X-linked hyper IgM syndrome: a novel sequence variant associated with an atypical mild phenotype

X-linked hyper IgM syndrome is associated with abnormalities in the gene encoding CD40 ligand (CD40LG). A typical phenotype evolves during infancy in affected males. This phenotype includes neutropenia, dysgammaglobulinemia, bacterial sinopulmonary infections, and opportunistic infections. In the absence of the typical phenotypic features, clinicians must maintain a high level of suspicion for X-linked hyper IgM syndrome. We describe a unique hemizygous CD40LG mutation which was discovered in a 12-year-old boy with chronic severe neutropenia, a normal IgG level, and absence of sinopulmonary or opportunistic infections. The clinical implications of this mutation and associated atypical phenotype are discussed.     

The hyper IgM syndrome--an evolving story

The hyper IgM syndromes (HIGM) are a group of primary immune deficiency disorders characterized by defective CD40 signaling by B cells affecting class switch recombination and somatic hypermutation. As a consequence, patients with HIGM have decreased concentrations of serum IgG and IgA and normal or elevated IgM, leading to increased susceptibility to infections. The most common HIGM syndrome is X-linked and due to mutations of CD40 ligand (CD40L) expressed by activated CD4(+) T lymphocytes. Four other genes, expressed by B cells, have been associated with the HIGM phenotype. Mutations of CD40, the receptor for CD40L, cause a rare autosomal form of HIGM with a clinical phenotype similar to CD40L deficiency. Mutations of Activation-Induced Cytidine Deaminase (AICDA) and Uracil (DNA) Glycosylase (UNG), both expressed by follicular B lymphocytes, lead to defective class switch recombination and somatic hypermutation. Mutations of Nuclear Factor kappa B Essential Modulator (NEMO), an X-chromosome associated gene, result in hypohidrotic ectodermal dysplasia and immune deficiency. Thus, the molecular definition of these rare primary immune deficiency disorders has shed light on the complex events leading to the production of high-affinity, antigen-specific antibodies of different isotypes.     

Hyper IgM syndrome: the other side of the coin.

The hyper IgM syndrome is a rare, inherited immune deficiency disorder resulting from defects in the CD40 ligand/CD40-signaling pathway. X-linked hyper IgM is caused by defects in the CD40 ligand gene that prevent it from delivering an activation signal to antigen-presenting cells via CD40. Over the past year, defects in molecules involved in CD40 signaling have been shown to cause other forms of hyper IgM. These newly identified defects emphasize the importance of interaction between CD40 and its ligand in immunity and the role of these molecules in the pathogenesis of immune deficiency. With genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitively, to perform genetic screening, and to delineate the clinical manifestations of this syndrome. Further research may lead to novel and definitive therapeutic options for patients with hyper IgM syndrome.     

Study of patients with Hyper-IgM type IV phenotype who recovered spontaneously during late childhood and review of the literature

Hyper-IgM syndromes are characterized by normal or elevated serum IgM levels with the absence or reduced levels of other immunoglobulins. There are some patients with defective class-switch recombination (CSR) who do not have CD40L, CD40, AID, and UNG defects. The aim of this study is to determine the B-cell functions of patients with Hyper-IgM type 4 phenotype. Ten patients (seven males and three females) 84.2 ± 16.5 months of age with initial low serum IgG and IgA and high or normal IgM levels were included. Clinically, 50% had recurrent upper respiratory tract, 10% urinary tract, 10% lower respiratory tract infections, and 30% had mixed type infections. Lymphoid hyperplasia, overt autoimmune manifestations, or malignancy was not noted. Seven of 10 patients were studied twice; at the age of 34.2 ± 13.7 and at 86.6 ± 12.3 months. Absolute lymphocyte counts and lymphocyte subsets were normal in all cases. All of them had normal expression of CD40 on B cells and CD40L on activated T cells for males. At first examination, all patients had normal in vitro sCD40L+rIL-4-induced B cell proliferation response and somatic hypermutation but CSR towards IgE was absent. AID and UNG genes did not show any abnormalities. All showed improvement in both clinical findings and Ig levels during the follow-up period of 55.8 ± 14.8 months. Ages for normalization of IgG and IgA were 68.2 ± 8.7 and 70.2 ± 21.6 months, respectively. During the second evaluation: In vitro sCD40L+rIL-4-induced B-cell proliferation was normal in all cases, whereas CSR was still abnormal in five of eight patients. Two of the patients had an increase in in vitro CSR response but still low IgG2 subclass levels. Three patients with initially absent in vitro CSR response also normalized. Conclusion: Clinical manifestations and immunoglobulin levels of the patients with Hyper-IgM type 4 phenotype recovered in late childhood at about 6 years of age. There was a transient CSR defect which was not observed in cases with transient hypogammaglobulinemia of infancy. Detection of a non-AID or non-UNG associated CSR defect in infancy should be confirmed later on since spontaneous recovery may occur.     

Successful haploidentical PBSCT with subsequent T‐cell addbacks in a boy with HyperIgM syndrome presenting as severe congenital neutropenia

Jasinska A, Kalwak K, Trelinska J, Borowiec M, Piatosa B, Zeman K, Mlynarski W. Successful haploidentical PBSCT with subsequent T‐cell addbacks in a boy with HyperIgM syndrome presenting as severe congenital neutropenia. Abstract: HIGM syndrome is a group of primary immunodeficiency disorders characterized by recurrent bacterial and opportunistic infections; it is also associated with normal to elevated serum IgM levels and a concomitant deficiency of IgG, IgA, and IgE. In this report, we give account of a boy with X‐linked HIGM and a novel Y172C mutation within his CD40LG gene. He presented with severe neutropenia as the dominating symptom. His bone marrow showed maturation arrest at the promyelocyte/myelocyte stage, typical of congenital neutropenia. This boy suffered from life‐threatening infections and required high doses of rhG‐CSF, and a haploidentical PBSCT was also successfully performed, thus leading to reconstitution of CD40L expression on activated CD4+ T cells (as assessed with flow cytometry six months after the procedure). Two low‐dose T‐cell addbacks were required to re‐establish full donor chimerism and clear CMV reactivation. The report demonstrates that in select cases, alternative donor allogeneic HSCT supported by DLI may be effective in correcting the defect in X‐linked HIGM, and HSCT in HIGM children is not necessarily limited to matched sibling donor transplantation.     

Immunological aspects of juvenile rheumatoid arthritis

This article reviews the evidence from recent studies on immunological abnormalities associated with pathophysiologic mechanisms operating in three clinical subtypes of juvenile rheumatoid arthritis (JRA) (polyarticular, pauciarticular and systemic). The main discussion is focused on three hallmarks of immunopathological studies. First, abnormalities in phenotype and function of lymphocytes from peripheral blood and inflamed synovium are discussed. The aberrations of lymphocytes are elucidated by T and B cells expressing phenotypic cell-markers such as CD20, CD21, CD4, CD8 and DR in association with different subtypes and disease activity. The functional imbalance and impairment of T and B cells are mainly observed by abnormal proliferation and/or in vitro Ig production in response to mitogens and alloantigens. Second, because the appearance of rheumatoid factors (RF) in serum indicates that the pathogenesis of JRA may be based on the autoimmune mechanism, the prevalence of RF including IgM, IgA and IgG isotype, hidden IgM RF and cross-reactive idiotype RF, and their characteristic properties are discussed. Moreover, specific auto-antibodies (antinuclear antibodies and others) for JRA are illustrated in this paper. Third, the production of various pro-inflammatory cytokines resulting in the release of tissue-damaging chemical mediators is also discussed. This may play a central role in the generation of systemic inflammation and joint involvement in JRA.     

Enteroviral meningoencephalitis as a complication of X-linked hyper IgM syndrome

We describe 5 children from 2 families with mutations in the CD40 ligand (CD40L) gene leading to absent expression of CD40L on activated CD4 cells. All subjects presented with interstitial pneumonia with low serum IgG and normal serum IgM. One child had normal and one child had elevated serum IgA. Four had confirmed Pneumocystis carinii pneumonia. In spite of intravenous immunoglobulin treatment yielding therapeutic serum immunoglobulin levels, 3 children had enteroviral encephalitis. When assessed by flow cytometry, the 3 surviving affected male children had absent CD40L expression on activated CD4(+) T cells. The affected children from both families were shown to have the same single nucleotide insertion (codon 131) resulting in frameshift and early termination within exon 4 (extracellular domain). This observation demonstrates that persistent enteroviral infection is not only observed in X-linked agammaglobulinemia but may also occur in patients with X-linked hyper IgM syndrome.     

中国汉族儿童散发性激素耐药型肾病综合征CD2AP基因突变分析

目的分析中国汉族散发性激素耐药型肾病综合征(SRNS)患儿CD2AP基因突变及其特点。方法40例中国汉族散发性SRNS患儿,以及50例尿检正常的汉族成年人,取外周静脉血3 ml,提取基因组DNA,应用聚合酶链反应(PCR)方法扩增CD2AP基因全部18个外显子及其周围的部分内含子,进行直接DNA序列测定。应用神经网络程序对CD2AP基因内含子突变进行隐蔽性剪接位点预测。结果在40例散发性SRNS患儿中检测出11种CD2AP基因多态性,并在3例散发性SRNS患儿中检测出3种在正常对照人群中未发现的CD2AP基因变异,IVS7-135G>A、1083T>C和IVS13-137G>A。神经网络程序分析结果结合临床表型提示,IVS7-135G>A突变为非致病突变、1083T>C和IVS13-137G>A突变的致病性不明确。结论中国汉族散发性SRNS患儿存在CD2AP基因突变,今后尚需对CD2AP基因突变与SRNS患儿临床表型的关联性进行详尽研究。     

幼儿反复发热、肝脾大、嗜酸性粒细胞增多

患儿,男,2岁,因咳嗽、发热第6次入院。患儿2月龄时发现腋下淋巴结结核,多次因发热、咳嗽住院,并发现嗜酸性粒细胞增多,以及多次免疫全套提示IgG、IgA、IgM降低。入院后予以抗结核、抗细菌、抗真菌治疗,仍反复发热、肝脾进行性增大,入院第35天出现果酱样大便、B超提示左侧腹局部肠管横断面呈“同心圆征”,于全麻下行剖腹探查、肠套叠复位+回盲部成形术以及肠壁结节、肠系膜淋巴结活检、肝活检术,术后患儿出现肝功能衰竭、DIC、电解质紊乱,救治无效死亡。入院后血培养及肝活检均发现马尔尼菲青霉菌;并进一步对患儿、患儿父母及弟弟进行免疫缺陷病相关基因检测,提示患儿存在CD40L基因半合突变 （IVS1-3T→G）,确诊为高IgM综合征。患儿母亲为此拼接点错误基因的携带者、父亲正常,患儿弟弟与患儿有相同的CD40L基因突变。     

Identical phenotype in patients with somatic and germline CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome

In a patient with a somatic mutation in the CD95 gene, the long-term evolution of the clinical phenotype was indistinguishable from that of patients with autoimmune lymphoproliferative syndrome caused by germline CD95 mutations. A new diagnostic algorithm for autoimmune lymphoproliferative syndrome is suggested incorporating studies on sorted TCRalpha/beta+CD3+CD8-CD4- T cells.     

X-linked severe combined immunodeficiency (X-SCID) with high blood levels of immunoglobulins and <Emphasis Type="Italic">Aspergillus</Emphasis> pneumonia successfully treated with micafangin followed by unrelated cord blood stem cell transplantation

In this report, we describe a patient with X-linked severe combined immunodeficiency (X-SCID) who had high serum IgG, IgA, and IgM levels. The boy did well until 6 months of age, when he developed interstitial pneumonia caused by Aspergillus species, with a white cell count of 12,840/μL and only 10% lymphocytes; IgG, 991 mg/dL; IgA, 65 mg/dL; IgM, 472 mg/dL. Cell markers showed only 6.3% CD3, 2.1% CD4, 0.7% CD8, but 92% CD19 and 0.1% CD16+CD56+ (NK cells). A mutation was detected within exon 2 (C196 A→C), leading to the substitution of proline for glutamine, which has not been reported previously. The boy was successfully treated with the new antifungal drug, micafangin (MCFG), at 5 mg/kg/day for 89 days. After resolution of the pneumonia, the patient underwent successful hematopoietic stem cell transplantation with completely matched unrelated female cord blood. The CD34 stem cell dose was 3.4×10⁴ cells/kg. In conclusion, MCFG can be a first line agent for Aspergillus pneumonia in immunocompromised hosts.     

Fibrillin-1 Gene Mutations in Left Ventricular Non-compaction Cardiomyopathy

Left ventricular non-compaction cardiomyopathy (LVNC) is a unique cardiomyopathy with a current yield of about 30–40 % in identifying a causative gene mutation. A retrospective review of all patients with LVNC at our institution was performed and genetic testing was reviewed. Echocardiographic and cardiac magnetic resonance imaging was reviewed to corroborate the reported phenotype. We present a series of patients with LVNC dilated phenotype associated with fibrillin-1 gene mutations. Fifty-one patients were identified as having LVNC with reduced left ventricular function and/or left ventricular dilation. We retrospectively reviewed gene testing in this cohort when available and identified 5 patients (10 %) with an FBN1 gene mutation. Syndrome breakdown as follows: 3 with Marfan, 1 with Shprintzen-Goldberg, and 1 with no identifiable syndrome. Derangements in fibrillin-1 may impact the compaction process resulting in LVNC. Although causation has not been proven by our report, it certainly raises interest in a possible mechanistic relationship between fibrillin-1 and LVNC given the increased prevalence of Marfan syndrome and fibrillin-1 gene mutations in this cohort.     

CD40 ligand deficiency presenting as unresponsive neutropenia.

A male child presented with recurrent respiratory infections, otitis media, and oral ulceration and was found to be neutropenic. Investigations showed hypogammaglobulinaemia with normal serum IgM and a novel deletion in the gene for CD40 ligand on his X chromosome. Intravenous gammaglobulin did not lead to resolution of his neutropenia; G-CSF was also necessary.     

CD40 ligand deficiency presenting as unresponsive neutropenia

A male child presented with recurrent respiratory infections, otitis media, and oral ulceration and was found to be neutropenic. Investigations showed hypogammaglobulinaemia with normal serum IgM and a novel deletion in the gene for CD40 ligand on his X chromosome. Intravenous gammaglobulin did not lead to resolution of his neutropenia; G-CSF was also necessary.     

儿童MSN基因突变致原发性免疫缺陷病1例并文献复习

目的：报告儿童MSN基因突变致原发性免疫缺陷病的临床特征及免疫表型。方法：总结分析1例MSN基因突变致原发性免疫缺陷病患儿的临床资料、免疫表型及治疗,并复习相关文献。结果：患儿男,8岁,临床表现为生后反复呼吸道和消化道感染,反复皮肤湿疹,频发足癣。中性粒细胞、淋巴细胞、单核细胞均降低,免疫球蛋白IgG、IgA和IgM低下,T、B和NK淋巴细胞计数降低,CD4+/CD8+比例倒置,DNT细胞比例增高,基因检测发现MSN基因外显子5有1个半合子、错义突变位点（c.511C＞T：p.R171W),为自发突变。在PubMed、Web of Science、中国知网、维普数据库和万方数据库中检索儿童Moesin（MSN）基因突变或缺陷,检索时间均从建库至2017年6月30日。共检索到相关文献2篇,均为英文文献,总结包括本文1例在内的6例MSN基因突变患儿的临床和免疫特点;临床均表现为生命早期发生反复感染,累及呼吸道、消化道和皮肤等,对细菌、真菌和病毒均易感,水痘-带状疱疹病毒感染尤为突出,易累及多系统。免疫表型方面,CD8+T细胞过量表达衰老细胞标志物CD57;给予免疫蛋白替代治疗以及预防性抗生素,可有效减少感染发生。结论：MSN基因突变所致免疫缺陷病表现为2岁以内即发生的反复感染,白细胞降低,低丙种球蛋白血症。     

Evaluation of the MTHFR C677T allele and the MTHFR gene locus in a German spina bifida population

A number of recent studies have demonstrated that the occurrence and recurrence risk of neural tube defects (NTD) is reduced by folic acid supplementation before and during pregnancy. Epidemiological studies have shown low plasma folate and raised plasma homocysteine in women with spina bifida aperta (SB) children suggesting an abnormal folate metabolism. The 5,10-methylenetetrahydrofolate reductase (MTHFR) variant C677T, resulting in a decreased activity of the enzyme, has been associated with the development of NTD. Several studies demonstrated that homozygosity for the C677T mutation occurs at a higher frequency in patients with SB phenotype than in control individuals. The SB risk is strongest if both the mother and her child have the mutation in the homozygous state. In the present study we compared the frequency of the C- and T-alleles in healthy German individuals (n=153) with German SB patients (n=137). Our study groups reveal no significant difference in C/T-allele frequencies and genotype distributions. A family based association study, the transmission disequilibrium test, confirms the absence of an association between T-allele and SB. In 9 of 40 families we were able to exclude linkage to the MTHFR locus (1p36.3) employing different inheritance models. Conclusion Our data show no evidence for an association between the C677T mutation and the occurrence of the SB phenotype. Therefore we cannot support the hypothesis that the MTHFR variant does account for a significant genetic predisposition to the SB phenotype in the studied German patients. Received: 11 June 1997 / Accepted in revised form: 3 November 1997     

新生儿感染性肺炎的临床和免疫功能研究

目的　探讨新生儿感染性肺炎的病因学、临床特征和免疫功能的变化。方法　采用酶联免疫吸附试验 (ELISA)检测 111例肺炎患儿血中 8型常见病毒及肺炎支原体特异性IgM ,速率散射比浊法测定C 反应蛋白 (CRP)和免疫球蛋白 (IgG及其亚类、IgA、IgM ) ,链菌素亲生物素 过氧化酶连接法 (SP)检测T淋巴细胞亚群 ,并对临床表现和其他实验室检查结果进行分析。选取同期非肺炎新生儿 30例作为对照。结果　⑴肺炎组 111例患儿血清中 ,特异性IgM阳性 4 0例 (36 0 % ) ;对照组 30例的血清中 ,特异性IgM检测均阴性。病毒及支原体感染 2 3例 (2 0 7% ) ,细菌感染 4 5例(40 5 % ) ,病毒及支原体与细菌混合感染 17例 (15 3% ) ,其他不明病原感染 2 6例 (2 3 4 % )。⑵新生儿感染性肺炎最常见的症状和体征是气促、发绀 ,其次是咳嗽、呛奶、肺部音、三凹征 ;X线检查以纹理模糊、纹理增多增粗、斑片影多见。⑶免疫学检查中 ,肺炎组CD3 、CD4细胞数小于对照组 (P <0 0 5 ) ,IgA、IgM含量大于对照组 (P <0 0 5 )。病毒及支原体感染组IgA含量大于其他不明病原感染组和对照组 (P <0 0 5 ) ;细菌感染组IgM含量大于对照组 (P <0 0 5 )。CD8、CD4/CD8、IgG、IgG1 4在肺炎组与对照组、各感染组两两间、各感染组与对照组之间     

Phenotypic analysis of circulating dendritic cells during the second half of human gestation

Dendritic cells (DCs) have been characterized as having an immature phenotype in infants when compared with adults; but it is unclear whether the phenotype or function of these populations changes during human intrauterine development. Three-colour flow cytometry was used to phenotype fetal/neonatal circulating DCs during the second half (>20-wk gestation) of pregnancy, (n = 34) and adults (n = 9). DCs were identified from peripheral blood mononuclear cells (PBMCs) or cord blood mononuclear cells (CBMCs) as staining brightly for HLA-DR but negative for T cell, B cell, monocyte, and NK cell lineage markers. The surface molecule of interest was detected in a third colour. During gestation CD34, a marker of immaturity was significantly higher, and CD4, a differentiation marker, was significantly lower than adult levels. The percentage of CD11c+ cells did not differ significantly at any age, although a trend to reduced intensity of expression at earlier stages of gestation was observed. Significantly fewer DCs expressed the IgG receptors CD32 and CD64 at all gestations. The percentage of HLA-DR+/lin- cells expressing CD40 was lowest at 20–23 wks and was always significantly lower on DCs from cord blood vs. adult blood. Similarly, the percentage of CD86+ and CD54+ DCs was significantly lower than adults throughout gestation. Thus, immaturity of cord blood DCs is likely to arise as a consequence of decreased ability to take up antigen (at least via IgG-mediated mechanisms) and reduced provision of co-stimulation.     

激素耐药型肾病综合征与CD2AP基因

CD2AP基因位于染色体6p12.3,编码CD2相关蛋白(CD2AP)。CD2AP对于维持肾小球足细胞裂孔隔膜结构和功能的完整性具有重要作用。CD2AP基因突变所致激素耐药型肾病综合征(SRNS)呈常染色体隐性遗传或常染色体显性遗传。CD2AP基因纯合突变导致早发型SRNS。CD2AP基因杂合突变可以增加患肾小球疾病的...