X- 连锁迟发性脊椎骨骺发育不良一家系TRAPPC2 基因变异分析

目的分析由TRAPPC2基因变异致X连锁迟发性脊椎骨骺发育不良(SEDT-XL)的临床及基因变异特点。方法回顾分析1个SEDT-XL家系的临床资料及基因检测结果。结果先证者,9岁2个月,因生长缓慢就诊,语言、运动及智力发育正常。身高115 cm(-3SD),臂间距109 cm,上部量56 cm,下部量59 cm,体质量21 kg,招风耳,尖下颌,牙列不齐,颈短,脊柱侧弯,心肺腹未见异常。采集先证者及其父母和舅舅的外周血行全外显子测序,结果显示先证者TRAPPC2基因4号外显子区域存在1个半合子变异c.115delC,导致氨基酸改变p.Q39Sfs*3。该半合子变异来自其母亲,其舅舅存在相同的半合子变异位点。结论 TRAPPC2基因4号外显子区域c.115delC突变为该家系SEDT-XL的致病原因。     

Prenatal molecular diagnosis of X‐linked hydrocephalus via a silent C924T mutation in the L1CAM gene

We present a case of a patient whose L1CAM gene in X‐chromosome has a C924T transition. Her first son's ventriculomegaly was prenatally detected. A mature infant was born, his head circumference was large, and thumbs were bilaterally adducted. X‐linked hydrocephalus (XLH) was suspected. The DNA examination revealed that both her and boy's LICAM gene had a C924T transition. She became pregnant 5 years later and amniocentesis was performed. The results of cytogenetic analysis revealed that the fetus was female. She continued her pregnancy and delivered a healthy girl. She again became pregnant 3 years later. The chromosomal analysis revealed that the fetus was male. Fetal DNA analysis determined that the fetus had the inherited mutation. She chose to terminate the pregnancy. A C924T mutation can be disease causing for XLH, and the detection of this mutation would aid in genetic counseling for the prenatal diagnosis of XLH.     

Diagnostic challenges for a novel SH2D1A mutation associated with X‐linked lymphoproliferative disease

Mutations in SH2D1A, encoding the intracellular adaptor signaling lymphocyte activation molecule associated protein (SAP), are associated with X‐linked lymphoproliferative disease type 1 (XLP1). We identified a novel hemizygous SH2D1A c.49G > A (p.E17K) variant in a 21‐year‐old patient with fatal Epstein‐Barr virus infection–associated hemophagocytic lymphohistiocytosis. Cellular and biochemical assays revealed normal expression of the SAP variant protein, yet binding to phosphorylated CD244 receptor was reduced by >95%. Three healthy brothers carried the SH2D1A c.49G > A variant. Thus, data suggest that this variant represents a pathogenic mutation, but with variable expressivity. Importantly, our results highlight challenges in the clinical interpretation of SH2D1A variants and caution in using functional flow cytometry assays for the diagnosis of XLP1.     

Transitional cell carcinoma in a patient with X‐linked hyperimmunoglobulin M syndrome

Patients with X‐linked hyperimmunoglobulin M syndrome (XHIGM) have a defective CD40–CD40 ligand system and further immunoglobulin class‐switching. They may present with recurrent infection and malignancy involving the liver, pancreas or biliary tract. We report here a case of poorly differentiated transitional cell carcinoma in a young man with XHIGM even on regular treatment and discuss the possible pathogenesis. Given that the triggering of the CD40–CD40 ligand system has been found to improve tumor immunogenicity in recent studies, future immunotherapy targeting the CD40 ligand for these patients may be feasible to prolong their survival.     

Haploidentical hematopoietic stem cell transplantation for a case with X‐linked chronic granulomatous disease

CGD is a rare primary immunodeficiency with high mortality rates when treated conventionally, especially for the X‐chromosome‐linked form. HSCT is the only curative therapy for CGD; however, haploidentical transplantation in CGD is rare. Here, we report a case of X‐linked CGD treated successfully by haploidentical HSCT. The patient showed a positive result with full donor chimerism, good quality of life, and the absence of recurrent infectious diseases at follow‐up (68 months). Thus, haploidentical HSCT may serve as an acceptable treatment approach for patients who have CGD, but no HLA‐matched related or unrelated donor.     

Lymphocytic vasculitis involving the central nervous system occurs in patients with X‐linked lymphoproliferative disease in the absence of Epstein–Barr virus infection

X‐linked lymphoproliferative disease (XLP) is an immunodeficiency caused by defects in the adaptor molecule SAP. The manifestations of XLP generally occur following Epstein–Barr virus (EBV) infection and include fulminant mononucleosis, hypogammaglobulinemia and lymphoma. In this report, we describe two unrelated patients with fatal T‐cell‐mediated central nervous system vasculitis for whom repeated serologic and molecular testing for EBV was negative. In both patients, clonal T‐cell populations were observed, but neither demonstrated evidence of lymphoma. Thus, loss of SAP function can lead to dysregulated immune responses characterized by the uncontrolled expansion and activation of T cells independent of EBV infection. Pediatr Blood Cancer 2009;53:1120–1123. © 2009 Wiley‐Liss, Inc.     

Novel p53 splicing site mutation in Li‐Fraumeni‐like syndrome with osteosarcoma

We describe a 15‐year‐old girl with a novel germline p53 splice site mutation who developed an osteosarcoma. She received several cycles of chemotherapy with complete resection of the primary tumor without amputation, and has maintained remission for 18 months. Li‐Fraumeni‐like syndrome was suspected based on familial history. Sequence analysis revealed the presence of a novel germline p53 gene mutation resulting in a G to A transition at position +1 at the donor splice site of intron 6, creating a 6 amino acid insertion. This case provides interesting insight into the phenotype‐genotype correlation in LFL syndrome with a TP53 splicing mutation.     

The role of allogeneic hematopoietic stem cell transplantation and Epstein‐Barr virus infection on the treatment for child primary hemophagocytic lymphohistiocytosis patients with X‐linked lymphoproliferative disease: A rare case report and family survey study

XLP‐2 is known as a rare primary immunodeficiency disease, which is characterized by the susceptibility to EBV infection and potential development into the pHLH. The existing studies believe that the dysfunction of XIAP represents one of the most significant pathogenic mechanisms of XLP‐2, and allo‐HSCT is regarded as a crucial treatment for the long‐term survival in XLP‐2 patients. In our present study, a 2‐year‐old male patient was diagnosed with XLP‐2. After receiving chemotherapy by using HLH‐2004 without allo‐HSCT, he reached a complete remission, and his EBV load was brought under control. Our family survey revealed a novel frameshift mutation in the XIAP gene in this patient, as well as in his cousin and grandfather. Until now, the patient has been followed up for 22 months with no recurrence reported yet. Based on these findings, it is believed that for child pHLH patients with XLP‐2, the treatment by controlling symptoms alone without allo‐HSCT and with regular monitoring of EBV load could be conducive to a long‐term survival.     

Treosulfan‐based reduced toxicity hematopoietic stem cell transplantation in X‐linked agammaglobulinemia: A cost‐effective alternative to long‐term immunoglobulin replacement in developing countries

X‐linked agammaglobulinemia (XLA) is a primary antibody disorder due to a mutation in the Bruton tyrosine kinase gene that requires lifelong immunoglobulin replacement resulting in a significant economic burden and treatment abandonment. Hematopoietic stem cell transplantation (HSCT) offers an alternative option for complete cure. In our series, two children with XLA underwent successful HSCT using a myeloablative conditioning with thiotepa, treosulfan, and fludarabine from a matched sibling donor. The second child had rejected his first graft following a busulfan‐based regimen with resultant autologous reconstitution. At 6 months post‐HSCT, serum IgG were normal, off IVIG, and had no infections. Both children after a median follow‐up of 20 months have 100% chimerism. Treosulfan‐based reduced toxicity myeloablative HSCT has encouraging results with a positive impact on the socioeconomics in developing countries.     

Fatal hemophagocytic lymphohistiocytosis in X‐linked chronic granulomatous disease associated with a perforin gene variant

A patient with previously unrecognized X‐linked chronic granulomatous disease (X‐CGD) died of multi‐organ failure, secondary to ongoing infection and hemophagocytic lymphohistiocytosis (HLH). Post mortem histological investigations were compatible with X‐CGD, and a CYBB gene mutation was confirmed. No homozygous mutations in the genes encoding perforin (PRF1), MUNC 13‐4 or syntaxin‐11 (STX11) were found; however, there was a heterozygous alteration c.1471G>A in the PRF1 gene causing a p.Asp491Asn substitution. Although this substitution has not been reported to cause primary or secondary HLH, we speculate that it may have made the patient more susceptible for HLH under the circumstances of ongoing infection associated with X‐CGD. Pediatr Blood Cancer 2009;52:527–529. © 2008 Wiley‐Liss, Inc.     

Urinary β2‐microglobulin and bronchopulmonary dysplasia: Trends in preterm infants

Background

The developmental process of bronchopulmonary dysplasia (BPD) is not identical between very preterm infants born small for gestational age (SGA) and those born appropriate for gestational age (AGA). In this study, we compared the pattern of the inflammatory response in infants of each group, by measuring urinary β2‐microglobulin (Uβ2M) as an alternative, concise, and less‐invasive biomarker.

Methods

Uβ2M and clinical details were examined at birth and at 4 weeks of age in 146 very preterm infants.

Results

Of the 57 infants diagnosed with BPD, 18 were SGA, and 39 were AGA. Uβ2M at birth was significantly lower in SGA BPD infants than in AGA BPD infants, but it increased with time. The prevalence of chorioamnionitis (CAM) was significantly lower in SGA BPD infants than in AGA BPD infants, while that of pregnancy‐induced hypertension was the opposite.

Conclusions

Exposure to prenatal factors other than CAM may sensitize fetal lungs to become vulnerable to postnatal inflammation in very preterm SGA infants with BPD.     

Wolcott–Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature*

Ozbek MN, Senée V, Aydemir S, Kotan LD, Mungan NO, Yuksel B, Julier C, Topaloglu AK. Wolcott–Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature. Wolcott‐Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by an early‐infancy‐onset diabetes mellitus associated with a variety of multisystemic clinical manifestations. Here, we present six patients with WRS, carrying the same homozygous mutation (EIF2AK3‐W522X), from two unrelated Turkish families. This is the largest series of patients with the same mutation for this rare syndrome. In this communication we compare clinical features of these six patients with the other 34 patients who have been reported to date, and review the clinical features of WRS. All WRS patients presented first with symptoms of insulin dependent diabetes mellitus, with a mean age at onset of 2 months. All patients had skeletal dysplasia or early signs of it, and growth retardation. Many of the patients with WRS have been reported to have developmental delay, mental retardation, and learning difficulties; in contrast, none of our patients showed abnormal development at age up to 30 months. Acute attacks of hepatic failure were reported in 23 cases out of 37 patients; in 15 of those 23 cases an acute attack of renal failure accompanied the liver failure. Exocrine pancreatic deficiency has been reported in only four cases other than our four patients. Central hypothyroidism was observed in six of 28 cases. We propose that central hypothyroidism is not a component of WRS, but rather a reflection of euthyroid sick syndrome. Four of our patients experienced severe neutropenia, compared to only five of the 27 other cases, suggesting that the W522X mutation may be specifically associated with neutropenia. Other than the consistent features of diabetes mellitus and epiphyseal dysplasia, WRS patients are otherwise characterized by extensive phenotypic variability that correlates poorly to genotype.