Diversity of RH and transfusion support in Brazilian sickle cell disease patients with unexplained Rh antibodies.

BACKGROUND: Genetic diversity in the RH genes among sickle cell disease (SCD) patients is well described but not yet extensively explored in populations of racially diverse origin. Transfusion support is complicated in patients who develop unexpected Rh antibodies. Our goal was to describe RH variation in a large cohort of Brazilian SCD patients exhibiting unexpected Rh antibodies (antibodies against RH antigens to which the patient is phenotypically positive) and to evaluate the impact of using the patient's RH genotype to guide transfusion support. STUDY DESIGN AND METHODS: Patients within the Recipient Epidemiology and Evaluation Donor Study (REDS)-III Brazil SCD cohort with unexpected Rh antibodies were selected for study. RHD and RHCE exons and flanking introns were sequenced by targeted next-generation sequencing. RESULTS: Fifty-four patients with 64 unexplained Rh antibodies were studied. The majority could not be definitively classified as auto- or alloantibodies using serologic methods. The most common altered RH were RHD*DIIIa and RHD*DAR (RHD locus) and RHCE*ce48C, RHCE*ce733G, and RHCE*ceS (RHCE locus). In 53.1% of the cases (34/64), patients demonstrated only conventional alleles encoding the target antigen: five of 12 anti-D (41.7%), 10 of 12 anti-C (83.3%), 18 of 38 anti-e (47.4%), and one of one anti-E (100%). CONCLUSION: RHD variation in this SCD cohort differs from that reported for African Americans, with increased prevalence of RHD*DAR and underrepresentation of the DAU cluster. Many unexplained Rh antibodies were found in patients with conventional RH allele(s) only. RH genotyping was useful to guide transfusion to determine which patients could potentially benefit from receiving RH genotyped donor units.

Clinical and genetic ancestry profile of a large multi-centre sickle cell disease cohort in Brazil.

Approximately 3500 children with sickle cell disease (SCD) are born in Brazil each year, but the burden of SCD morbidity is not fully characterised. A large, multi-centre cohort was established to characterise clinical outcomes in the Brazilian SCD population and create the infrastructure to perform genotype-phenotype association studies. Eligible patients were randomly selected from participating sites and recruited at routine visits. A biorepository of blood samples was created and comprehensive demographic and clinical outcome data were entered in a centralized electronic database. Peripheral blood genome-wide single nucleotide polymorphism (SNP) genotyping was performed using a customized Transfusion Medicine (TM) Array. A total of 2795 participants at six Brazilian sites were enrolled between 2013 and 2015. The cohort included slight predominance of children <18 years (55·9%) and females (53·0%). Haemoglobin (Hb) SS was the most common SCD genotype (70·7%), followed by HbSC (23%), Sß0 (3·0%) and Sß+ (2·9%). SNP data from the TM Array were analysed to evaluate the genetic ancestry of the cohort and revealed significant admixture among the population. Demographics and clinical complications, stratified by age and SCD genotype, are summarized and future studies in this cohort are discussed.

Valve-sparing aortic root replacement in patients with Marfan syndrome enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions.

BACKGROUND AND AIM OF THE STUDY: The long-term outcomes of aortic valve-sparing (AVS) root replacement in Marfan syndrome (MFS) patients remain uncertain. The study aim was to determine the utilization and outcomes of AVS root replacement in MFS patients enrolled in the Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). METHODS: At the time of this analysis, 788 patients with MFS were enrolled in the GenTAC Registry, of whom 288 had undergone aortic root replacement. Patients who had undergone AVS procedures were compared to those who had undergone aortic valve replacement (AVR). RESULTS: AVS root replacement was performed in 43.5% of MFS patients, and the frequency of AVS was increased over the past five years. AVS patients were younger at the time of surgery (31.0 versus 36.3 years, p = 0.006) and more likely to have had elective rather than emergency surgery compared to AVR patients, in whom aortic valve dysfunction and aortic dissection was the more likely primary indication for surgery. After a mean follow up of 6.2 +/- 3.6 years, none of the 87 AVS patients had required reoperation; in contrast, after a mean follow up of 10.5 +/- 7.6 years, 11.5% of AVR patients required aortic root reoperation. Aortic valve function has been durable, with 95.8% of AVS patients having aortic insufficiency that was graded as mild or less. CONCLUSION: AVS root replacement is performed commonly among the MFS population, and the durability of the aortic repair and aortic valve function have been excellent to date. These results justify a continued use of the procedure in an elective setting. The GenTAC Registry will be a useful resource to assess the long-term durability of AVS root replacement in the future.

New incidence, prevalence, and survival of Aicardi syndrome from 408 cases.

We sought to determine the incidence, prevalence, and life expectancy of Aicardi syndrome from 408 cases compiled from multiple international sources. Last known age ranged from less than 1 month to 42 years. The incidence rates per live births for the United States and The Netherlands were 1 per 105 000 and 1 per 93 000, respectively. The prevalence in the United States is greater than 853 cases, and the worldwide estimate is several thousand. Forty-five cases were deceased (age range, 1 month to 33 years), and the risk of death peaked at age 16. The probability of survival at 27 years of age was 0.62 (95% CI, 0.47-0.77). The risk of death by age follows other congenital neurological disorders with a wide range in severity of functional disability. The longer life expectancy found in our study hints at a higher functioning capacity in Aicardi syndrome and may inform counseling to families.

Marfan Syndrome and Quality of Life in the GenTAC Registry.

BACKGROUND: Previous small studies suggested reduced quality of life (QOL) for people with Marfan syndrome (MFS) compared with those without MFS. The national registry of GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) is a longitudinal observational cohort study of patients with conditions that predispose to thoracic aortic aneurysms and dissections, including MFS. At the time of registry enrollment, GenTAC study participants are asked to complete questionnaires about demographics, medical history, health habits, and QOL. OBJECTIVES: This study assessed QOL in GenTAC participants with MFS and identify associated factors using self-reported data. METHODS: QOL was assessed using the 4 subscales of the Physical Component Summary (PCS) of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36): physical functioning; role limitations due to physical health; bodily pain; and general health. We studied the association of QOL with self-reported demographics, health behaviors, physical impairments, surgeries, comorbid medical conditions, medications, and MFS severity. RESULTS: In the GenTAC registry, 389 adults with MFS completed the SF-36. Mean age was 41 years, 51% were men, 92% were white, and 65% were college graduates. The mean PCS composite score was 42.3. In bivariate analysis, predictors of better QOL included college education, marital status, higher household income, private health insurance, full-time employment, moderate alcohol use, fewer prior surgeries, fewer comorbid conditions, absence of depression, and less severe MFS manifestations. In a multivariable analysis, insurance status and employment remained significant predictors of QOL. CONCLUSIONS: In a large cohort of patients with MFS in the GenTAC registry, health-related QOL was below the population norm. Better QOL was independently associated with socioeconomic factors, not factors related to general health or MFS severity.

Associations of Age and Sex With Marfan Phenotype: The National Heart, Lung, and Blood Institute GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry.

BACKGROUND: The associations of age and sex with phenotypic features of Marfan syndrome have not been systematically examined in a large cohort of both children and adults. METHODS AND RESULTS: We evaluated 789 Marfan patients enrolled in the National Heart, Lung, and Blood Institute GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry (53% male; mean age 31 [range: 1-86 years]). Females aged ≥15 and males aged ≥16 years were considered adults based on average age of skeletal maturity. Adults (n=606) were more likely than children (n=183) likely to have spontaneous pneumothorax, scoliosis, and striae but were comparable in revised Ghent systemic score, ectopia lentis, and most phenotypic features, including prevalence of aortic root dilatation. Prophylactic aortic root replacement and mitral valve surgery were rare during childhood versus adulthood (2% versus 35% and 1% versus 9%, respectively, both P<0.0001). Adult males were more likely than females to have aortic root dilatation (92% versus 84%), aortic regurgitation (55% versus 36%), and to have undergone prophylactic aortic root replacement (47% versus 24%), all P<0.001. Prevalence of previous aortic dissection tended to be higher in males than females (25% versus 18%, P=0.06); 44% of dissections were type B. Type B dissection was strongly associated with previous prophylactic aortic root replacement. CONCLUSIONS: Pulmonary, skeletal, and aortic complications, but not other phenotypic features, are more prevalent in adults than children in Marfan syndrome. Aortic aneurysms and prophylactic aortic surgery are more common in men. Aortic dissection, commonly type B, occurs in an appreciable proportion of Marfan patients, especially in men and after previous prophylactic aortic root replacement.

Aortic Dissection in Patients With Genetically Mediated Aneurysms: Incidence and Predictors in the GenTAC Registry.

BACKGROUND: Aortic dissection (AoD) is a serious complication of thoracic aortic aneurysm (TAA). Relative risk for AoD in relation to TAA etiology, incidence, and pattern after prophylactic TAA surgery are poorly understood. OBJECTIVES: This study sought to determine the incidence, pattern, and relative risk for AoD among patients with genetically associated TAA. METHODS: The population included adult GenTAC participants without AoD at baseline. Standardized core laboratory tests classified TAA etiology and measured aortic size. Follow-up was performed for AoD. RESULTS: Bicuspid aortic valve (BAV) (39%) and Marfan syndrome (MFS) (22%) were the leading diagnoses in the studied GenTAC participants (n = 1,991). AoD occurred in 1.6% over 3.6 ± 2.0 years; 61% of AoD occurred in patients with MFS. Cumulative AoD incidence was 6-fold higher among patients with MFS (4.5%) versus others (0.7%; p < 0.001). MFS event rates were similarly elevated versus those in patients with BAV (0.3%; p < 0.001). AoD originated in the distal arch or descending aorta in 71%; 52% of affected patients, including 68% with MFS, had previously undergone aortic grafting. In patients with proximal aortic surgery, distal aortic size (descending thoracic, abdominal aorta) was larger among patients with AoD versus those without AoD (both p < 0.05), whereas the ascending aorta size was similar. Conversely, in patients without previous surgery, aortic root size was greater in patients with subsequent AoD (p < 0.05), whereas distal aortic segments were of similar size. MFS (odds ratio: 7.42; 95% confidence interval: 3.43 to 16.82; p < 0.001) and maximal aortic size (1.86 per cm; 95% confidence interval: 1.26 to 2.67; p = 0.001) were independently associated with AoD. Only 4 of 31 (13%) patients with AoD had pre-dissection images that fulfilled size criteria for prophylactic TAA surgery at a subsequent AoD site. CONCLUSIONS: Among patients with genetically associated TAA, MFS augments risk for AoD even after TAA grafting. Although increased aortic size is a risk factor for subsequent AoD, events typically occur below established thresholds for prophylactic TAA repair.

Risk of classic Kaposi sarcoma with exposures to plants and soils in Sicily.

BACKGROUND: Ecologic and in vitro studies suggest that exposures to plants or soil may influence risk of Kaposi sarcoma (KS). METHODS: In a population-based study of Sicily, we analyzed data on contact with 20 plants and residential exposure to 17 soils reported by 122 classic KS cases and 840 sex- and age-matched controls. With 88 KS-associated herpesvirus (KSHV) seropositive controls as the referent group, novel correlates of KS risk were sought, along with factors distinguishing seronegatives, in multinomial logistic regression models that included matching variables and known KS cofactors - smoking, cortisone use, and diabetes history. All plants were summed for cumulative exposure. Factor and cluster analyses were used to obtain scores and groups, respectively. Individual plants and soils in three levels of exposure with Ptrend ≤ 0.15 were retained in a backward elimination regression model. RESULTS: Adjusted for known cofactors, KS was not related to cumulative exposures to 20 plants [per quartile adjusted odds ratio (ORadj) 0.96, 95% confidence interval (CI) 0.73 - 1.25, Ptrend = 0.87], nor was it related to any factor scores or cluster of plants (P = 0.11 to 0.81). In the elimination regression model, KS risk was associated with five plants (Ptrend = 0.02 to 0.10) and with residential exposure to six soils (Ptrend = 0.01 to 0.13), including three soils (eutric regosol, chromic/pellic vertisol) used to cultivate durum wheat. None of the KS-associated plants and only one soil was also associated with KSHV serostatus. Diabetes was associated with KSHV seronegativity (ORadj 4.69, 95% CI 1.97 - 11.17), but the plant and soil associations had little effect on previous findings that KS risk was elevated for diabetics (ORadj 7.47, 95% CI 3.04 - 18.35) and lower for current and former smokers (ORadj 0.26 and 0.47, respectively, Ptrend = 0.05). CONCLUSIONS: KS risk was associated with exposure to a few plants and soils, but these may merely be due to chance. Study of the effects of durum wheat, which was previously associated with cKS, may be warranted.

Hemophilic siblings with chronic hepatitis C: Familial aggregation of spontaneous and treatment-related viral clearance.

BACKGROUND & AIMS: Hemophilic siblings provide a unique population to explore the natural history of chronic hepatitis C. METHODS: From 3993 hemophilic patients with hepatitis C, 257 sibling pairs, of which both members had evidence of hepatitis C infection, were studied to evaluate the genetic contribution to spontaneous and treatment-induced clearance of hepatitis C infection and progression of liver disease. Familial aggregation was assessed by comparing observed probabilities of concordance for these disease characteristics within sibling pairs to those expected for randomly paired hemophilic subjects. Additional measures of familial aggregation, heritability, and sibling relative risk were also calculated. RESULTS: Among human immunodeficiency virus-negative subjects, concordance for spontaneous viral clearance was 2-fold higher in siblings compared with randomly paired subjects (8.8% vs 4.3%, respectively, P = .04). Similarly, the concordance rate for treatment-related viral clearance was over twice that among sibling pairs than among randomly paired hemophiliacs (31.3% vs 13.3%, respectively, P = ns). Heritability estimates for spontaneous and treatment-induced viral clearance were 0.24 +/- 0.14 (P = .04) and 0.43 +/- 0.42 (P = .10), respectively. The sibling relative risks for these respective characteristics were 1.6 and 1.7. Concordance for advanced liver disease was higher among siblings but did not reach statistical significance (4.0% vs 2.3%, respectively, P = ns). The heritability estimate was 0.29 +/- 0.13 (P = .02). CONCLUSIONS: Concordance rates and heritability estimates for spontaneous and treatment-related viral clearance indicate that genetic factors have a modest influence on the outcome of hepatitis C, although shared environmental factors cannot be excluded. Investigations to map candidate disease-susceptibility genes associated with these characteristics must be approached with caution.