Autosomal Recessive hyper-IgE Syndrome Research Articles

P27 Successful treatment of severe eczema and plane warts with Dupilumab in a child with Dedicator of Cytokinesis 8 (DOCK8) deficiency (Autosomal recessive form of hyper-IgE syndrome)

Abstract A six-year-old girl first presented with severe eczema at the age of 6 months, which was difficult to control with topical treatments. She was found to have severely elevated total IgE and multiple food allergies. Due to recurrent ear and chest infections, and persistent varicella zoster, she was screened for a primary immunodeficiency and found to have a homozygous exon 29-46 deletion in the DOCK8 gene. Her eczema remained challenging, with coalescing warts on her limbs. She started Methotrexate with an initial good response; however, the frequency of infections and hospitalizations increased. After the diagnosis of DOCK8 deficiency was confirmed, she started Dupilumab, resulting in the complete resolution of her eczema and warts. She is awaiting haematopoietic stem cell transplant (HSCT) . DOCK8 deficiency is an autosomal recessive hyper-IgE syndrome that presents early in life with severe eczema, skin abscesses, multiple food allergies, recurrent respiratory tract infections, and severe viral (including skin) infections. Older patients invariably develop bronchiectasis and are at high risk of malignancy. Patients have a combined immunodeficiency, with T-cell lymphopenia, reduced thymic output and T-cell skewing to a Th2 response. Children with this condition often present to dermatologists because of severe eczema, which is usually difficult to treat with standard topical treatments. The decision to treat with systemic immunosuppression is often challenging due to recurrent infections. Although HSCT is the curative treatment for DOCK8 deficiency, Dupilumab can be used to reduce inflammation and infections, and improve quality of life in patients awaiting HSCT.

Association of hyper IgE with herpetic viral encephalitis and ecthyma gangrenosum in a male Egyptian patient

There are two forms of hyper-immunoglobulin E syndromes (HIES): a dominant form (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3), and a recessive form (AR-HIES) is caused by mutations in dedicator of cytokinesis 8 (DOCK8). DOCK8 autosomal recessive hyper IgE syndrome (AR-HIES) patients have a more symptomatic neurologic disease than those with STAT3 deficiency. Involvement of the central nervous system in patients with HIES has been rarely reported. Being a rare primary immuno-deficiency, the disease may be underdiagnosed and under-reported. In the central nervous system abnormalities with definite neurologic manifestations, very few articles were published previously which may vary from hemiplegia to partial facial nerve paralysis in children and acute disseminated encephalomyelitis (ADEM), but viral encephalitis has not been reported. Herein, we describe a 21-year-old male with hyper-immunoglobulin E syndrome presented with fever, pneumonia, skin abscesses, and altered consciousness who proved to have herpetic viral encephalitis. The purpose of this study is to emphasize that neurologic complications with herpetic viral encephalitis may occur in patients with hyper IgE syndrome. In the case series, no cases of hyper IgE were described to have viral encephalitis, and to the best of our knowledge, this is the first description of herpes simplex encephalitis in a patient with hyper IgE syndrome.

A CASE OF DOCK8 DEFICIENCY TREATED WITH DUPILUMAB

<h3>Introduction</h3> Dedicator of cytokinesis 8 gene (DOCK8) deficiency is an immune disorder associated with autosomal recessive hyper-IgE syndrome, characterized by elevated IgE levels, atopic dermatitis, and predisposition to recurrent skin and lung infections. <h3>Case Description</h3> A 12-year-old male presented to Immunology clinic for DOCK8 deficiency. He was diagnosed in infancy due to diffuse papulopustular eruption positive for candidiasis and known family history. Past medical history included severe eczematous dermatitis, asthma, interstitial lung disease, food allergies, and poor growth, with cutaneous HSV and fungal infections, HSV keratitis, and MRSA bacteremia. Family history was notable for two siblings with DOCK8 deficiency, both deceased. Physical exam demonstrated severe generalized eczematous papules and plaques and intermittent coarse breath sounds. IgE ranged from 22.9–14,730 kU/L. Absolute eosinophil count fluctuated between 30–10,350 cells/mcL. Sequencing of the <i>DOCK8</i> gene revealed a novel 2 base pair deletion resulting in a frame shift mutation in exon 14 at codon 510. He was managed on weekly subcutaneous immunoglobulin replacement, prophylactic Bactrim and valacyclovir, and followed by Immunology, Dermatology, Pulmonology, and Ophthalmology. Family declined bone marrow transplantation. Due to the severity of his eczematous dermatitis, monthly dupilumab injections were initiated. Within a year, he reported significant improvement in cutaneous and respiratory symptoms, with increase in lung function from FEV1 of 32% to 63%. <h3>Discussion</h3> In patients with DOCK8 deficiency, hematopoietic stem cell transplantation is curative. For patients who are unable or unwilling to undergo or awaiting transplant, dupilumab is a treatment option for improvement of both cutaneous and respiratory manifestations.

Hyper-IgE syndrome caused by DOCK8 mutation with a tumour-like lesion of the lip: a case report

Autosomal recessive hyper-IgE syndrome caused by DOCK8 gene mutation is an immunodeficiency. However, the presentation of a tumour-like lesion of the lip in autosomal recessive hyper-IgE syndrome has not yet been reported. This article reports the case of a 20-year-old man with autosomal recessive hyper-IgE syndrome who presented with a tumour-like lesion of the lip, and hyperplasia and erosion of the gingiva. The clinical manifestations included coarse face and neck skin, a diffuse tumour-like lesion on the upper lip showing a reddish erosive nodular surface with yellowish-white exudation, erosive buccal mucosa, and severe periodontitis. The swollen gingival and palatal mucosa indicated nodular hyperplasia and redness with pseudomembrane. The patient had a significantly increased peripheral blood eosinophil count and serum IgE level and an abnormal T lymphocyte count. His oral lesions improved markedly after prednisolone acetate use and local symptomatic treatment for 2 years. However, the patient unfortunately died of a cerebral infection 6 months after the oral lesions had resolved. The novel features of the labial tumour-like lesion described here extend our understanding of the manifestations of autosomal recessive hyper-IgE syndrome.

CRISPR/Cas-Based Gene Editing Strategies for DOCK8 Immunodeficiency Syndrome.

Defects in the DOCK8 gene causes combined immunodeficiency termed DOCK8 immunodeficiency syndrome (DIDS). DIDS previously belonged to the disease category of autosomal recessive hyper IgE syndrome (AR-HIES) but is now classified as a combined immunodeficiency (CID). This genetic disorder induces early onset of susceptibility to severe recurrent viral and bacterial infections, atopic diseases and malignancy resulting in high morbidity and mortality. This pathological state arises from impairment of actin polymerization and cytoskeletal rearrangement, which induces improper immune cell migration-, survival-, and effector functions. Owing to the severity of the disease, early allogenic hematopoietic stem cell transplantation is recommended even though it is associated with risk of unintended adverse effects, the need for compatible donors, and high expenses. So far, no alternative therapies have been developed, but the monogenic recessive nature of the disease suggests that gene therapy may be applied. The advent of the CRISPR/Cas gene editing system heralds a new era of possibilities in precision gene therapy, and positive results from clinical trials have already suggested that the tool may provide definitive cures for several genetic disorders. Here, we discuss the potential application of different CRISPR/Cas-mediated genetic therapies to correct the DOCK8 gene. Our findings encourage the pursuit of CRISPR/Cas-based gene editing approaches, which may constitute more precise, affordable, and low-risk definitive treatment options for DOCK8 deficiency.

Hyper-Ig E syndrome in adult patient: a clinical case and a review of the literature

Hyper-Ig E syndrome (HIES) includes a rare group of primary immunodeficiency conditions with frequently recurrent lung and skin infections. The respiratory system is affected by acute and chronic bronchitis, otitis, recurrent pneumonia, pneumocele, pleurisy, severe and prolonged sinusitis. Cutaneous manifestations are presented with “cold abscesses” and eczema/dermatitis. A pathognomic feature for the syndrome is the increased level of serum Ig E. The etiology of HIES still remains unclear. HIES occurs sporadically or is inherited - as an autosomal dominant HIES or autosomal recessive HIES. The type of inheritance determines the variable clinical picture of the syndrome. The pathogenetic diversity, the absence of specific clinical criteria as well as the presentation of few or minor symptoms in some patients complicate the diagnosis. We report а clinical case of a sporadic hyper-Ig E syndrome in an adult man suffering from atopic dermatitis since childhood presented with recurrent bacterial, viral, fungal and protozoan infections of the respiratory tract, gastrointestinal tract, skin and mucosal surfaces. A brief review of the scientific literature is also included.

M189 DOCK8 DEFICIENCY PRESENTING AS MULTIFOCAL EBV-ASSOCIATED SMOOTH MUSCLE TUMORS

DOCK8 deficiency is a combined primary immunodeficiency (PID) that causes autosomal recessive hyper-IgE syndrome and is characterized by recurrent infections, atopy, and risk of autoimmunity and malignancy.[1] We report a case of EBV-associated smooth muscle tumors secondary to DOCK8 deficiency requiring allogeneic bone marrow transplant.

Inborn errors of immunity: Recent progress

Recent advances in the field of inborn errors of immunity (IEIs) have been wide in scope, including progress in mechanisms of disease, diagnosis, and management. New gene defects affecting the immune response continue to be reported, as many as 26 in the year 2020. It was noted that the presentation of IEIs might not include recurrent infections in 9% of cases, and that current diagnostic methods can identify molecular causes in 92% of patients with severe combined immunodeficiency. Progress in immunopathogenesis explained mechanisms leading to symptoms of autosomal-recessive hyper-IgE syndrome. There was an emphasis on research in primary antibody deficiencies. The benefit of antibiotic prophylaxis to reduce the frequency of infections was demonstrated in these patients. The regimen of rituximab and azathioprine or mycophenolate was proven effective for chronic granulocytic interstitial pneumonia. The efficacy and adverse events of hematopoietic stem cell transplant in different IEI conditions were reported, as well as different strategies to improve outcomes, supporting its use in immunodeficiency and immunodysregulatory syndromes. The recent pandemic of coronavirus disease 2019 affected patients with IEIs, in particular those with deficiency in the interferon-mediated activation of the immune response. Initial data suggest that coronavirus disease 2019 vaccines might elicit anti-coronavirus disease 2019-neutralizing antibody responses in some patients with IEI conditions.

Autosomal recessive hyper-IgE syndrome caused by DOCK8 gene mutation with new clinical features: a case report

BackgroundAutosomal recessive hyper-IgE syndrome (AR-HIES) caused by DOCK8 gene is a rare immunodeficiency disease, the main clinical manifestations include recurrent Eczema-like rash, skin and lung abscesses, accompanied with increased serum IgE level. Here, we report a 7-year-old Chinese girl with a new clinic features caused by DOCK8 gene mutations.Case presentationA 7-year-old girl was admitted to our hospital because of abnormal walking posture. The clinical manifestations of the patient included abnormal gait, eczema-like rash, fingertip abscess, high muscle tone, and facial paralysis. Among them, high muscle tone and facial paralysis are new clinic features which have not been reported previously. The blood eosinophils and serum IgE levels were significantly increased, and the lymphocyte subsets indicated a decrease of T lymphocytes. The magnetic resonance imaging (MRI) of her brain suggested myelin dysplasia and brain atrophy. Two novel compound heterozygous mutations (c.1868 + 2 T > C and c.5962-2A > G) of DOCK8 gene were identified by whole exome sequencing. By literature review, there are 11 mutations of DOCK8 gene in Chinese AR-HIES patients.ConclusionsTwo novel splice-site mutations(c.1868 + 2 T > C and c.5962-2A > G) of DOCK8 gene and new clinic features were found in a Chinese girl with AR-HIES, which extends our understanding of DOCK8 gene mutation spectrum and phenotype of AR-HIES in children.

Rare Case of Adult Onset DOCK8 Mutated Hyper Ige Syndrome

Background: Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immune deficiency characterized by the classic triad of recurrent skin boils, cyst-forming pneumonias, and extreme elevations of serum IgE. AD-HIES is classically associated with mutations in the signal transducer and the activator of the transcription 3 gene (STAT3) gene. To date, the majority of cases have been caused by de novo pathogenic variants. The dedicator of the cytokinesis 8 gene (DOCK8) has been identified as the cause of many cases with autosomal recessive hyper-IgE syndrome (AR-HIES). The autosomal dominant hyper-IgE syndrome is associated with a cluster of facial, dental, skeletal, and connective tissue abnormalities which are not observable in the recessive type. Here we present a rare case of a patient meeting criteria for AD-HIES but with DOCK8 p.R83Q mutation.Methods: Case study involving retrospective chart review from May 2015 to present.Clinical case: Patient is a 49 yo female with past medical history of moderate eczema, innumerable recurrent sinopulmonary infections, 4 episodes of pneumonia, mild scoliosis, 8 digital fractures with minimal trauma, 5 skin abcesses, recurrent vulvovaginal candidiasis, monthly urinary tract infections who presented to the emergency room in May 2015 with left facial paralysis and progressive paralysis in left upper and lower extremity associated with numbness. Physical examination revealed diffuse scaly pruritic rash, high palate, left facial droop, left sided upper and lower extremity weakness and numbness (Figure 1). MRI of the brain with contrast May 2015 showing scattered periventricular, subcortical and deep white matter FLAIR signal hyperintensities (Figure 2). CSF for viral, fungal, bacterial cultures, Cryptococcus, west nile, flow cytometry, protein electropheresis at that time was normal. She was found to have low IGG 579 mg/dL, normal IGA 191 mg/dL, IGM 111mg/Dl IGD 2.09 mg/dL, and increased IGE (297 IU/mL, currently 807 IU/mL, peak 1171 IU/mL). She had a complete negative workup for infections: Blood cultures, HIV, TB, EBV, CMV, HTLV-1&2, Colorado Tick Fever, Tropheryma Whipplei, Stongyloides, Schistosoma, Toxocara Abs, Ascaris, Plasmodium, Trichinella, Influenza A B, HSV, Hepatitis A B C, Echinococcues, West Nile virus, Cystercercosis, Lyme Disease, Syphilis, Amoebic cultures, Aspergillus, Mucormycosis. Stool was negative for ova & parasites, Shigella, Yersenia, Clostridium, Giardia, E. Coli, Trichome stain. Malignancy evaluation was negative including: CT brain, chest, abdomen, and pelvis, flow cytometry, protein electrophoresis, tumor markers, bone marrow biopsy and aspirate (figure 3), upper & lower endoscopy. Electrolytes, metal screen (arsenic, copper, lead, mercury, zinc), complete chemistries were negative. A complete autoimmune and allergy panel was negative. Immunology profile showed normal CBC (normal PLT size), low CH 50 of 38 U/mL, normal helper CD3% 78%, 1884 cell/mcL, elevated helper CD4% 68.5%, 1601 cell/mcL, low suppressor CD8% of 11% with normal absolute number 249 cell/mcL. IL 6 = 3.1 pg/mL, IL 10 =11.5 pg/mL, IL 12 was undetectable. Genetic analysis revealed normal NOTCH3, SPINK5, STAT3, TYK2 genes. A heterozygous mutation in DOCK8 p.Arg83Gln (R83Q) was discovered in this patient. Based on a clinical scoring system developed by the National Institutes of Health patient has features suggestive of AD-HIES (> 40 is cutoff, our patient scored 52). The patient has been receiving IVIG 40 grams IV every 3 weeks with clinical improvement in infectious symptoms but continued progression of neurological symptoms. Due to rarity of this case the patient is currently being referred to the NIH for further management.Conclusion: Here we present a rare adult onset case with the patient meeting criteria for AD-HIES and symptoms of DOCK8 AR-HIES harboring R83Q variant DOCK8. This patient may likely harbor an undiscovered mutation in another allele. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature

Serine/threonine kinase-4 (STK4) deficiency is an autosomal recessive combined immunodeficiency. We aimed to define characteristic clinical and laboratory features to aid the differential diagnosis and determine the most suitable therapy. In addition to nine STK4 deficiency patients, we reviewed 15 patients from the medical literature. We compared B lymphocyte subgroups of the cohort with age-matched healthy controls. In the cohort, median age at symptom onset and age at diagnosis were 6 years 8 months (range, 6-248 months) and 7 years 5 months (range, 6-260 months), respectively. The main clinical findings were infections (in all nine patients [9 of 9]), autoimmune or inflammatory diseases (7 of 9), and atopy (4 of 9). CD4 lymphopenia (9 out 9), lymphopenia (7 out 9), intermittent eosinophilia (4 out 9), transient neutropenia (3 out 9), low IgM (4 out 9), and high IgE (4 out 9) were common. Decreased recent thymic emigrants, naive and central memory T cells, but increased effector memory T cells were present. The increase in plasmablasts (P= .003) and decrease in switched memory B cells (P= .022) were significant. When 24 patients are analyzed, cutaneous viral infections (n= 20), recurrent pneumonia (n= 18), Epstein Barr virus-associated lymphoproliferation (n= 11), atopic dermatitis (n= 10), autoimmune cytopenia (n= 7), and lymphoma (n= 6) were frequent. Lymphopenia, CD4 lymphopenia, high IgG, IgA, and IgE were common laboratory characteristics. The differential diagnosis with autosomal recessive hyper-IgE syndrome is crucial. Because, atopy and CD4 lymphopenia are common in both diseases. Immunoglobulins, antibacterial, and antiviral prophylaxis are the mainstays of treatment. Clinicians may use immunomodulatory therapies during inflammatory or autoimmune complications. However, more data are needed to recommend hematopoietic stem cell transplantation as a safe therapy.

Treatment options for DOCK8 deficiency-related severe dermatitis.

Cutaneous manifestations of dedicator of cytokinesis 8 gene (DOCK8) deficiency, a combined type of T and B cell immunodeficiency, previously designated as autosomal recessive hyper IgE syndrome, includes dermatitis and skin infections. There are limited treatment options for dermatitis related to the syndrome. To describe a cohort of patients with DOCK8 deficiency with a focus on the treatment of their cutaneous manifestations. A retrospective study on all children with the genetic diagnosis of DOCK8 deficiency treated at the Sheba Medical Center between 1/1/2003 and 1/1/2021 was preformed. Collected data included: demographic features, family history, laboratory, genetic testing, skin manifestations, treatment, and disease course. Description of two cases of severe recalcitrant dermatitis treated with dupilumab is detailed. Nine children with a genetic diagnosis of DOCK8 deficiency were included, of whom six were girls (66%) with a median age of 8.5 (±2.2 SD) years. The median age at diagnosis was 2.8 (±2.6 SD) years. Six patients were born to consanguineous parents. Five out of six patients who received hematopoietic stem cell transplantation (HSCT) had a complete response, and one was recently transplanted. Of note, two patients, while awaiting HSCT, were treated with dupilumab for their severe dermatitis resulting in a marked improvement of the cutaneous manifestations and pruritus. Hematopoietic stem cell transplantation is the gold standard and most effective therapy for patients with DOCK8 deficiency. Dupilumab, a biological therapy indicated for atopic dermatitis and other Th2 derived dermatoses, is an excellent option for dermatitis in patients with DOCK8 deficiency and can be used as a bridge before HSCT. Larger studies are needed to confirm this observation.

ILC3 deficiency and generalized ILC abnormalities in DOCK8-deficient patients.

Dedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans. Peripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n=12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays. DOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls. DOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.

Autosomal recessive hyper‐IgE syndrome successfully treated with hematopoietic stem cell transplantation

Autosomal recessive hyper-IgE syndrome is a primary immunodeficiency that results from a mutation in the DOCK8 gene. We report a case of a patient presenting with severe eczema, atopy, and recurrent skin infections since the first months of life. The diagnosis of autosomal recessive hyper-IgE syndrome was made at the age of 7 by a positive DOCK8 genetic test. The patient underwent hematopoietic stem cell transplantation, with complete remission of the various manifestations.

Hyper IgE syndrome associated with novel and recurrent STAT3 mutations

Rationale:Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency presenting as two forms including autosomal dominant HIES (AD-HIES) and autosomal recessive HIES (AR-HIES), which are mainly caused by mutations in STAT3 and DOCK8, respectively. To date, only about 500 cases have been reported worldwide including 37 cases in China. The spectrum and prevalence of mutations and molecular pathogenesis in HIES remain poorly understood.Patient concerns:Here we reported two Chinese children presenting clinical manifestations of HIES.Diagnosis:Based on medical history, clinical manifestations, and laboratory findings, a diagnosis of HIES was made for both children. Targeted next-generation sequencing (NGS) identified a novel heterozygous deletion of 15 bp (c.1960_1974del, p.G654_D658del or alternatively c.1966_1980del, and p.G656_D660del), and a recurrent missense mutation (c.1144C>T, p.R382W) in STAT3 in the two patients, respectively.Interventions:The two patients have been given the successful treatment of skin infections with cefaclor.Outcomes:Both patients have been under follow-up for more than 6 months, with no signs of recurrent infections.Lessons:Our results extend the spectrum of STAT3 mutations associated with ADHIES and highlight the value of targeted NGS in confirming diagnosis of genetic disorders.

Neutrophil Functions in Immunodeficiency Due to DOCK8 Deficiency

ABSTRACTNeutrophil chemotactic defects have been reported previously in patients with hyper-IgE syndrome. Bi-allelic mutations in dedicator of cytokinesis 8 (DOCK8) gene usually cause an autosomal recessive hyper-IgE syndrome phenotype. Data are lacking about expression of DOCK8 protein in neutrophils or the possible role of DOCK8 in neutrophil function. We sought to determine if DOCK8 protein is expressed in neutrophils and if DOCK8 plays a role in neutrophil function. The expression of DOCK8 protein was assessed in neutrophils from healthy volunteers with and without activators. Neutrophil chemotaxis, phagocytosis and superoxide generation were studied in neutrophils from DOCK8-deficient patients compared to neutrophils from healthy controls before and after stimulation with activators: phorbol 12-myristate 13-acetate (PMA) or N-Formylmethionyl-leucyl-phenylalanine (fMLP). DOCK8 protein is expressed in resting neutrophils from healthy controls, with a significant increase in DOCK8 expression after stimulation. Neutrophil functions were assessed in 6 DOCK8-deficient patients. All patients had the same non-sense mutation (c.C5134A, p.S1711X). Normal chemotaxis was recorded in 4/6 patients while a mild to moderate chemotaxis defect was recorded in 2/6. Superoxide generation was mainly normal in neutrophils from all six patients and phagocytosis was normal in five patients tested. We conclude that DOCK8 protein is expressed in resting human neutrophils and DOCK8 expression is increased after stimulation with either PMA or fMLP. Most patients with a disease-causing mutation in DOCK8 have normal neutrophil functions, while a minority showed a mild to moderate chemotactic defect.

Clinical Diagnosis of Autosomal Recessive Hyper-IgE Syndrome: Report of Three Cases

Clinical Diagnosis of Autosomal Recessive Hyper-IgE Syndrome: Report of Three Cases

Phenotyping and long-term follow up of patients with hyper IgE syndrome

Introduction and objectivesLong-term follow up of patients with hyper IgE syndrome (HIES), as a primary immunodeficiency disorder, has been poorly investigated. This study describes common clinical and immunological features of patients with HIES in the last 10 years in Shiraz University of Medical Sciences, Shiraz, Iran. Methods and patientsIn this cross-sectional study, the symptoms and medical records of 18 patients, who were diagnosed with HIES, were observed. Genetic and immunologic study was also performed. ResultsEighteen patients with the mean age of 13 years old were investigated. Ten patients were detected to have mutations in DOCK8 gene and autosomal recessive HIES (AR-HIES); and four patients were found with STAT3 mutation and autosomal dominant HIES (AD-HIES). So, 14 patients with known genetic results were considered for further data analysis. Food allergy, eczema, viral and skin infections were the major complications of AR-HIES patients. The major clinical complications of AD-HIES patients were pneumonia, skin infections and eczema. Food allergy and viral infection were significantly higher in DOCK8 deficient patients. The most common causes of hospitalization in both AR-HIES and AD-HIES patients were pneumonia, skin infections and sepsis. The most common cause of death was found to be sepsis. ConclusionsAD-HIES and AR-HIES cannot be differentiated only based on the clinical presentations. Genetic features are also necessary for better diagnosis. This study, summarizing the clinical, immunological and genetic information of the patients with AD-HIES and AR-HIES, may open a way for better diagnosis and management of HIES.

Job Syndrome in a 9 Year Old Female

Hyper IgE Syndrome (HIES) is a rare primary immunodeficiency disease. Most of HIES cases are sporadic. Autosomal dominant HIES is caused by mutation in signal transducer and activator of transcription-3 (STAT-3). A number of mosaicism HIES has been reported that is associated with intermediate phenotype. Autosomal recessive HIES is due to mutation in Dock-8 or cytokinesis-8 and TYK-2 or tyrosine kinase-2. The common manifestations are atopic eczema, staphylococcal dermatitis, cellulitis and folliculitis (cold dermal abscesses that are not warm, painful and without redness), recurrent pneumonia and pulmonary abscesses, osteopenia and recurrent bone fracture. The diagnosis of standard HIES is based on clinica suspicion. There is no specific treatment for HIES. The treatment should be based on the prevention of developing infections. Prophylactic antibiotics such as cotrimoxazole and IVIG are administered. Hematopoietic stem cell transplantation was done for all types of HIES, but there is a little information and experience about the long term results of this therapy.

The clinical and laboratory spectrum of dedicator of cytokinesis 8 immunodeficiency syndrome in patients with a unique mutation.

Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency usually diagnosed as autosomal recessive hyper IgE syndrome. We sought to reveal the varying manifestations in patients with a unique mutation in DOCK8 gene by a retrospective medical record review. Ten patients from five consanguineous families and three tribes were included. Seven patients were homozygous for the c.C5134A, p.S1711X mutation, and the remaining three patients were their siblings manifesting hyper IgE syndrome features without a genetic diagnosis. Prior to the genetic diagnosis, the clinical diagnosis was "hyper IgE syndrome" in six patients and "anti-pneumococcal antibody deficiency," "recurrent pneumonia with bronchiectasis," and "asthma with hypereosinophilic syndrome" each diagnosed once. One additional patient was diagnosed due to family history. The age of presentation varied from 1 to 16months. Eczema was diagnosed in all patients, food allergies in three, and severe herpes keratitis or malignancy or autoimmunity in two patients. Elevated IgE was recorded in nine patients; however, in six patients, the initial serum IgE concentration was equal to or less than three times the normal concentration for age, and in these patients, the median age at IgE evaluation was 7.5months compared with 21.5months in patients with an initial IgE concentration above three times the normal concentration for age (P=0.067). The spectrum of disease manifestations in patients with a unique mutation in DOCK8 is variable. The genotype-phenotype correlations may be modified by genetic and/or epigenetic modifiers beyond the monogenic effect. Younger patients tend to have lower IgE concentrations at the initial measurement of IgE.