Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality.

BACKGROUND: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce. OBJECTIVE: Our aim was to describe the natural history of XLA. METHODS: A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base. RESULTS: Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease. CONCLUSIONS: This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients' clinical management and increase awareness among physicians.

Adducted thumb as an isolated morphologic finding: an early sonographic sign of impaired neurodevelopment: A STROBE compliant study.

Fetal adducted thumbs have been described in association with hydrocephalus and other abnormalities, but in cases without other structural malformations the determination of prognosis and recurrence risk is challenging. The aim of our study is to analyze the characteristics, natural history, and postnatal outcome of such cases.A retrospective study was conducted over a period of 4 years in a tertiary referral center. All fetuses diagnosed as adducted thumbs without other structural malformations comprised the study group. Prenatal sonographic features and neonatal outcome are documented.There were 4 cases of fetal adducted thumbs diagnosed during the study period. No cases demonstrated other structural malformations throughout the gestation. A smaller head was noted in 2 cases during the follow-up, and all cases presented with polyhydramnios on the first or ensuing scans. Three cases died after birth due to swallowing or breathing difficulty, and the surviving 1 showed convulsion and mental retardation.Fetal adducted thumb might be an early and specific sonographic marker of impaired neurodevelopment. Close follow-up and genetic investigation should be performed in these cases. Ultrasound examination plays an important role in the prenatal diagnosis and counseling of cases without detailed prenatal genetic analysis.

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study.

BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. OBJECTIVE: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. METHODS: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. RESULTS: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. CONCLUSIONS: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

Thinking of VACTERL-H? Rule out Fanconi Anemia according to PHENOS.

VACTERL-H association includes three of eight features: vertebral anomalies, anal atresia, congenital heart disease, tracheo-esophageal fistula, esophageal atresia, renal, limb anomalies, and hydrocephalus. The VACTERL-H phenotype among cases with FA is considered to be about 5%; the frequency of FA among patients with VACTERL-H is unknown. We examined 54 patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome Cohort for features of VACTERL-H, including imaging studies (radiology and ultrasound). Eighteen of the fifty-four patients had three or more VACTERL-H features. The presence of VACTERL-H association in 33% of those with FA is much higher than the previous estimate of 5% (P < 0.0001). We created the acronym PHENOS (Pigmentation, small Head, small Eyes, central Nervous system (not hydrocephalus), Otology, and Short stature) which includes all major phenotypic features of FA that are not in VACTERL-H; these findings were more frequent in the patients with FA who had VACTERL-H. Identification of any components of the VACTERL-H association should lead to imaging studies, and to consideration of the diagnosis of FA, particularly if the patient has radial ray and renal anomalies, as well as many features of PHENOS. There was no association of the presence or absence of VACTERL-H with development of cancer, stem cell transplant, or survival. Early diagnosis will lead to genetic counseling and early surveillance and management of complications of FA. © 2016 Wiley Periodicals, Inc.

Barlow's Mitral Valve Disease: A Comparison of Neochordal (Loop) and Edge-To-Edge (Alfieri) Minimally Invasive Repair Techniques.

BACKGROUND: Barlow's mitral valve (MV) disease remains a surgical challenge. We compared short- and medium-term outcomes of neochordal ("loop") versus edge-to-edge ("Alfieri") minimally invasive MV repair in patients with Barlow's disease. METHODS: From January 2009 to April 2014, 123 consecutive patients with Barlow's disease (defined as bileaflet billowing or prolapse [or both], excessive leaflet tissue, and annular dilatation with or without calcification) underwent minimally invasive MV operations for severe mitral regurgitation (MR) at our institution. Three patients (2.4%) underwent MV replacement during the study period and were excluded from subsequent analysis. The loop MV repair technique was used in 68 patients (55.3%) and an edge-to-edge repair was performed in 44 patients (35.8%). Patients who underwent a combination of these 2 techniques (n = 8 [6.5%]) were excluded. The median age was 48 years, and 62.5% of patients were men. Concomitant procedures included closure of a patent foramen ovale or atrial septal defect (n = 19), tricuspid valve repair (n = 5), and atrial fibrillation ablation (n = 15). Follow-up was performed 24.7 ± 17 months postoperatively and was 98% complete. RESULTS: No deaths occurred perioperatively or during follow-up. Aortic cross-clamp time (64.1 ± 17.6 minutes versus 95.9 ± 29.5 minutes) and cardiopulmonary bypass (CPB) time (110.0 ± 24.2 minutes versus 146.4 ± 39.1 minutes) were significantly shorter (p < 0.001) in patients who received edge-to-edge repair. Although patients who underwent edge-to-edge repair received a larger annuloplasty ring (38.6 ± 1.5 mm versus 35.8 ± 2.7 mm; p < 0.001), the early postoperative resting mean gradients were higher (3.3 ± 1.2 mm Hg versus 2.6 ± 1.2 mm Hg; p = 0.007) and the mitral orifice area tended to be smaller in this group (2.8 ± 0.7 cm(2) versus 3.0 ± 0.7 cm(2); p = 0.06). The amount of residual MR was similar between groups (0.3 ± 0.6 versus 0.6 ± 1.0 for edge-to-edge versus loop procedures, respectively; p = 0.08). More than mild MR requiring early MV reoperation was present in 3 patients who underwent loop procedures (4.4%) and in no patients who had edge-to-edge procedures (p = 0.51). During follow-up, 2 patients (1 in each group) required MV replacement for severe MR. The 4-year freedom from MV reoperation was 92.8% ± 5.0% in the Alfieri group compared with 90.9% ± 4.6% in the loop group (p = 0.94). CONCLUSIONS: Minimally invasive MV repair can be accomplished with excellent early and medium-term outcomes in patients with Barlow's disease. The edge-to-edge (Alfieri) repair can be performed with reduced operative times when compared with the loop technique, but it results in mildly increased transvalvular gradients and mildly decreased valve opening areas without any difference in residual MR.

Fetal-onset IPEX: report of two families and review of literature.

Early-life autoimmunity is an IPEX characteristic, however intrauterine forms had not yet been described. Here, two unrelated families with clear evidence of fetal-onset IPEX are reported. One had 5 miscarriages of males in two generations, and a newborn presenting type-1 diabetes mellitus immediately after birth, diarrhea, thrombocytopenia, eczematous dermatitis, eosinophilia, high IgE levels and autoantibodies to pancreatic islet antigens at 4-days-old. Maternal serology was negative. He presented a FOXP3 mutation, c.1189C>T, p.Arg397Trp, previously described only in another family with IPEX at birth. The second family had several miscarriages of males in three consecutive generations and a novel FOXP3 c.319_320delTC mutation was observed in two miscarried monochorionic twin male fetuses. These twins died at 21weeks of gestation due to hydrops, and CD3+ infiltrating lymphocytes were found in their pancreas. We demonstrate that: i) IPEX may develop in fetal life; and ii) c.1189C>T and c.319_320delTC mutations are associated with early-onset phenotype.

Hematopoietic Stem Cell Transplantation for X-Linked Thrombocytopenia With Mutations in the WAS gene.

X-linked thrombocytopenia (XLT) is a mild form of the Wiskott-Aldrich syndrome (WAS) caused by mutations in the WAS gene. A recent retrospective study of the clinical outcome and molecular basis of a large cohort of XLT patients demonstrated that although overall survival is excellent, event free survival is severely affected with conservative treatment. To answer the question whether hematopoietic stem cell transplantation (HSCT) offers a viable alternative therapeutic option in XLT, we retrospectively investigated the outcome of HSCT in a cohort of 24 XLT patients who received HSCT between 1990 and 2011 at 14 transplant centers in the United States, Italy, Germany, Canada, and Japan. The engraftment rate was 100% and the overall survival rate was 83.3%. Of the four non-survivors, 2 underwent splenectomy prior to HSCT and died of sepsis, and two of aspergillus infections associated with severe GVHD. In all but one patient, pretransplant complications were resolved by HSCT. Our data indicate that HSCT following myeloablative conditioning is curative and associated with acceptable risks as a treatment option for XLT.

Mortality and morbidity in patients with X-linked agammaglobulinaemia.

BACKGROUND: X-linked agammaglobulinaemia (XLA) is a genetic disorder characterised by a defect in the generation of mature B cells, lack of antibodies production, and susceptibility to recurrent bacterial infections. Understanding of the risk factors responsible for morbidity and mortality in these patients can help in a better management of this disorder. However, there is a lack of specific studies in the literature regarding the morbidity and mortality of XLA patients. This study is designed to evaluate morbidities and mortality and survival rates in Iranian patients with XLA diagnosis during the past 20 years. METHODS: We have registered the clinical data of the XLA patients and followed them up until 2010. At the time of diagnosis, a four-page questionnaire including complete medical information was filled out for all patients. Follow-up information was gathered either by reviewing the patients' hospital records or regularly visiting the patients. RESULTS: Among 41 patients, 26.8% died during the follow up period. All of the complications before the initiation of treatment such as pneumonia, otitis media and diarrhoea were reduced after immunoglobulin replacement, except sinusitis and conjunctivitis. There were significant associations between some immunological and clinical characteristics such as lymphocyte subsets, consanguinity marriage and mortality. CONCLUSION: Despite recent advances in the treatment of XLA, these patients still suffer from severe complications. Associations between poor prognosis and clinical and some immunological characteristics of the patients may help physicians to select poor prognoses patients at higher risk of mortality to develop prevention strategies for them.

Allogeneic hematopoietic cell transplantation for XIAP deficiency: an international survey reveals poor outcomes.

There have been no studies on patient outcome after allogeneic hematopoietic cell transplantation (HCT) in patients with X-linked inhibitor of apoptosis (XIAP) deficiency. To estimate the success of HCT, we conducted an international survey of transplantation outcomes. Data were reported for 19 patients. Seven patients received busulfan-containing myeloablative conditioning (MAC) regimens. Eleven patients underwent reduced intensity conditioning (RIC) regimens predominantly consisting of alemtuzumab, fludarabine, and melphalan. One patient received an intermediate-intensity regimen. Survival was poor in the MAC group, with only 1 patient surviving (14%). Most deaths were from transplantation-related toxicities, including venoocclusive disease and pulmonary hemorrhage. Of the 11 patients who received RIC, 6 are currently surviving at a median of 570 days after HCT (55%). Preparative regimen and HLH activity affected outcomes, and of RIC patients reported to be in remission from HLH, survival is 86% (P = .03). We conclude that MAC regimens should not be used for patients with XIAP deficiency. It is possible that the loss of XIAP and its antiapoptotic functions contributes to the high incidence of toxicities observed with MAC regimens. RIC regimens should be pursued with caution and, if possible, efforts should be made to ensure HLH remission before HCT in these patients.

Mitral valve reconstruction in Barlow disease: long-term echographic results and implications for surgical management.

OBJECTIVE: Owing to the complexity of the underlying lesions, Barlow disease remains a challenge for surgeons performing mitral valve repair. We aimed to assess whether our most recent results involving several surgeons were comparable with those of a previous experience in which mitral valve repair was performed by a more limited group of surgeons. METHODS: From September 2000 to January 2007, 200 patients with Barlow disease (135 men and 65 women; mean age, 56 ± 13 years) were referred to our institution for surgical treatment of their mitral regurgitation. We retrospectively analysed the mitral lesions characteristics, the surgical techniques used, and clinical outcomes. Follow-up echocardiograms were biannually reviewed. RESULTS: Lesions comprised annular dilatation, excess tissue, and leaflet prolapse in all cases. The most frequent prolapsed segments were P2 (88.5%; n = 177) and A2 (55.5%; n = 111). Annular calcifications and restrictive valvular motion were associated in 20% (n = 40). Repair was feasible in 94.7% (n = 179/189) of non-redo interventions. Immediate postoperative echocardiography showed residual mitral regurgitation greater than 1+ in 6 cases; these patients were all reoperated on within the next months. Operative mortality was 1.5% (n = 3). Mean follow-up was 77.5 ± 25.6 months. At 8 years postoperatively, overall survival was 88.6% ± 3.1%, freedom from reintervention was 95.3% ± 1.7%, and freedom from late recurrent moderate mitral regurgitation (>2+) was 90.2% ± 3.1% CONCLUSIONS: Provided that the fundamental principles of mitral valve reconstruction are respected, the surgical techniques are highly reproducible with good long-term results, similar to those published during the pioneering phase of this surgery.

Experience with bidirectional cavopulmonary anastomosis and modified Fontan operation in patients with single ventricle and concomitant visceral heterotaxy.

The object of our study was to analyze the results of bidirectional cavopulmonary anastomosis (BCPA) and modified Fontan operations (MFO) in patients with a functionally single ventricle and heterotaxy syndrome and to reveal risk factors for these surgical interventions. During 1983-2010, 681 patients underwent BCPA or MFO. Thirty-nine had heterotaxy syndrome. The median follow-up period after BCPA and MFO was nine and 1.5 years, respectively. Risk factors for lethal outcomes were determined by logistic regression analysis. Hospital mortality after BCPA and MFO was 7.9% and 12.5%, respectively and did not significantly differ from patients without heterotaxy. The most frequent hospital complications were heart failure, pleural effusions, and arrhythmias. Late mortality after BCPA and MFO was 8.7% and did not significantly differ from patients without heterotaxy. Late deaths were caused by congestive heart failure or pulmonary thromboembolism. The main non-lethal complication was arrhythmia. Patients have significantly improved their functional class at follow-up. The independent risk factor for lethal outcomes after BCPA and MFO was preoperative regurgitation at atrioventricular valves (P=0.012). BCPA and MFO in patients with a functionally single ventricle and heterotaxy syndrome allow to significantly improves their quality of life. Preoperative regurgitation at atrioventricular valves worsens surgical results.

Results of mitral valve repair for Barlow disease (bileaflet prolapse) via right minithoracotomy versus conventional median sternotomy: a randomized trial.

OBJECTIVE: The results of mitral repair for complex Barlow valves are adequate and support earlier intervention. It is unknown whether these results are reproducible in the context of minimally invasive surgery via right minithoracotomy. METHODS: We randomized patients with Barlow mitral disease (bileaflet prolapse) to have conventional open repair via median sternotomy (MS group) or minimally invasive (MI group) repair. Repair was done using polytetrafluoroethylene chordal reimplantation for both leaflets. In the MI group, we adopted right minithoracotomy, peripheral cannulation, external aortic clamping, and surgery under direct vision. RESULTS: Both groups comprised 70 patients. The operative and the cardiopulmonary bypass times were significantly longer in the MI group (P = .003 and P = .012). Mitral repair was successful in 98.5% MI patients and 100% MS patients. Operative mortality was comparable. The mean mechanical ventilation time, intensive care unit stay, and hospital stay were lower in the MI group (P = .014, P =.02, and P = .03,). Mean pain score was lower in the MI group at postoperative days 2 and 4. At follow-up, the freedom from moderate (2+) or severe (3+ or 4+) mitral regurgitation was 98% versus 97% (P = .9). Two patients underwent reoperation (1 in each group) for late failure of repair. The Kaplan-Meier analysis confirmed these results. CONCLUSIONS: Our data indicate that the optimal standard-of-care results of mitral repair for complex disease (Barlow) are reproducible in the minimally invasive settings through right minithoracotomy and direct vision. The minimally invasive technique can be proposed for complex mitral disease and early referral of these patients can be encouraged.

Increased postoperative and respiratory complications in patients with congenital heart disease associated with heterotaxy.

OBJECTIVE: Patients with heterotaxy and complex congenital heart disease underwent cardiac surgery with high mortality and morbidity. Recent studies have revealed an association among heterotaxy, congenital heart disease, and primary ciliary dyskinesia. We undertook a retrospective review of patients undergoing cardiac surgery at Children's National Medical Center between 2004 and 2008 to explore the hypothesis that there is increased mortality and respiratory complications in heterotaxy patients. METHODS: Retrospective review was performed on postsurgical outcomes of 87 patients with heterotaxy and congenital heart disease exhibiting the full spectrum of situs abnormalities associated with heterotaxy. As controls patients, 634 cardiac surgical patients with congenital heart disease, but without laterality defects, were selected, and surgical complexities were similar with a median Risk Adjustment in Congenital Heart Surgery-1 score of 3.0 for both groups. RESULTS: We found the mean length of postoperative hospital stay (17 vs 11 days) and mechanical ventilation (11 vs 4 days) were significantly increased in the heterotaxy patients. Also elevated were rates of tracheostomies (6.9% vs 1.6%; odds ratio, 4.6), extracorporeal membrane oxygenation support (12.6% vs 4.9%: odds ratio, 2.8), prolonged ventilatory courses (23% vs 12.3%; odds ratio, 2.1) and postsurgical deaths (16.1% vs 4.7%; odds ratio, 3.9). CONCLUSIONS: Our findings show heterotaxy patients had more postsurgical events with increased postsurgical mortality and risk for respiratory complications as compared to control patients with similar Risk Adjustment in Congenital Heart Surgery-1 surgical complexity scores. We speculate that increased respiratory complications maybe due to ciliary dysfunction. Further studies are needed to explore the basis for the increased surgical risks for heterotaxy patients undergoing cardiac surgery.

Heterotaxy syndrome: defining contemporary disease trends.

The purpose of this study was to define a population of visceral heterotaxy and to investigate the incidence of bacterial sepsis in the current era of universal pediatric pneumococcal immunization. Pediatric echocardiography and radiology databases, along with electronic medical records, were searched for patients followed-up since birth between 1999 and 2009 with either asplenia or polysplenia and cardiac anatomy consistent with heterotaxy syndrome. A total of 29 patients were identified. Seven patients (24%) had a total of 8 sepsis events, and 6 patients (86%) developed sepsis while taking appropriately prescribed antibiotic prophylaxis. Of the patients with sepsis, 5 had polysplenia and 2 had asplenia. Sixty-two percent of sepsis events were nosocomially acquired. No cases of pneumococcal sepsis occurred after the introduction of the conjugated pneumococcal vaccination to the pediatric vaccination schedule. Bacterial sepsis was associated with a 44% mortality rate. An unexpected finding in 3 patients with visceral heterotaxy, asplenia, and an interrupted inferior vena cava (IVC) as the only anomaly on echocardiography was associated intestinal malrotation. Children with visceral heterotaxy remain at significant risk of life-threatening bacterial infection. In addition, the finding of interrupted IVC on echocardiography should prompt screening for intestinal malrotation, even in the absence of additional structural heart disease.

Trends and racial disparities in muscular dystrophy deaths in the United States, 1983-1998: an analysis of multiple cause mortality data.

To identify trends and patterns associated with muscular dystrophy (MD)-associated deaths, we analyzed population-based data from death certificates in the Multiple Cause Mortality Files compiled by the National Center for Health Statistics. From 1983 to 1998, 14,499 deaths in the United States were associated with ICD-9 codes for MD. The mortality rate for MD in the general U.S. population over this time period was 0.365 per 100,000 persons per year. Stratification by age at death revealed a trimodal distribution with peaks at 0, 17, and 62 years. The male-to-female ratio varied with age at death, a pattern consistent with a mixture of autosomal and X-linked MDs with different prognoses. Deaths related to MD appeared to be equally divided between presumed autosomal and X-linked MDs. The mortality rate was higher in Whites than in Blacks, for both autosomal and X-linked MDs. The median age at death was lower in Blacks than Whites for both males and females. Cardiac complications were more commonly noted among MD-associated deaths in Blacks (38.9%) than Whites (28.6%). Respiratory infections were noted in about 20% of MD-associated deaths and were more common in winter than summer months. Potential reasons for the racial differences include differences in prevalence rates, rates of diagnosis, and reporting on death certificates. Additional studies are needed to resolve these issues. Challenges in the interpretation of these data include the lack of ICD-9 codes specific for individual MDs and potential recording biases in underlying cause of death and contributing factors. We also present a method for estimating autosomal and X-linked contributions to the overall mortality rate of a genetically heterogeneous condition such as MD.