Clinical Features And Molecular Diagnosis Of Hyperimmunoglobulin E Syndrome

Background: Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency disease with the presentation of recurrent staphylococcal and fungal infections, remarkably high serum IgE levels and eosinophilia. Autosomal dominant Hyper-IgE syndrome (AD-HIES) and autosomal recessive Hyper-IgE syndrome (AR-HIES) are two different forms of HIES that divided by inherited manner, clinical status and molecular basis. Most of the cases reported in the literature were AD-HIES and sporadic, patients manifest immune, skeletal and connective tissue abnormalities. In 2007, signal transducers and activator of transcription 3 (STAT3) mutations were found to be the cause of AD-HIES, and patients showed extremely low or absent T help 17 cells (Th17) in their peripheral blood, leading patients vulnerable to pathogens like Staphylococcus aureus and candida albicans. Clinical diagnosis is made according to the NIH scoring system if total score is higher than the suggested diagnostic cutoff of 40 points. In mainland China, there are only few case reports of HIES, so misdiagnosis and mistreatment always occur due to lack of experience. In this study, we analyzed clinical data and molecular diagnosis of 5 HIES cases in our hospital from March 2007 to July 2009 in order to arouse awareness among clinician and improve diagnosis and treatment level.Objective:1. To investigate the clinical features of HIES children in our cohort.2. To analyze Th17 cells count in peripheral blood of our cohort for differential diagnosis, further genetic diagnosis, treatment and evaluating prognosis.3. Genetic diagnosis has provided valuable evidences for identification of HIES patients and genetic counseling in HIES families.Methods:1. To analyze the clinical data of 5 HIES cases by NIH scoring system.2. Th17 cell numbers from CD4+T cells of peripheral blood PBMCs of HIES patients were deteced by Flow cytometry.3. The STAT3 gene of peripheral blood cells from patients was analyzed by PCR-directed sequencing.4. The STAT3 gene polymorphism from 50 healthy controls was analyzed by PCR-directed sequencing.5. The diversity of mRNA transcriptional product of the STAT3 gene in one patient was analyzed by T-A cloning.Results:1. Clinical feature Of the 5 patients, 4 were males and 1 was female. The onset age revealed early at 3 days after birth to 2 years, the average age of onset was 6 months. The initial symptoms in 4 patients were cutaneous manifestations (2 of them were newborn rash, 2 of them were eczema) and in 1 patient were abscesses of skin and internal organs. All patients had recurrent eczema and pneumonia, particularly high serum IgE levels and eosinophilia. NIH scores of them were 60,48,72,48, 45 points respectively. Patients present diverse clinical status in this group: patient 1 presented recurrent Staphylococcus aureus pneumonia and complications (lung abscess, pneumatoceles and pneumothorax) which were life-threatening; the features in patient 2 were recurrent Staphylococcus aureus"cold abscesses"and mucocutaneous fungal infections; while in patient 3, he manifested not only recurrent Staphylococcus aureus pneumonia and complications, but also mucocutaneous fungal infections; the condition in patient 4 was recalcitrant eczema and gingival hyperplasia without Staphylococcus aureus and fungal infections; predominant feature of patient 5 was recurrent skin and internal abscesses, plus severe bronchiectasis that leading to hemoptysis that may the cause of death. There were all sporadic cases in this group, three are well followed-up, one patient didn't follow the doctor's advice and receive treatment, then suffered pneumatocele again, one patient deceased.2. Th17 cell numbers from CD4+T cells of peripheral blood PBMCsThe proportion of Th17 cells in CD4+ T cells was tested in 3 patients. Th17 cell numbers in patients 1 and 2 were 0.03% and 0.13% respectively, virtually absent compared with a healthy control (0.69%), Th17 cell numbers in patient 4 were 0.53 %, almost normal compared with healthy donors. (n=18, mean Th17 numbers was 0.598%, with a range of 0.224% to 0.972%). The samples of other two patients were not available for testing.3. Gene analysisThree STAT3 heterozygous mutations were identified in patients 1-3, including a novel mutation (T620S) and two hotspot mutations (V637M and R382Q), whereas patients 4 and 5 had no mutation in coding region of the STAT3 gene. The father of patient 1 and the parents of patient 2 did not have the same STAT3 gene mutation of their children.Conclusions:1. The five cases in our cohort were diagnosed as HIES based on their NIH score higher than 40 points, HIES patients present multisystem disorder especially defects in immune system. Typical AD-HIES patients suffer rare Staphylococcus aureus infestions (pneumatoceles that not localized and skin cold abscesses) and mucocutaneous fungal infections, extremely elevated serum IgE level and eosinophilia are the main laboratory characteristics. Prognosis is good for those patients who were diagnosed early and receive active prophylactic treatment.2. Most of the patients in 3 typical AD-HIES cases showed Th17 defiency, thus Th17 cell count is a key molecular parameter to HIES diagnosis.3. A novel and two hotspot mutations in the STAT3 gene were identified in 3 typical AD-HIES cases, they were all a single one allele missense mutations on one chromosome in the STAT3 gene.4. Our data suggested: NIH score above 40 points should be highly suspected as HIES, but not all such HIES cases bear STAT3 mutations, those whose NIH score more than 40 points associate with Th17 cell numbers strikingly deceased probably had STAT3 mutation.