Clinical Features and Genetic Analysis of Autosomal Dominant and Recessive Hyperimmunoglobulin E Syndrome / 罕见病研究

  Objective  To summarize the clinical and genetic features of children with autosomal dominant and recessive hyperimmunoglobulin E syndrome (HIES).  Methods  HIES patients were studied at the dermatology department of Beijing Children's Hospital, Capital Medical University were collected, from January 2013 to December 2021, diagnosed by both clinical manifestation and genetic assessment. The general data were summarized, the clinical and genetic characteristics were analyzed, and the similarities and differences between autosomal dominant HIES (AD-HIES) and autosomal recessive HIES (AR-HIES) were compared.  Results  A total of 7 children with HIES were studied, including 3 cases of AD-HIES and 4 cases of AR-HIES. There were 4 males and 3 females. All children had recurrent eczema-like lesions, recurrent skin and pulmonary infections, and elevated serum IgE and eosinophil levels. The differences between AD-HIES and AR-HIES mainly include: the main cutaneous infection in 3 children with AD-HIES were bacterial infections (such as abscess and impetigo), while in 4 children with AR-HIES, cutaneous infections were mostly severe viral infection (such as verruca vulgaris and molluscum contagiosum). There were pulmonary parenchymal changes (such as pneumatoceles, cyst and atelectasis) in 3 children with AD-HIES, whilst there were no similar changes in the lungs of 4 children with AR-HIES; 75% of children with AR-HIES had allergic diseases (including asthma and food allergy), while there were no reports of allergic diseases in children with AD-HIES. As for manifestations outside of immune system, AD-HIES was more likely to appear facial dysmorphism(such a broad nasal bridge and a high-arched palate). Furthermore, the incidence of tumor in AR-HIES was higher than that in AD-HIES. AD-HIES was mainly caused by the mutation of STAT3 gene, and AR-HIES was mainly caused by the mutation of DOCK8 gene. We reported two new mutation sites of DOCK8 gene c.1798-2A > T and c.874G > A in two cases, respectively.  Conclusions  For children with clinical manifestations of recurrent eczema-like lesions, repeated infection and significant increase in serum IgE levels, HIES should be suspected, and genetic screening should be carried out to make definite diagnosis and classification, to achieve better long-term management and improve prognosis.

Hyper IgE syndromes: clinical and molecular characteristics / 国际儿科学杂志

Hyper IgE syndromes(HIES)comprise a group of rare primary immunodeficiency disorders characterized by a triad of atopic dermatitis, recurrent skin and lung infections along with elevated IgE levels.According to clinical and molecular characteristics, HIES can be classified into 2 types: autosomal dominant HIES(AD-HIES)and autosomal recessive HIES(AR-HIES). At present, STAT3, DOCK8, IL6ST and ZNF341 are included in OMIM database.AD-HIES, caused by STAT3 mutations, can present multiple systemic clinical symptoms and even lead to the development of pulmonary structural abnormalities including pneumatoceles and bronchiectasis.AR-HIES, caused by DOCK8, IL6ST or ZNF341 mutations, often present with severe fungal, bacterial or viral infections.Neurologic manifestations are frequent complications, such as vasculitis, hemangioma and cerebral infarction.The mortality rate is high.There is no specific index for the clinical diagnosis of HIES, and the final diagnosis still needs to be combined with genetic diagnosis.This article reviews the above genes and their possible pathogenesis.

Hyper IgE syndromes: clinical and molecular characteristics / 国际儿科学杂志

Hyper IgE syndromes (HIES) comprise a group of rare primary immunodeficiency disorders characterized by a triad of atopic dermatitis,recurrent skin and lung infections along with elevated IgE levels.According to clinical and molecular characteristics,HIES can be classified into 2 types:autosomal dominant HIES (AD-HIES) and autosomal recessive HIES (AR-HIES).At present,STAT3,DOCK8,IL6ST and ZNF341 are included in OMIM database.AD-HIES,caused by STAT3 mutations,can present multiple systemic clinical symptoms and even lead to the development of pulmonary structural abnormalities including pneumatoceles and bronchiectasis.AR-HIES,caused by DOCK8,IL6ST or ZNF341 mutations,often present with severe fungal,bacterial or viral infections.Neurologic manifestations are frequent complications,such as vasculitis,hemangioma and cerebral infarction.The mortality rate is high.There is no specific index for the clinical diagnosis of HIES,and the final diagnosis still needs to be combined with genetic diagnosis.This article reviews the above genes and their possible pathogenesis.

Clinical manifestations of different types of gene mutations in hyper-IgE syndrome / 国际儿科学杂志

Hyper-IgE syndrome (HIES)is a complex primary immunodeficiency characterized by extremely high serum IgE levels, while presented a normal level of other immunoglobulins (IgG, IgA and IgM).Recent studies demonstrated that gene mutations, namely STAT3,Tyk2 or DOCK8 gene mutations, are the main mechanism of HIES.The clinical manifestations in HIES are significantly different in patients with different gene mutation.Therefore, investigation of the clinical manifestations caused by various gene mutations is very important, because it is beneficial not only for the clinical diagnosis and therapeutic evaluation, but also for scientific research.

Inmunodeficiencia combinada con compromiso cutáneo asociada a mutación en DOCK8 / Combined immunodeficiency with cutaneous manifestations associated with DOCK8 mutation

Diferentes inmunodeficiencias primarias se caracterizan por niveles elevados de IgE e infecciones cutáneas de origen viral. Describimos el caso de un niño de 2 años y 8 meses de edad, con inmunodeficiencia combinada, dermatitis y molusco contagioso diseminado. El paciente presentaba niveles aumentados de IgE, eosinofilia y marcada linfopenia a predominio de TCD8. Se encontraron alteraciones en los ensayos funcionales por cultivo y en la respuesta a la vacunación. Resultados normales de la proteína ZAP-70, funcionalidad NK y niveles de HLA I, tendientes a verificar alteraciones cuantitativas y funcionales de las células citotóxicas, llevaron a la sospecha de deficiencia en el gen DOCK8. El resultado positivo del estudio molecular, junto con las características clínicas e inmunológicas del paciente, confirmaron el diagnóstico de esta nueva inmunodeficiencia, que, de acuerdo con nuestro conocimiento, sería el primer caso diagnosticado en un hospital pediátrico en nuestro país.

Different primary immunodeficiencies present increased levels of IgE and cutaneous infections of viral etiology. We report a case of a 2 y, 8 m old boy with combined immunodeficiency, dermatitis and disseminated molluscum contagiosum. The patient presented high titers of IgE, eosinophilia and pronounced TCD8 lymphopenia. Impaired proliferation assays and abnormal antibody response to vaccination were found. Normal results of ZAP-70 protein, NK function, and HLA I levels, to test quantitatives and functional defects of cytotoxic cells, lead us to suspect a mutation in DOCK8 gene. Positive result in molecular study together with clinical and immunology features in the patient confirmed the diagnosis of this new immunodeficiency, being to the authors ́ knowledge the first case recorded in a paediatric hospital in our country.