Peripheral lymphocytes and intracellular cytokines in C282Y homozygous hemochromatosis patients

BACKGROUND/AIMS: Several abnormalities in the immune status of hereditary hemochromatosis patients have been reported. We evaluated the peripheral blood lymphocytes phenotype and cytokine profile of CD8(+) and CD4(+) T cells in C282Y homozygous hereditary hemochromatosis patients compared to control subjects. METHODS: Peripheral blood lymphocytes from 17 asymptomatic patients and 14 control subjects were analyzed. We determined the distribution of lymphocyte subsets and investigated at single-cell level by flow-cytometry the potential of cytokines production. The frequency of cytokine (interferon gamma, tumor necrosis factor alpha, interleukin 2 (IL-2), IL-4, IL-5, IL-10 and IL-13) producing cells was assessed in total T-lymphocytes, CD3(+)CD8(+) and CD3(+)CD4(+) subsets. RESULTS: The patients studied showed a significant decrease of total lymphocyte count, T CD4(+)CD3(+), CD28(+), CD8(+)CD28(+) lymphocytes and natural killer (NK) CD56(+)CD16(+)CD3(-) cells. The reduction of CD28(+) and CD8(+)CD28(+) lymphocyte count was inversely related to transferrin saturation index. An increase in the ability of T-cells to produce all the cytokines studied and a major increase in IL-4 and IL-10 production in the CD3(+)CD8(+) subset was found. Our results demonstrate that activated Th1 and Th2 lymphocytes coexist in the peripheral blood of hereditary hemochromatosis patients and that T-cytotoxic (Tc) 2 subset is more expanded than in control population. CONCLUSIONS: The association of a decreased number of T CD8(+) cytotoxic lymphocytes and NK cells, and the development of Tc2 cells in asymptomatic C282Y homozygous patients represents an imbalance in their immune function that might contribute to the high incidence of hepatocarcinoma.     

Expresividad variable de una mutación fundadora en el gen EIF2AK4 en pacientes con enfermedad venooclusiva pulmonar hereditaria. Impacto en la supervivencia

Introduction and objectives

Hereditary pulmonary veno-occlusive disease (PVOD) has been associated with biallelic mutations in EIF2AK4 with the recent discovery of a founder mutation in Iberian Romani patients with familial PVOD. The aims of this study were phenotypical characterization and survival analysis of Iberian Romani patients with familial PVOD carrying the founder p.Pro1115Leu mutation in EIF2AK4, according to their tolerance to pulmonary vasodilators (PVD). Familial genetic screening was conducted, as well as assessment of sociocultural determinants with a potential influence on disease course.

Synchronous splenectomy during cholecystectomy for hereditary spherocytosis: Is it really necessary?

Background/Purpose

Expert guidelines recommend performing synchronous splenectomy in patients with mild hereditary spherocytosis (HS) and symptoms of gallstone disease. This recommendation has not been widely explored in the literature. The aim of this study is to determine if our data support expert opinion and if different practice patterns should exist.

Methods

This is an IRB-approved retrospective study. All HS patients under 18 years of age who underwent cholecystectomy for symptomatic gallstones at a single institution between 1981 and 2009 were identified. Patients who underwent cholecystectomy without concurrent splenectomy were reviewed retrospectively for future need for splenectomy and evidence of recurrent gallstone disease.

Results

Of the 32 patients identified, 27 underwent synchronous splenectomy. The remaining 5 patients underwent cholecystectomy without splenectomy and had a mean age of 9.4 years. One of the 5 patients eventually required splenectomy for left upper quadrant pain. None of the remaining 4 required hospitalization for symptoms related to hemolysis or hepatobiliary disease. Median follow-up is 15.6 years.

Conclusion

The need for splenectomy in patients with mild HS and symptomatic cholelithiasis should be assessed on a case by case basis. Our recommendation is to not perform synchronous splenectomy in conjunction with cholecystectomy for these patients if no indication for splenectomy exists.     

Spastin mutation screening in Chinese patients with pure hereditary spastic paraplegia

BackgroundHereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative diseases. Mutations in the spastin (SPAST) gene are the most common cause of pure HSP. However, few data are available regarding the clinical and genetic spectrum of HSP among Chinese patients.MethodsClinical data were collected at diagnosis and follow-up of 42 Chinese patients with pure HSP. All seventeen exons of the SPAST gene were directly sequenced. Additionally, we used a multiplex ligation dependent probe amplification (MLPA) assay targeting the SPAST gene to evaluate large exon deletion or insertion mutations in patients without SPAST point mutations.ResultsThe age of disease onset of our patients was 19.6 ± 14.4 years. Six novel variations were found, including three missense mutations (p. L363P, p. D441V, and p. S595R), one insertion (c.1511dupT (p. Y505Ifs*7)), and two larger deletions (exons 5–17 and exons 10–17). Four previously reported mutations, including p. S399L, c.1215_c.1219delTATAA (p. N405Kfs*36), exon 1 deletion, and exon 16 deletion, were detected. The SPAST mutation rate was 40% (4/10) in Chinese familial patients and 33.33% (7/21) in Chinese sporadic pure HSP patients. The frequency of large deletions was high in both AD-HSP (20%, 2/10) and sporadic HSP (14.28%, 3/21).ConclusionSPAST mutations are common in Chinese patients with pure HSP. Large exon deletions are an important cause of AD-HSP and sporadic pure HSP in Chinese patients. Large fragment tests should be performed to explore large SPAST mutations in familial and sporadic HSP patients without SPAST point mutations.     

东莞地区16182名个体18个耳聋易感基因100个变异位点的测序筛查

目的确定东莞地区耳聋基因的变异类型和携带率。方法收集新生儿及门诊筛查的16182名个体,新生儿采集足跟血片,非新生儿采集外周静脉血样,对18个耳聋易感基因的100种变异进行检测。结果共检出1631例耳聋基因变异,总体检出率为10.08%,其中5例为纯合变异。SLC26A4基因变异的检出率最高(5.22%),共845例,其余依次为GJB2(673例,4.16%)、GJB3(100例,0.62%)、TMC1(12例,0.07%)、MYO15A(1例,0.01%)。GJB2基因c.235delC变异检出率最高(3.24%),共524例,其次为SLC26A4基因IVS7-2A>G变异(270例,1.67%)。33名个体(0.20%)同时携带两个变异,其中7例(0.04%)携带同一基因的复合杂合变异。结论扩大耳聋易感基因变异的筛查范围有助于了解携带情况及耳聋的遗传因素,对提早发现先天性耳聋、对受检者提供干预和遗传咨询具有重要的价值。     

The spectrum of Lynch syndrome-associated germ-line mutations in Russia

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome (LS), is a common cancer-predisposing syndrome. This study aimed to investigate the spectrum of germ-line mutations in Russian LS patients. LS-related mismatch repair (MMR) genes were analyzed in 16 patients, who were forwarded to genetic testing due to strong clinical features of LS and had high-level microsatellite instability (MSI-H) in the tumor (n = 14) or unknown MSI status (n = 2). In addition, 672 consecutive colorectal cancer (CRC) cases were screened for family history; 15 patients were younger than 50 years and reported 2 or more instances of LS-related cancers in 1st- or 2nd-degree relatives. Seven of these cases demonstrated MSI-H and therefore were subjected to DNA germ-line testing. Overall, 17/23 (74%) subjects carried LS-associated gene variants (MLH1: 10; MSH2: 4; MSH6: 2; PMS2: 1), with 2 alleles (MLH1 c.677G > T and MSH2 с.1906G > C) detected twice. Testing for recurrent mutations of 30 consecutive MSI-H CRCs led to the identification of 2 additional subjects with LS. The analysis of all relevant publications identified 28 unrelated LS patients presented in Russian medical literature and 3 unrelated Russian LS subjects described in international journals. Overall, 15/49 (31%) genetic defects revealed in Russian LS patients were represented by six recurrent alleles (MLH1: c.350C > T, c.677G > T, c.1852_1854del; MSH2: c.942+3A > T, c.1861C > T, с.1906G > C). We conclude that the founder effect for LS in Russia is seemingly less pronounced than the one for hereditary breast-ovarian cancer syndrome, however testing for recurrent LS mutations may be considered feasible in some circumstances.     

Identification of germline pathogenic variants in DNA damage repair genes by a next-generation sequencing multigene panel in BRCAX patients

BackgroundApproximately 5–10% of breast carcinomas have been related to hereditary conditions and are attributable to pathogenic variants in the BRCA1 and BRCA2 genes, which is referred to as hereditary breast and ovarian cancer (HBOC) syndrome. The inclusion of additional genes that can be related to HBOC syndrome is under intense evaluation due to the high proportion of patients with HBOC criteria who do not present pathogenic mutations in BRCA genes, named BRCAX, despite having high clinical suspicion of hereditary cancer. The main aim is to identify new potentially pathogenic gene variants that may contribute to HBOC to improve the efficiency of routine diagnostic tests in this hereditary condition.MethodsA retrospective cohort of 77 HBOC BRCAX patients was analyzed by next-generation sequencing using a targeted multigene panel composed of 25 genes related to hereditary cancer and deficiencies in DNA repair pathways.ResultsWe found 9 variants in 7 different genes, which were confirmed by automated sequencing. Six variants were classified as pathogenic or likely pathogenic. Three of them were located in the PALB2 gene, one in the BRIP1 gene, one in the BARD1 gene and 1 in the RAD50 gene. In addition, three variants of uncertain significance (VUS) were detected in the TP53, CHEK2, and CDH1 genes.ConclusionsWe identified that 8% of BRCAX patients were carriers of pathogenic variants in genes other than BRCA1 and BRCA2. Therefore, wide gene panels, including clinically actionable genes, should be routinely used in the screening of HBOC in our population. We observed differences from other studies in the prevalence of mutated genes, most likely due to differences in the selection criteria of the probands and in the population analyzed. The high incidence of deleterious variant detection in PALB2 supports its significant role in breast cancer susceptibility and reinforces its inclusion in the HBOC genetic diagnostic process.     

Successful management with C1-inhibitor concentrate of hereditary angioedema attacks during two successive pregnancies: a case report

Backgroud Hereditary angioedema (HAE) is a rare genetic disorder caused by a deficiency of the plasma protein C1 inhibitor (C1-INH). HAE is characterised by the onset of angioedema, which may develop in one or several organs, and may last from a few hours to several days. Oedema of the upper airway can be life-threatening. As a result of hormonal changes, some women experience more frequent angioedema attacks during pregnancy. During pregnancy, antifibrinolytic agents should only be used with caution, and attenuated androgens are contraindicated; therefore, replacement therapy with C1-INH concentrate represents one of few therapeutic options, but it is not widely documented. Case study We report the first case study of the successful management with regular infusions of C1-INH concentrate, of two successive pregnancies in a patient with HAE. During the second half of the first pregnancy, C1-INH was administered on demand at home. For the second pregnancy, on demand treatment was intensified to prophylactic therapy, with once or twice weekly infusions from the middle of the second trimester in order to efficiently control the frequent attacks. Conclusions This report illustrates that HAE can be successfully managed during pregnancy with C1-INH infusions at home. Since the number of crises may vary between pregnancies, the treatment regimen must be adapted to the patient’s need.     

Treatment of three hereditary leiomyomatosis patients with cryotherapy

Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is an autosomal dominant disorder characterized by cutaneous leiomyomas (CLM), uterine leiomyomas, and the increased risk of renal cell carcinoma. Piloleiomyomas develop from the arrectorpili muscle and are usually painful. For 22% of the affected patients, the pain is reported to impair their life quality. Since there are few case reports about cryotherapy for cutaneous leiomyomas in the literature, we have decided to present three patients who had painful cutaneous leiomyomas treated with cryotherapy.