropathy, Allergies (Food Allergy, asthma, allergic rhinitis) High IgE, High Eosinophils, Severe Eczema, Warts (HPV and molluscum), Herpes Viridae infections, CARMIL2 Deficiency CARMIL2 Eosinophilic GI Disease, Inflammatory Bowel Disease, Asthma/Bronchiectasis, EBV associated malignancy IDF Patient & Family Handbook 97 a propensity to aneurysm formation of brain and fractures from seemingly insignificant trauma, and cardiac blood vessels. Severe allergic diseases, such bone density may be reduced. Scoliosis is common as food allergies, are not common in individuals with and typically emerges during adolescence or later in STAT3 Deficiency. However, they often have positive life. Craniosynostosis, fused skull bones, and extra/ skin prick tests making it appear that they have abnormally formed ribs or vertebrae are also found significant allergies. more often in those with AD-HIES than in the general population. These skeletal abnormalities are not A newborn rash or eczema is frequently the first usually seen in individuals with DOCK8 deficiency. manifestation of AD-HIES. Pustular and eczema-like rashes usually begin within the first month of life, first Abnormalities affecting dentition are another affecting the face and scalp. Skin abscesses are a common feature of AD-HIES with STAT3 mutations. classic finding in this disorder, caused by a particular Retention of primary teeth even after the permanent susceptibility to infections with Staphylococcus teeth have erupted is a consistent finding. This aureus. The degree of inflammatory symptoms, such abnormality is revealed on panoramic x-ray views as tenderness and warmth, often is quite variable. as double rows of retained primary teeth overlaying The term cold abscesses is applied to those lesions the permanent ones. Surgical extraction of the that lack external signs of inflammation despite retained primary teeth is often necessary for healthy the presence of pus. The occurrence and severity dentition. Children who have had their retained of these abscesses is substantially decreased primary teeth extracted will have normal eruption of with prophylactic therapy with antibiotics against their permanent teeth. Staphylococcus aureus. Deep tissue abscesses, such as liver or bone infections, are much less common in AD-HIES. DOCK8 Deficiency Individuals with AR-HIES due to DOCK8 deficiency Recurrent bacterial pneumonias are often have characteristics similar to STAT3 deficiency encountered in individuals with AD-HIES. in that they have eczema, skin abscesses caused Pneumonias typically start in childhood and are by Staphylococcus aureus, recurrent respiratory most frequently caused by Staphylococcus aureus, infections, mucocutaneous candidiasis and other Streptococcus pneumoniae, and Haemophilus fungal infections. However, those with DOCK8 influenzae. Similar to the occurrence of cold skin deficiency are distinguished from those with AD- abscesses, these pneumonias may present with HIES by the lack of joint, bone, and teeth changes. fewer symptoms than would be expected in a person They tend to have frequent occurrence of severe, with intact immunity. This relative lack of symptoms recurrent viral infections not seen in those individuals and subsequent delay in clinical presentation may with STAT3-LOF. Individuals with DOCK8 deficiency contribute to advanced disease and significant often have frequent outbreaks from Herpes simplex tissue damage before identification and initiation (cold sores or other skin lesions) and Herpes zoster of appropriate therapy. Infection-induced tissue (shingles), and difficult to treat warts, like Human destruction in individuals with AD-HIES may give Papillomavirus (HPV), and Molluscum contagiosum rise to pneumatocele formation, large cavities in the a viral skin infection that causes round, firm, painless lung, which is a distinguishing feature of AD-HIES bumps that can occur on any part of the body. due to STAT3 deficiency. When pneumatoceles or bronchiectasis are present in the lungs, the Recurrent lung infections are common in DOCK8 individuals are more susceptible to lung infections deficiency, and they may also lead to chronic lung with other bacteria such as Pseudomonas and molds disease with damage to the airways (bronchiectasis) such as Aspergillus. and lung tissues. However, cavitary lesions are not commonly seen in DOCK8 deficiency. DOCK8 Involvement of both the connective and skeletal deficiency is also associated with a higher incidence tissues is an important feature of STAT3 deficiency. of pneumonia caused by the bacteria Pneumocystis An asymmetrical facial appearance with prominent jirovecii. Liver disease can result from chronic forehead and chin, deep-set eyes,
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