Hereditary haematologic disorders in Najaf province-Iraq

BackgroundHereditary hematologic disorders (HHDs) originate from genetic factors that cause disruptions of blood homeostasis. The Thalassemia Unit, Najaf province, Iraq, keeps all medical records of all patients with HHD from the Najaf province.ObjectivesWe aimed to conduct an epidemiological study to obtain a comprehensive epidemiological picture concerning sex distribution, and effects of blood groups and consanguinity.Patients and methodsAll registered HHD patients (until May 2019) in the Thalassemia Unit (1033 patients, aged 0.5–65 years old) were included in the study.ResultsThe prevalence of HHD in Najaf city is 69.60 per 100,000 population. There are significantly more male than female HHD patients (Male = 53.437%, Female = 46.563%, p = 0.019). The top 3 prevalent HHD are transfusion-dependent thalassemia (36.012%), non-transfusion dependent thalassemia (34.656%), and sickle-β thalassemia disorder (13.746%).The highest percentage of patients were in the centre of Najaf (56.42%), followed by Kufa, Mishkhab, Haidariah, Manathera, and Abbasiya. The distribution of blood groups and Rh factors of HHD patients in the Najaf population was not significantly different from that in the normal population. The consanguinity rate observed in our patients’ parents (78.67%) was significantly higher (p < 0.0001) as compared with the consanguinity rate in the population (45.8%).ConclusionsDuring the last few years, there was an increase in HHD cases in Najaf city and, therefore, there is an urgent need to increase awareness about the effects of consanguinity marriages on HHD in order to limit the incidence of HHD.     

新型冠状病毒肺炎疫情防控期间遗传性共济失调患者管理策略专家共识

2019年12月以来,在湖北省武汉市陆续发现了一系列传染性极强的不明原因肺炎病例,后经证实为感染"严重急性呼吸道综合症冠状病毒2型(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)"所致的"2019冠状病毒病(corona virus disease 2019,COVID-19)"。SARS-CoV-2病毒能够侵犯人体肺部等多个系统,中枢神经系统受累者会表现出一系列的神经症状,容易误诊漏诊,从而增加了COVID-19扩散的风险。遗传性共济失调(hereditary ataxia)是一大类具有高度的临床和遗传异质性、病死率和病残率较高的神经系统退行性疾病。鉴于疫情的严重性,政府采取的一系列防控措施,使得许多患者去医院的随访和诊疗受到了限制,对于患者的心身健康产生了较大的影响。为使患者在疫情防控期间得到规范的管理,中国医师协会神经内科医师分会神经遗传专委会特别制定了本共识,旨在帮助患者共克时艰,平安度过防疫期。     

遗传性FⅪ缺陷症一家系的F11基因新复合杂合变异分析

目的对1个复合杂合变异导致的遗传性凝血因子Ⅺ(coagulation factorⅪ,FⅪ)缺陷症家系进行表型和基因变异分析,探讨其发病的分子机制。方法检测先证者及其家系成员(共3代11人)的活化部分凝血活酶时间(activated partial thromboplastin time,APTT)、凝血酶原时间(prothrombin time,PT)、纤维蛋白原(fibrinogen,FIB)、血浆FⅪ活性(FⅪactivity,FⅪ∶C)及FⅪ抗原(FⅪantigen,FⅪ∶Ag)等指标以明确诊断;用Sanger测序法分析先证者F11基因的所有外显子及侧翼序列、5′和3′非翻译区及家系成员相应的变异位点区域,用反向测序予以证实。用PolyPhen-2和SIFT软件分析变异对蛋白质功能的影响;用Swiss-PdbViewer软件对变异位点进行蛋白模型和氨基酸相互作用分析。结果先证者和其姐姐APTT、FⅪ∶C、FⅪ∶Ag均明显异常,分别为73.0 s、10.0%、15.0%和87.1 s、2.0%、11.5%;其部分家系成员的APTT稍有延长,FⅪ∶C和FⅪ∶Ag也均有不同程度的下降。基因分析发现先证者及其姐姐F11基因第7外显子存在c.738G>A杂合变异(p.Trp228stop),第9外显子存在c.938G>T杂合变异(p.Ser295Ile);其父亲、妹妹、女儿均为p.Trp228stop的杂合子,而母亲、外甥则为p.Ser295Ile的杂合子。p.Ser295Ile变异PolyPhen-2评分结果为0.840分,预示此变异很可能是有害变异;SIFT评分结果为0.00分,预示此变异为有害变异,可影响蛋白质功能;模型分析显示p.Ser295Ile变异破坏了氨基酸间其中一个氢键的联系,使蛋白结构发生变化,不稳定性增加。结论该先证者的F11基因第7外显子存在c.738G>A(p.Trp228stop)杂合变异及第9外显子存在c.938G>T(p.Ser295Ile)杂合变异;p.Trp228stop遗传自父亲,p.Ser295Ile遗传自母亲,且与该家系FⅪ水平降低有关。     

PRSS1 and SPINK1 mutations in idiopathic chronic and recurrent acute pancreatitis

AIM: To identify gene mutations in PRSS1 and SPINK1 in individuals with early onset idiopathic chronic or recurrent acute pancreatitis.METHODS: The cationic trypsinogen gene (PRSS1; exons 2 and 3) and the serine protease inhibitor Kazal 1 gene (SPINK1; exon 3) were selectively amplified and sequenced from blood samples of 19 patients admitted to the Pancreas Clinic at our institution with chronic pancreatitis and/or idiopathic recurrent acute pancreatitis that were diagnosed or with onset before age 35. Fifty healthy volunteers served as controls. Whole blood samples were collected and gene specific sequences were amplified by polymerase chain reaction (PCR). All PCR products were subsequently sequenced in order to identify the presence of any mutations.RESULTS: Nineteen patients with pancreatitis (14 males; median age 24 years, range 15-48 years) were included in this study, of which five showed the presence of gene mutations. Direct sequencing results indicated the presence of two previously unidentified mutations in exon 2 of PRSS1 (V39E and N42S) in two patients with recurrent acute pancreatitis. Two cases had the N34S SPINK1 mutation. Analysis of the relatives of one patient homozygous for this mutation showed that five of the six family members carried the N34S SPINK1 mutation. Of these members, three were healthy heterozygous carriers and two were homozygotes (one sibling had diabetes, the other was healthy). Another patient was heterozygous for a novel SPINK1 mutation located on exon 3 (V46D). All members from this patient’s family had normal genotypes, indicating that it was a de novo mutation. No mutations in either gene were present in the control subjects.CONCLUSION: Two novel PRSS1 mutations and one novel SPINK1 mutation were identified in Mexican patients with early onset idiopathic recurrent acute pancreatitis.     

杭州地区4842例新生儿耳聋基因筛查结果分析

目的应用遗传性耳聋基因芯片筛查杭州地区新生儿常见遗传性耳聋基因的突变频率和类型。方法收集杭州地区2016年2月～2017年10月送检的4842例新生儿足底血制成的干血斑,应用PCR+导流杂交法检测中国人常见的4个致聋基因14个突变位点,包括GJB2基因(176-191del 16、235 del C、299-300 del AT)、GJB3基因(538CT、547 GA)、SLC26A4基因(IVS7-2AG、IVS15+5GA、2168 AG、1229CT、1174AT、1975GC、1226GA)、线粒体DNA 12S rRNA基因(1555AG、1494CT)。结果 4842例新生儿中200例携带耳聋基因突变,总体阳性率为4.13%,其中GJB2基因突变58例,突变携带率为1.20%,SLC26A4基因突变98例,突变携带率为2.02%,12S rRNA基因19例,突变携带率为0.39%,GJB3基因突变31例,突变携带率为0.64%。200例耳聋基因突变携带者195例(97.50%)通过听力筛查。结论耳聋基因筛查是现有听力筛查模式的良好补充,对遗传性非综合征性耳聋早诊断、早预防、早治疗极为重要。     

Hereditary thrombocytopenia with familial novel mutation in MYH9 gene: A familial case report

One of the rarest types of hereditary thrombocytopenia is the MYH9-related disorder. This spectrum of disorders is characterized by large platelets with or without leukocyte inclusion bodies, a decrease in the total number of platelets, and autosomal dominant inheritance. Proteinuric nephropathy that frequently progresses to end-stage renal failure, as well as the beginning of progressive high-frequency sensorineural hearing loss in young adults, is also associated with MYH9-related disorder. In this case report, we presented three family members who had thrombocytopenia and in whom a heterozygous novel 22 bp deletion (c.4274_4295del) was detected which is located in exon 31 of the MYH9 gene. There was no evidence of bleeding in the family members we presented and thrombocytopenia was detected incidentally. Additionally, renal failure, hearing loss, presenile cataracts, and clinical symptoms were not detected in these family members. This novel mutation detected in the MYH9 gene has not been reported in the literature before.     

Novel mutations c.[5121_5122insAG]+[6859C>T] of the SPG11 gene associated with cerebellum hypometabolism in a Chinese case of hereditary spastic paraplegia with thin corpus callosum

Hereditary spastic paraplegia (HSP) is a very heterogeneous disease, both genetically and clinically. To date, approximately 52 loci and 31 genes have been reported to be involved in the causality of HSP. The pattern of inheritance of the disease can be autosomal dominant, autosomal recessive, or X-linked recessive. Autosomal recessive HSP with thin corpus callosum (ARHSP-TCC) is one form of this disease, and a recessive gene, SPG11, is responsible for 41–77% of all ARHSP-TCC cases. SPG11 encodes the protein SPATACSIN, which is most prominently expressed in the cerebellum. However, little is known about its function. Despite diverse clinical presentations, diffuse hypometabolism in the cerebellum has not been reported previously. We have identified an HSP-TCC patient that presented with prominent intellectual disability rather than spasticity. ¹⁸Fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸FDG-PET/CT) examination showed diffuse hypometabolism in both cerebella. Mutation screening of the SPG11 gene using Sanger sequencing identified the novel compound heterozygous mutation c.[5121_5122insAG]+[6859C>T] (p.[I1708RfsX2]+[Q2287X]) in the patient. The mother bears the c.5121_5122insAG mutation, which results in a frameshift and is predicted to truncate the 735 amino acids from the C-terminus, and the father carries the c.6859C>T mutation, which terminates the 157 amino acids from the C-terminus. Therefore, these mutations may result in the loss of function of wild-type SPATACSIN. Our results suggest that SPATACSIN may be involved in cerebella metabolism, and the novel mutations provide more data for the mutational spectrum of this gene, which will aid in the development of quick and accurate genetic diagnostic tools for this disease.     

Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism

Background

Primary hyperparathyroidism (PHPT) is uncommon in children. The surgical management of PHPT in children has evolved over the past two decades.

Methods

A retrospective study of patients who underwent parathyroidectomy for PHPT diagnosed at age < 18 years and managed at a tertiary referral center for endocrine and familial disorders.

Results

Thirty-eight patients met eligibility criteria (1981–2012). Median age at PHPT diagnosis was 15 years. Two-thirds of patients were symptomatic (68%, n = 26), most commonly from nephrolithiasis. Twenty-six (68%) patients underwent a standard cervical exploration while 32% underwent a focused unilateral parathyroidectomy. Multiple endocrine neoplasia type 1 (MEN1) was diagnosed preoperatively in 22/26 patients. Patients with a preoperative diagnosis of MEN1 were more likely to undergo a complete initial operation (≥ 3 gland parathyroidectomy with transcervical thymectomy, 13/22, 59% vs. 0/4, 0%; P = 0.03) and less likely to have recurrent disease (10/22, 45% vs. 3/4, 75%; P < 0.001) during follow up than patients diagnosed postoperatively.

Conclusions

Children with PHPT should raise suspicion for MEN1. Preoperative MEN1 evaluation helped guide the extent of initial parathyroidectomy and was associated with lower rates of recurrence in sporadic and familial PHPT in pediatric patients. Management should occur at a high volume center with experienced clinicians and genetic counseling services.     

Congenital pyloric atresia,presentation, management,and outcome: A report of 20 cases

Background

Congenital pyloric atresia (CPA) is a very rare anomaly. It is usually seen as an isolated condition with excellent prognosis. Few cases are familial. These are usually associated with other hereditary conditions and have a poor prognosis. This is a review of our experience with 20 patients with CPA outlining aspects of diagnosis, associated anomalies and management.

Patients and methods

This is a retrospective analysis of 20 cases seen over a 22 year period (December 1990 to December 2012). Their records reviewed for: age, sex, presentation, prenatal history, associated anomalies, investigations, treatment, operative findings and the outcome.

Results

20 cases (9 Males, 11 Females) were treated. 7 patients were full term and the remaining 13 were prematures. Their mean birth weight was 2.1 kg (1.1 kg to 3.9 kg). Polyhydramnios was seen in 13 patients (65%). Two were brothers and four were members of the same family. Isolated CPA was seen in 7 (35%); 13 had an associated conditions: epidermolysis bullosa (EB) in 8 (40%) and multiple intestinal atresias (MIA) in 5 (25%). Three patients had associated esophageal atresia. All were operated on except two who died early due to unrelenting sepsis. The variety of pyloric atresias encountered were as follows: pyloric diaphragm in 13 including double diaphragms in 2, pyloric atresia with a gap in 4 and pyloric atresia without gap in 3. Ten died postoperatively giving an overall survival of 40%.

Conclusions

CPA is a very rare condition. Isolated CPA carries a good prognosis. Association of CPA with other familial and congenital anomalies like EB and MIA carries a poor prognosis.     

Combined liver-kidney transplantation for rare diseases

Combined liver and kidney transplantation(CLKT) is indicated in patients with failure of both organs, or for the treatment of end-stage chronic kidney disease(ESKD) caused by a genetic defect in the liver. The aim of the present review is to provide the most up-to-date overview of the rare conditions as indications for CLKT. They are major indications for CLKT in children. However, in some of them(e.g., atypical hemolytic uremic syndrome or primary hyperoxaluria), CLKT may be required in adults as well. Primary hyperoxaluria is divided into three types, of which type 1 and 2 lead to ESKD. CLKT has been proven effective in renal function replacement, at the same time preventing recurrence of the disease. Nephronophthisis is associated with liver fibrosis in 5% of cases and these patients are candidates for CLKT. In alpha 1-antitrypsin deficiency, hereditary C3 deficiency, lecithin cholesterol acyltransferase deficiency and glycogen storage diseases, glomerular or tubulointerstitial disease can lead to chronic kidney disease. Liver transplantation as a part of CLKT corrects underlying genetic and consequent metabolic abnormality. In atypical hemolytic uremic syndrome caused by mutations in the genes for factor H, successful CLKT has been reported in a small number of patients. However, for this indication, CLKT has been largely replaced by eculizumab, an anti-C5 antibody. CLKT has been well established to provide immune protection of the transplanted kidney against donor-specific antibodies against class I HLA, facilitating transplantation in a highly sensitized recipient.