Clinical and genetic diagnosis of thirteen Japanese patients with hereditary spherocytosis

Hereditary spherocytosis is the most frequent cause of hereditary hemolytic anemia and is classified into five subtypes (SPH1-5) according to OMIM. Because the clinical and laboratory features of patients with SPH1-5 are variable, it is difficult to classify these patients into the five subtypes based only on these features. We performed target capture sequencing in 51 patients with hemolytic anemia associated with/without morphological abnormalities in red blood cells. Thirteen variants were identified in five hereditary spherocytosis-related genes (six in ANK1 [SPH1]; four in SPTB [SPH2]; and one in each of SPTA1 [SPH3], SLC4A1 [SPH4], and EPB42 [SPH5]). Among these variants, seven were novel. The distribution pattern of the variants was different from that reported previously in Japan but similar to those reported in other Asian countries. Comprehensive genomic analysis would be useful and recommended, especially for patients without a detailed family history and those receiving frequent blood transfusions due to chronic hemolytic anemia.

Novel Mutation in APC Gene Associated with Multiple Osteomas in a Family and Review of Genotype-Phenotype Correlations of Extracolonic Manifestations in Gardner Syndrome

Gardner syndrome is a neoplasic disease that associates intestinal polyposis and colorectal adenocarcinoma with osteomas and soft tissue tumors determined by germline mutations in the APC gene. The early diagnosis and identification of high-risk individuals are important because patients have a 100% risk of colon cancer. We present the case of a family with Gardner syndrome. Cephalometric, panoramic X-rays and CBCT of the proband and her brother showed multiple osteomas affecting the skull bones, mandible and paranasal sinuses. The detailed family history showed an autosomal dominant transmission with the presence of the disease in the mother and maternal grandfather of the proband. Both had the typical signs of disease and died in the fourth decade of life. Based on these aspects the clinical diagnosis was Gardner syndrome. By gene sequencing, a novel pathogenic variant c.4609dup (p.Thr1537Asnfs*7) in heterozygous status was identified in the APC gene in both siblings. We reviewed literature data concerning the correlation between the localization of mutations in the APC gene and the extracolonic manifestations of familial adenomatous polyposis as well as their importance in early diagnosis and adequate oncological survey of patients and families based on abnormal genomic variants.

Symptoms, ecg-changes and family history of cardiac disease precedes sudden cardiac death in hypertrophic cardiomyopathy - A nationwide study among the young in Sweden 2000-2010

Funding Acknowledgements Type of funding sources: None. BACKGROUND - Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disease associated with increased morbidity and mortality, and may be the most common cause of sudden cardiac death (SCD) in the young. PURPOSE - To characterize detailed family history, symptoms, hospital utilization and ECG-changes before SCD due to HCM. METHODS - Cases were identified using the SUDDY.se cohort database, a nationwide comprehensive cohort consisting of 903 individuals aged 0-35, who suffered from SCD, in Sweden 2000-2010. The database also includes five population-based controls from Statistics Sweden, per case, together with parents of cases and controls (n = 15 633). Our database encompasses data from mandatory national registries together with the autopsy reports, medical records, ECGs (also military conscript), and detailed family history from an interview-based questionnaire (relatives, post-mortem). All individuals with autopsy findings or clinical diagnosis pre-mortem consistent with HCM were included in the study. RESULTS- HCM was the cause of death in 38 cases, (38/903, 4,2%); 31 male and 7 female, mean age 22 years. The majority of cases (27/38= 71%) presented with possible cardiac symptoms (Including chest pain (10/27 = 26,3%), syncope 22%, palpitations 37%), prior to death. A majority,69%, were attending hospital or outpatient care (vs 21% in controls) within 180 days prior to death. The majority of cases (68%) died during recreational activity (n = 14; 37%) or exercise/competitive sports (n = 12; 31%). In seven of the 12 sports-related cases, death occurred during competitive sports, with basketball being the most common sport (43%). Almost half of the cases had a known cardiac disorder prior to death (15/38, 39%), where HCM was diagnosed premortem in nine cases (9/38, 24%). In addition, we found that over half of the SCD-cases with HCM, presented with an abnormal ECG (n = 22; 58%) prior to death, 12 (55%) in the absence of symptoms. Half of the cases (n = 19) had a positive family history (1st-3rd generation) for heart disease. CONCLUSION(S) - In this nation-wide study of SCD due to HCM, more than 2/3 of cases, had experienced cardiac symptoms prior death, and a high percentage was seeking hospital or outpatient care, in the last 6 months prior to death. A positive family history for cardiac disease, as well as ECG-abnormalities, was seen in half of the cases, respectively. These findings demonstrate that clinical screening including ECG and family history is of great importance in identifying individuals at risk of SCD due to HCM. Such screening, as well as increased attention to possible cardiac symptoms in the young, should possibly be expanded beyond professional athletes to aid prevention of SCD in the young population with HCM.

Case Report: Coinheritance of Germline Mutations in APC and BRCA1 in Colorectal Cancer

Deleterious mutations inAPCgene cause the autosomal dominant familial adenomatous polyposis (FAP) which is typically characterized by the occurrence of hundreds to thousands of colorectal adenomas that eventually lead to colorectal cancers (CRCs).BRCA1/2are the two major susceptibility genes for breast and ovarian cancers. Here, we reported a coinheritance of mutations inAPCandBRCA1genes in a 20-year-old CRC patient with typical clinical features for FAP. Multiple relatives in the family of the patient were affected by colorectal and other cancers. Next-generation sequencing analysis using a panel consisting of 53 hereditary cancer related genes revealed a maternally inheritedAPC(exon15cn_del) mutation and a paternally inheritedBRAC1(p.lle1824AspfsX3) mutation. This is the first coexistence ofAPCandBRCA1mutations in a CRC patient with the mutation inheritance pattern comprehensively characterized in the family. The patient underwent a colonoscopy and a subtotal colectomy and was subsequently diagnosed with colonic adenocarcinomas accompanied with hundreds of tubulovillous adenomas. The case reveals the scenario where two disease-causing mutations of different hereditary tumor syndromes coexist, and illustrates the importance of evaluating detailed family history and performing a multiple-gene panel test in patients with hereditary cancer.

A simple algorithm for a clinical step-by-step approach in the management of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease with an autosomal dominant pattern and a reported prevalence of about 0.2%. In this review, we present a simple algorithm for the management of first diagnosed HCM patients. Initially, the clinical examination, medical and detailed family history and the ECG are essential. The etiological diagnosis of left ventricular hypertrophy is important in order to differentiate HCM due to sarcomeric genes mutation from other phenocopies, such as cardiac amyloidosis. The next step consists of the cardiovascular imaging and ambulatory electrocardiography. Cardiopulmonary exercise testing may also be considered if available. All of the above provide evidence for the critical step of the risk stratification of patients for sudden cardiac death. The therapeutic strategy, with respect to obstructive and nonobstructive disease, arrhythmias and end-stage HCM is also described.

Prevalence of Familial Cluster Headache: A Systematic Review and Meta-Analysis

Introduction: The population rate of familial cluster headache (CH) has been reported to be as high as 20%, however this varies considerably across studies. To obtain a true estimate of family history in CH, we conducted a systematic review and meta-analysis of previously published data. Methods: Our systematic review involved a search of electronic databases (Medline, EMBASE, PubMed, CINAHL) to identify and appraise studies of interest utilising the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. To further ameliorate the accuracy of our analysis we included an additional unpublished cohort of CH patients recruited at a tertiary referral centre for headache, who underwent detailed family history with diagnostic verification in relatives. Data was extracted and meta-analysis conducted to provide a true estimation of family history. Results: In total, we identified 7 studies which fulfilled our inclusion criteria. The estimated true prevalence of CH patients with a positive family history was 6.27% (95% CI:4.65-8.40%) with an overall I 2 of 73% . Fitted models for gender subgroups showed higher estimates 9.26% (95% CI: 6.29-13.43%) in females. However the I 2 for the female model was 58.42% and significant (p=0.047). Conclusion: Our findings estimate a rate of family history in CH to be approximately 6.27% (95% CI:4.65-8.40%) . While estimates were larger for female probands, we demonstrated high heterogeneity in this subgroup. These findings further support a genetic role in the aetiology of CH.

Prevalence of Familial Cluster Headache: A Systematic Review and Meta-Analysis

Introduction: The population rate of familial cluster headache (CH) has been reported to be as high as 20%, however this varies considerably across studies. To obtain a true estimate of family history in CH, we conducted a systematic review and meta-analysis of previously published data. Methods: Our systematic review involved a search of electronic databases (Medline, EMBASE, PubMed, CINAHL) to identify and appraise studies of interest utilising the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. To further ameliorate the accuracy of our analysis we included an additional unpublished cohort of CH patients recruited at a tertiary referral centre for headache, who underwent detailed family history with diagnostic verification in relatives. Data was extracted and meta-analysis conducted to provide a true estimation of family history. Results: In total, we identified 7 studies which fulfilled our inclusion criteria. The estimated true prevalence of CH patients with a positive family history was 6.27% (95% CI:4.65-8.40%) with an overall I 2 of 73% . Fitted models for gender subgroups showed higher estimates 9.26% (95% CI: 6.29-13.43%) in females. However the I 2 for the female model was 58.42% and significant (p=0.047). Conclusion: Our findings estimate a rate of family history in CH to be approximately 6.27% (95% CI:4.65-8.40%) . While estimates were larger for female probands, we demonstrated high heterogeneity in this subgroup. These findings further support a genetic role in the aetiology of CH.

Self-induced pneumoparotitis – a rare case report

Pneumoparotitis (pneumoparotiditis, pneumosialoadenitis) is a rare and frequently misdiagnosed condition. Signs of subcutaneous emphysema in parotid gland, the neck or the mediastinum are alarming symptoms that should be promptly addressed. Computed tomography, which is the gold diagnostic standard, may be successfully replaced with ultrasonography in the paediatric population. Sialography has a complementary role in the imaging of the gland, and allows for parotid duct irrigation to remove deposits and prevent recurrent inflammation. The paper presents a case of a 12-year-old boy who deliberately inflated his both parotid glands for about 6 months, and thus developed parotid pneumatocele with a diameter of about 25 mm. Diagnostic imaging was extended to include autoimmune diseases. Detailed family history was obtained. Conservative treatment, including dexamethasone irrigation of the Stensen’s duct, was used and the symptoms fully resolved. A 3-month follow-up showed no increase in the size of pneumatocele or episodes of parotiditis.

Muir-Torre Syndrome: The Importance of a Detailed Family History

Muir-Torre syndrome, a variant of Lynch syndrome or hereditary nonpolyposis colorectal cancer, is an autosomal dominant disease characterized by skin neoplasms (sebaceous or keratoacanthomas) and visceral malignancies. Due to the rarity of the syndrome there are no firm guidelines on how and when to test patients with its typical skin lesions. We describe a case that highlights the importance of a detailed family history.