Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) is one of the causes of STAT3 hyperimmunoglobulin E (IgE) syndrome (STAT3-HIES), while gain-of-function (GOF) mutations in STAT3 lead to immune dysregulation diseases. We retrospectively analyzed the age, common clinical symptoms, immunologic and molecular manifestations in 11 patients with LOF STAT3 mutations and 1 patient with a GOF STAT3 mutation.Twelve patients were enrolled in our study. Serum immunoglobulin measurements, lymphocyte subset detection and whole-exome sequencing were performed.The median age at diagnosis of STAT3-HIES patients was 4.74 years. Eczema, recurrent respiratory infections, fevers, abscesses and Staphylococcus aureus infections were the classic manifestations. Elevated serum IgE levels are not always observed in conjunction with high eosinophil counts. A moderate viral DNA load was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common mutation site, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients achieved notable improvement after receiving intravenous immunoglobulin.We updated the current knowledge of this topic. We found an earlier median age at diagnosis, a higher survival rate, and a general lack of nonimmunological abnormalities; we also described the treatment details and novel mutations involve in STAT3-HIES and compared STAT3 LOF and GOF mutations.
We aimed to report the clinical and immunological characteristics of variant type X91+ chronic granulomatous disease (CGD) in a Chinese cohort.The clinical manifestations and immunological phenotypes of patients with X91+ CGD were collected. A dihydrorhodamine (DHR) analysis was performed to evaluate neutrophil function. Gp91phox protein expression was determined using extracellular staining with the monoclonal antibody (mAb) 7D5 and flow cytometry.Patients with X91+ CGD accounted for 8% (7/85) of all patients with CGD. The median age of onset in the seven patients with X91+ CGD was 4 months. Six patients received the BCG vaccine, and 50% (3/6) had probable BCG infections. Mycobacterium tuberculosis infection was prominent. The most common sites of infection were the lung (6/7), lymph nodes (5/7), and soft tissue (3/7). Two patients experienced recurrent oral ulcers. The stimulation index (SI) of the patients with X91+ CGD ranged widely from 1.9 to 67.3. The difference in the SI among the three groups of patients (X91+ CGD, X91- CGD, and X910 CGD) was statistically significant (P = 0.0071). The three groups showed no significant differences in onset age, diagnosis age, or severe infection frequency. CYBB mutations associated with X91+ CGD were commonly located in the second transmembrane or intracellular regions. Three novel X91+ CGD-related mutations (c.1462-2 A > T, c.1243C > T, and c.925G > A) were identified.Variant type X91+ CGD may result in varied clinical manifestations. Moreover, the laboratory findings might indicate a moderate neutrophil SI. We should deepen our understanding of variant X91+ CGD to prevent missed diagnoses.
Activated phosphoinositide 3 kinase (PI3K) -delta syndrome (APDS) is an inborn error of immunity with variable clinical phenotype of immunodeficiency and immune dysregulation and caused by gain-of-function mutations in PIK3CD. The hallmark of immune phenotype is increased proportions of transitional B cells and plasmablasts (PB), progressive B cell loss, and elevated levels of serum IgM. To explore unique B cell subsets and the pathomechanisms driving B cell dysregulation beyond the transitional B cell stage in APDS. Clinical and immunological data was collected from 24 patients with APDS. In five cases, we performed an in-depth analysis of B cell phenotypes and cultured purified naïve B cells to evaluate their survival, activation, Ig gene class switch recombination (CSR), PB differentiation and antibody secretion. We also analyzed PB differentiation capacity of sorted CD27-IgD- double-negative B (DNB) cells. The patients had increased B cell sizes and higher proportions of IgM+ DNB cells than healthy controls (HC). Their naïve B cells exhibited increased death, impaired CSR but relatively normal PB differentiation. Upon stimulation, patient's DNB cells secreted a similar level of IgG but a higher level of IgM than DNB cells from HC. Targeted therapy of PI3K inhibition partially restored B cell phenotypes. The present study suggests additional mechanistic insight into B cell pathology of APDS: (1) decreased peripheral B cell numbers may be due to the increased death of naïve B cells; (2) larger B cell sizes and expanded DNB population suggest enhanced activation and differentiation of naïve B cells into DNB cells; (3) the impaired CSR yet normal PB differentiation can predominantly generate IgM-secreting cells, resulting in elevated IgM levels.
Objective To identify variants in the coding sequence of PHOX2B and RET using Sanger sequencing in two independent neonates with congenital central hypoventilation syndrome (CCHS) and to evaluate genotype-phenotype relationships.Methods Genomic DNA samples were obtained from two CCHS neonates admitted to Department of Neonatology,Children's Hospital of Fudan University in January and August of 2013.The coding regions in PHOX2B and RET were screened using Sanger sequencing.Genotype-phenotype analysis was performed on the basis of extensive literature search.Results Two male patients with CCHS were included in this study.Case 1 was a premature newborn with asphyxia at birth who showed subsequent ventilator dependence and abdominal distension.Hirschsprung disease was confirmed by surgery.Despite active treatment the patient died.Case 2 was a mature newborn who had multiple episodes of cyanosis and showed ventilator dependence.DNA sequencing demonstrated a heterozygous 38 bp deletion within exon 3 from bp 722-759 of the coding region [non-polyalanine repeat expansion mutations (NPARMs) ; genotype c.722_759het_del] in Case 1 and a heterozygous 21 bp polyalanine repeat expansion mutation (PARMs; genotype c.776_777het_dup) in Case 2.A homozygous c.1296 A＞G nucleotide change in RET was detected in both patients which was a common single nucleotide polymorphism (rs1800860).Following a literature review,mutations in PHOX2B were identified in 670 patients with CCHS.Over 90％ of CCHS cases were heterozygous for polyalanine expansion repeat mutations.The remaining patients with a CCHS phenotype were heterozygous for non-polyalanine expansion repeat mutations.Conclusions CCHS may be characterized by ventilator dependence in the neonatal period.Some of CCHS patients are likely to develop Hirschsprung disease.Symptoms of autonomic nervous system dysregulation such as diminished heart rate variability,esophageal dysmotility,and reduced basal body temperature may be atypical.The type of PHOX2B mutation and the length of PARMs determine the severity of CCHS.Patients with NPARMs show a more severe phenotype.Hirschsprung disease is more prevalent in cases with NPARMs.Individuals with genotypes from 20/27 to 20/33 often require continuous ventilatory support,especially as the expanded allele becomes larger.Genetic testing can not only provide evidence for definite diagnosis,but also guide treatment.
Key words:
Sleep apnea, central; Hypoventilation; Genetic association studies
Abstract Purpose: We aimed to report the clinical and immunological characteristics of variant type X91 + CGD in a Chinese cohort. Methods: The clinical manifestations and immunological phenotypes of X91 + CGD patients were collected. Dihydrorhodamine (DHR) analysis was performed to evaluate neutrophil function. Gp91 phox protein expression was determined by flow cytometry-based extracellular staining with the monoclonal antibody (mAb) 7D5. Results: X91+CGD patients accounted for 8% (7/85) of all patients with GCD. The median onset age in the 7 X91 + CGD patients was 4 months. Six patients received the same BCG vaccine strain, and three had probable BCG infections. Moreover, 4 patients were highly suspected of having Mycobacterium tuberculosis infection. Recurrent infections of the lungs and soft tissues (3/7) were the most common symptoms. Two patients had noninfectious recurrent oral ulcers and received interferon gamma (IFN-γ) treatment afterward. In our cohort, the stimulation index (SI) of the 7 X91 + CGD patients ranged widely from 1.9 to 67.5, while the SI ranged from 1.2 to 35.7 in patents with X91 0 CGD. The level of SI between these two groups was statistically significant (P<0.05). CYBB mutations associated with X91+CGD were usually located in or near the FAD and NADPH binding domains. Three new X91+ CGD related mutations (c.1462-2 A>T, c.1243C>T and c.925G>A) were identified. Conclusions: Variant type X91 + CGD may have varied severities of clinical manifestations. Moreover, the laboratory findings of X91 + CGD could present with a moderate neutrophil stimulation index. We should deepen our understanding of the X91 + variant CGD to prevent missed diagnosis.
Abstract Congenital hyperinsulinism ( CHI ) has been mostly associated with mutations in seven major genes. We retrospectively reviewed a cohort of 32 patients with CHI . Extensive mutational analysis ( ABCC 8 , KCNJ 11 , GCK , GLUD 1 , HADH , HNF 4A, and UCP 2 ) was performed on Ion torrent platform, which could analyze hundreds of genes simultaneously with ultrahigh‐multiplex PCR using up to 6144 primer pairs in a single primer pool and address time‐sensitive samples with single‐day assays, from samples to annotated variants, to identify the genetic etiology of this disease. Thirty‐seven sequence changes were identified, including in ABCC 8 / KCNJ 11 ( n = 25, 65.7%), GCK ( n = 2), HNF 4A ( n = 3), GLUD 1 ( n = 2), HADH ( n = 4), and UCP 2 ( n = 1); these mutations included 14 disease‐causing mutations, eight rare SNP s, 14 common SNP s, and one novel mutation. Mutations were identified in 21 of 32 patients (65.6%). Among the patients with an identified mutation, 14 had mutations in ABCC 8 , one of which was combined with a GLUD 1 mutation. Four patients had mutations in KCNJ 11 , 1 had a GCK mutation, 1 had a mutation in HADH , and two had a mutation in HNF 4A . Among the 32 patients, the age at the onset of hyperinsulinemia ranged from the neonatal period to 1 year of age; five patients underwent a pancreatectomy due to intractable hyperinsulinemia. This study describes novel and previously identified mutations in patients with CHI . The spectrum of mutations in CHI patients represents an important tool for the diagnosis and prognosis of CHI patients in the Chinese population as well as for the genetic counseling of CHI families.
Abstract Background: Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) is one of the causes of STAT3 hyperimmunoglobulin E (IgE) syndrome (STAT3-HIES), while gain-of-function (GOF) mutations in STAT3 lead to immune dysregulation diseases. We retrospectively analyzed the age, common clinical symptoms, immunologic and molecular manifestations in 11 patients with LOF STAT3 mutations and 1 patient with a GOF STAT3 mutation. Methods: Twelve patients were enrolled in our study. Serum immunoglobulin measurements, lymphocyte subset detection and whole-exome sequencing were performed. Results: The median age at diagnosis of STAT3-HIES patients was 4.74 years. Eczema, recurrent respiratory infections, fevers, abscesses and Staphylococcus aureus infections were the classic manifestations. Elevated serum IgE levels are not always observed in conjunction with high eosinophil counts. A moderate viral DNA load was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common mutation site, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients achieved notable improvement after receiving intravenous immunoglobulin. Conclusion: We updated the current knowledge of this topic. We found an earlier median age at diagnosis, a higher survival rate, and a general lack of nonimmunological abnormalities; we also described the treatment details and novel mutations involve in STAT3-HIES and compared STAT3 LOF and GOF mutations.
Abstract Background: Loss-of-function (LOF) mutation in signal transducer and activator of transcription 3 (STAT3) was one of the causes of the hyper immunoglobulin E (IgE) syndrome (HIES), while gain-of-function mutation (GOF) in STAT3 leads to immune dysregulation diseases. We retrospectively report 11 LOF STAT3 patients and 1 GOF STAT3 patient and illustrate their onset age, common clinical symptoms, immunologic and molecular manifestation. Methods: 12 patients were enrolled in our study. Serum immunoglobulins, lymphocyte subset detection and whole-exome sequencing were performed. Results: The median onset age of STAT3-deficient patients was 1.89 years. Eczema, recurrent respiratory infection, apparent fever, abscesses and Staphylococcus aureus infection was the classical manifestation. Elevated serum IgE level is not entirely unanimous with high eosinophils counts. Moderate viral DNA was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common spot, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients obtained a notable improvement after received intravenous immunoglobulin (IVIG). Conclusion: We believe IVIG may help reduce the opportunity of infection in STAT3-deficient patients. Significant variance at onset age probably is a great challenge for clinicians and urgently needs early diagnosis and treatment.
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