Refining the phenotype associated with biallelic DNAJC21 mutations.

Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes involved in genomic stability. Although they may be recognized by the association of typical clinical features, variable penetrance and expressivity are common, and clinical diagnosis is often challenging. DNAJC21, which is involved in ribosome biogenesis, was recently linked to bone marrow failure. However, the specific phenotype and natural history remain to be defined. We correlate molecular data, phenotype, and clinical history of 5 unreported affected children and all individuals reported in the literature. All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities. Additional features present in some individuals include retinal abnormalities, pancreatic insufficiency, liver cirrhosis, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, and cryptorchidism. We suggest that DNAJC21-related diseases constitute a distinct IBMFS, with features overlapping Shwachman-Diamond syndrome and Dyskeratosis congenita, and additional characteristics that are specific to DNAJC21 mutations. The full phenotypic spectrum, natural history, and optimal management will require more reports. Considering the aplastic anemia, the possible increased risk for leukemia, and the multisystemic features, we provide a checklist for clinical evaluation at diagnosis and regular follow-up.

Loss of the proprioception and touch sensation channel PIEZO2 in siblings with a progressive form of contractures.

Dominant mutations in PIEZO2, which codes for the principal mechanotransduction channel for proprioception and touch sensation, have been found to cause different forms of distal arthrogryposis. Some observations suggest that these dominant mutations induce a gain-of-function effect on the channel. Here, we report a consanguineous family with three siblings who showed short stature, scoliosis, gross motor impairment, and a progressive form of contractures involving the distal joints that is distinct from that found in patients with dominant mutations in PIEZO2. These siblings also displayed deficits in proprioception and touch sensation. Whole-exome sequencing performed in the three affected siblings revealed the presence of a rare homozygous variant (c.2708C>G; p.S903*) in PIEZO2. This variant is predicted to disrupt PIEZO2 function by abolishing the pore domain. Sanger sequencing confirmed that all three siblings are homozygous whereas their parents and an unaffected sibling are heterozygous for this variant. Recessive mutations in PIEZO2 thus appear to cause a progressive phenotype that overlaps with, while being mostly distinct from that associated with dominant mutations in the same gene.

Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly.

We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare variant, a missense in SLC1A4 (c. 766G>A [p. E256K]), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. L-Serine is essential for neuronal survival and differentiation. Indeed, L-serine biosynthesis disorders affect brain development and cause severe ID. In the brain, L-serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of L-serine into neurons and the release of glia-borne L-serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of L-serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID.

Polymicrogyria with dysmorphic basal ganglia? Think tubulin!

Dominant mutations in TUBB2B have been reported in patients with polymicrogyria. We further explore the phenotype associated with mutations in TUBB2B. Twenty patients with polymicrogyria (five unilateral) were tested for mutations in TUBB2B by Sanger sequencing. We identified two novel de novo mutations, c.743C>T (p.Ala248Val) and c.1139G>T (p.Arg380Leu) in exon 4 of TUBB2B in three unrelated families. Brain magnetic resonance images showed polymicrogyria involving predominantly the perisylvian regions. In addition, there was a dysmorphic appearance of the basal ganglia, thin corpus callosum, enlargement of the ventricles, thinning of the white matter and hypoplasia of pons and cerebellar vermis. This combination of associated features was absent in all 17 patients with polymicrogyria in whom no mutation was identified. This report underlines that the association of polymicrogyria with thin or absent corpus callosum, dysmorphic basal ganglia, brainstem and vermis hypoplasia is highly likely to result from mutations in TUBB2B and provides further insight in how mutations in TUBB2B affect protein function.

Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype.

Despite a wide range of clinical tools, the etiology of mental retardation and multiple congenital malformations remains unknown for many patients. Array-based comparative genomic hybridization (aCGH) has proven to be a valuable tool in these cases, as its pangenomic coverage allows the identification of chromosomal aberrations that are undetectable by other genetic methods targeting specific genomic regions. Therefore, aCGH is increasingly used in clinical genetics, both in the postnatal and the prenatal settings. While the diagnostic yield in the postnatal population has been established at 10-12%, studies investigating fetuses have reported variable results. We used whole-genome aCGH to investigate fetuses presenting at least one major malformation detected on ultrasound, but for whom standard genetic analyses (including karyotype) failed to provide a diagnosis. We identified a clinically significant chromosomal aberration in 8.2% of tested fetuses (4/49), and a result of unclear clinical significance in 12.2% of tested fetuses (6/49). Our results document the value of whole-genome aCGH as a prenatal diagnostic tool and highlight the interpretation difficulties associated with copy number variations of unclear significance.

Isolated mitral valve replacement with St. Jude medical prosthesis: long-term results: a follow-up of 19 years.

BACKGROUND: In this retrospective study, approximately 440 patients received mitral valve replacements with the St Jude Medical prosthesis. The last patient was operated on 10 years before the beginning of the follow-up. The extended follow-up was 19 years. METHODS AND RESULTS: Four hundred forty patients (sex ratio, 1.32 [men to women]; age, 60+/-11.4 years; age range, 7 to 75 years) were operated on from 1979 to 1987. All patients underwent isolated mitral valve replacement. Tricuspid plasty was the only associated procedure. The follow-up at 19 years was 98% complete. The overall actuarial survival rate was 63+/-3.3% at 19 years, and the actuarial survival rate (only valve related) was 83+/-2.7%. The operative mortality rate (0 to 30 days) was 4.09%. We found that 89.4% of the patients alive at 19 years were in NYHA class I/II. Multivariate analysis showed that age and sex were significantly correlated with valve-related mortality and that age, sex, NYHA class, and atrial fibrillation were significantly correlated with overall mortality. The linearized rates (percent patient-years) of thromboembolism, thrombosis, and hemorrhage were 0.69, 0.2, and 1, respectively. At 19 years, freedom from endocarditis and reoperation was 98.6+/-1% and 90+/-3%, respectively. CONCLUSIONS: In this study, the very-long-term results confirm the excellent durability of the St Jude Medical prosthesis in the mitral position and show the difficulty of adjusting the anticoagulation protocol, even after long-term treatment.

ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus.

One major function of the hypothalamus is to maintain homeostasis by modulating the secretion of pituitary hormones. The paraventricular (PVN) and supraoptic (SON) nuclei are major integration centers for the output of the hypothalamus to the pituitary. The bHLH-PAS transcription factor SIM1 is crucial for the development of several neuroendocrine lineages within the PVN and SON. bHLH-PAS proteins require heterodimerization for their function. ARNT, ARNT2, and BMAL1 are the three known general heterodimerization partners for bHLH-PAS proteins. Here, we provide evidence that Sim1 and Arnt2 form dimers in vitro, that they are co-expressed in the PVN and SON, and that their loss of function affects the development of the same sets of neuroendocrine cell types within the PVN and SON. Together, these results implicate ARNT2 as the in vivo dimerization partner of SIM1 in controlling the development of these neuroendocrine lineages.

[Recent progress in treatment of malignant pleural mesothelioma]. / Progrès thérapeutiques récents dans le mésothéliome malin primitif de la plèvre.

Incidence of malignant pleural mesothelioma will rise until 2030-2040 because the elapsed time between exposure and diagnostic is up to several decades. Prognosis remains very poor with median survival less than one year and five-year survival not exceeding 5%. As compared to 1999, standart treatment adds chemotherapy with cisplatin and pemetrexed to local radiotherapy for prevention of local seeding after invasive diagnostic procedures. Despite various growth factors and their receptors are involved in malignant mesothelioma, first clinical trials of targeted therapies reported poor results. Multimodality therapy with extrapleural pneumonectomy and radiation therapy (+/-chemotherapy) can be of benefit in subgroups of patients but it cannot be recommended in a routine approach. As compared to bronchial carcinoma, inclusion of patients in clinical trials (using intensity-modulated radiation therapy) is the only way to somewhat improve results.

Safety, tolerability and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil based formulation of cyclosporine--results at six months after transplantation.

BACKGROUND: The introduction of cyclosporine has resulted in significant improvement in the survival of cardiac allograft recipients due to decreased mortality from infection and rejection. The original oil-based cyclosporine formulation exhibits variable and unpredictable bioavailability that correlates with an increased incidence of acute and chronic rejection in those patients in whom this is most pronounced. The primary objectives of this prospective, multicenter, randomized, double-blind study in cardiac transplant patients were: to compare the efficacy of cyclosporine microemulsion (CsA-NL) with oil-based cyclosporine (CsA-SM) as measured by cardiac allograft and recipient survival and the incidence and severity of acute rejection episodes; and to assess the safety and tolerability of CsA-NL compared with CsA-SM in this population. This report represents the analysis of results 6 months after transplantation. METHODS: A total of 380 patients undergoing their first cardiac transplant at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial examining the safety and efficacy of CsA-NL versus CsA-SM. Rejection was diagnosed using endomyocardial biopsy and were graded according to standardized criteria of the International Society of Heart and Lung Transplantation (ISHLT). Clinical parameters were monitored during the study. Survival and freedom from were used for analysis as was Fisher's exact test for comparisons between groups. RESULTS: At 6 months after transplantation, allograft and patient survival were the same for both groups. The frequency of ISHLT grade 3A or greater episodes in the two groups was identical. Fewer CsA-NL patients (5.9%) required antilymphocyte antibody (ATG or OKT-3) therapy for rejection compared with the CsA-SM-treated patients (14.1%, P=0.01). Females with ISHLT rejection grade > or = 3A treated with CsA-NL had a 46% lower incidence of rejection compared with the CsA-SM-treated group (31.3% vs. 57.6%, P=0.032). Fewer infections were seen in the CsA-NL. With the exception of baseline and 1 week posttransplant creatinines which were higher in the CsA-NL group, the overall creatinine was not significantly different between the two groups. CONCLUSIONS: This multicenter, randomized study of cardiac transplant recipients documented less severe rejection (in particular those requiring antibody therapy) and a lower incidence of infection in CsA-NL-treated patients. Results from the female subgroup analysis suggest that the improved bioavailability of CsA-NL might reduce the frequency of rejection episodes in female patients. The use of CsA-NL was not associated with an increased risk of adverse events.

Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.

BACKGROUND: The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. METHODS: A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. RESULTS: After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. CONCLUSIONS: The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.

Atrial myxoma mimicking systemic disease. Profile modified by flurbiprofen administration.

A patient had a left atrial myxoma which was modified by flurbiprofen administration. The diagnosis was made 42 months after the first symptoms appeared. Flurbiprofen may have reduced interleukin-6 secretion by the tumor, leading to a delayed diagnosis.

Aggressive surgical management in localized pulmonary mycotic and nonmycotic infections for neutropenic patients with acute leukemia: report of eighteen cases.

OBJECTIVE: To prevent hemoptysis and relapse during subsequent chemotherapy-induced neutropenia in patients with localized forms of invasive pulmonary aspergillosis, we adopted an aggressive surgical approach. METHODS: From 1988 to 1996, 18 patients with hematologic diseases were referred with the diagnosis of localized invasive pulmonary aspergillosis. The diagnosis was based on clinical features, failure to respond to antibiotic therapy, an air crescent sign suggestive of aspergillosis on the computed tomographic scan (39%), and retrieval of fungi by bronchoalveolar lavage (44%). RESULTS: The following procedures were done: one pneumonectomy, four bilobectomies, seven lobectomies, six wedge resections, and one lobectomy with wedge resection (one patient had two procedures). No perioperative deaths or complications occurred. The histologic examination confirmed the diagnosis of invasive pulmonary aspergillosis in 12 patients. The six other diagnoses were as follows: one case of classic aspergilloma, one case of pneumonia, and four cases of pulmonary abscess. According to univariate analysis, thoracic pain was less common in the group with noninvasive pulmonary aspergillosis (1/6) than in the group with invasive pulmonary aspergillosis (8/12) (p < 0.05). Sixteen patients required subsequent hematologic treatments. Sixty-six percent of the patients are alive with a mean follow-up of 29.1 +/- 27.8 months (range 2 to 103 months), with no statistically significant difference between the invasive and the noninvasive pulmonary aspergillosis groups. Five patients died of a recurrence of their malignant disease at a mean of 17.2 +/- 12.5 months (range 2 to 30 months), and one had a cerebral recurrence of Aspergillus infection during a bone marrow transplantation 3 months later. CONCLUSION: Aggressive surgical management radically improves the prognosis of invasive pulmonary aspergillosis, even if the surgical indications include some nonmycotic infections because of the difficulty in establishing the clinical diagnosis.

Complete myocardial revascularization through a right thoracotomy.

We report the case of a 57-year-old woman who benefited from a complete revascularization of the heart, including a circumflex marginal coronary bypass grafting, through a right thoracotomy. This approach avoids sternal wound complications that can occur after high-dose mediastinal radiotherapy and omental flap reconstruction on the sternum.

Right ventricular function early after total or standard orthotopic heart transplantation.

Right ventricular failure after orthotopic heart transplantation (OHT) is classically related to preoperative pulmonary hypertension. However, the role of the enlarged atria in right ventricular dysfunction after OHT remains unclear. For that purpose, the right ventricular function in the first 2 days after OHT was compared in two groups of transplant recipients: 11 patients who underwent standard OHT (group I) and 9 patients who underwent total OHT, which consisted of total excision of both the left and right atria and OHT of an intact donor heart with its atria as well as its ventricle (group II). Right ventricular ejection fraction, cardiac index, and right-sided pressures were recorded at baseline and 4, 8, 12, 24, and 48 hours after OHT using a Swan-Ganz catheter with a rapid-response thermistor. Right ventricular function parameters did not differ between groups; they were characterized by a decrease in right ventricular ejection fraction and an increase in right ventricular end-diastolic volume index whereas cardiac index and right-sided pressures remained normal or slightly increased. Ischemic time (177 +/- 41 minutes in group I versus 178 +/- 39 minutes in group II) and preoperative pulmonary vascular resistance (1.9 +/- 0.7 Wood units in group I versus 3.0 +/- 1.5 Wood units in group II) were not different between groups. These results suggest that the anatomic and physiologic advantages offered by the modified technique of OHT had no clinical relevance in this group of patients with low preoperative pulmonary vascular resistances when compared with a group of patients who underwent transplantation with the standard technique.(ABSTRACT TRUNCATED AT 250 WORDS)

Early and late outcome after elective cardiac surgery in patients with cirrhosis.

BACKGROUND: A prospective study was performed to evaluate the early and late outcome after elective cardiac surgery in patients with cirrhosis. METHODS: All patients who underwent elective cardiac surgery between 1995 and 1997, and were suspected of having a history of cirrhosis, were followed in the intensive care unit (ICU), during hospitalization and after hospital discharge. All patients received high doses of aprotinin during surgery. RESULTS: Ten patients of Child-Pugh class A and 2 patients of Child-Pugh class B were studied. All patients had signs of portal hypertension, and 11 of 12 patients had thrombocytopenia. In the first 24 h after operation, the median chest tube output was 810 mL (range 350 to 1,500 mL). Median ICU and hospital stays were 3 and 15 days, respectively (range 2 to 10 and 7 to 36 days, respectively). Seven patients experienced postoperative morbidity and 7 patients had significant complications after their hospital discharge. One death occurred in the ICU. Two deaths occurred after hospital discharge and were related to further hepatic damage. CONCLUSIONS: These results suggest that, in patients with mild or moderate cirrhosis, the incidence of significant complications was high after elective cardiac surgery, increasing the length of stay in ICU and overall hospitalization time and compromising the health status, even well after the operation.

Mitral valve replacement with the St. Jude Medical prosthesis: a 15-year follow-up.

BACKGROUND: A retrospective study was conducted to analyze the results of St. Jude Medical mitral valve replacement. METHODS: From January 1979 to December 1989, 870 patients (54% women, 46% men; mean age, 55.8 +/- 6.2 years) underwent mitral valve replacement with the St. Jude Medical prosthesis. Of these operations 616 were isolated mitral valve replacements and 254 were double valve replacements. Coronary artery bypass grafting was performed concomitantly in 55 patients (6.3%). RESULTS: Overall, early mortality was 5.05%, with 4.2% for the isolated mitral valve procedure and 7.08% for the double valve replacement. Follow-up at 15 years was complete in 859 patients (98.74%). Mean follow-up time was 93.5 months, for a total of 6,436 years. Actuarial survival at 15 years was 59.5% +/- 5%, 60.5% +/- 6%, and 56.9% +/- 9%, for the entire group, the isolated mitral valve and double valve procedures, respectively. Multivariate analysis identified age, sex, hospital stay, and preoperative mitral regurgitation as independent prognosis factors for overall mortality. Of 606 patients alive at the latest follow-up, the New York Heart Association class improved significantly (from 67% class III/IV before the operation to 88% class I/II after the operation). All patients received warfarin to maintain an international normalized ratio between 3.5 and 4. The linearized rates (% per patient-year) of thrombosis, thromboembolism, and major hemorrhage were, respectively, 0.21, 0.75, and 0.94 for the entire group; 0.18, 0.67, and 0.88 for the isolated mitral valve operation; and 0.15, 0.92, and 1.08 for the double valve replacement. For the entire group the freedom from thrombosis and thromboembolism at 15 years was 98.1% +/- 1% and 88% +/- 4%, respectively. No case of structural dysfunction occurred. The freedom from paravalvular leak and endocarditis at 15 years was 95.3% +/- 2% and 97.3% +/- 2.4%, respectively. The probability of remaining free from reoperation at 15 years was therefore 95.6% +/- 2.5%. CONCLUSIONS: These results confirm that the St. Jude Medical valve is a reliable prosthesis with very low thrombosis and thromboembolism rates, allowing the use of a low dose of anticoagulation with an international normalized ratio of about 3.

Surgical resection of pulmonary metastases from colorectal carcinoma. Five-year survival and main prognostic factors.

Between 1986 and 1994, 19 patients underwent pulmonary resection for metastatic colorectal carcinoma. The mean interval between colon resection and appearance of pulmonary metastasis was 41 +/- 21 months. All the patients had no more than two metastases. Wedge resection alone or associated with lobectomy was performed in four patients, lobectomy in ten, and pneumonectomy in five. One patient died within the month after surgery. Mean follow-up was 35 +/- 26 months. The 5-year survival rate was 38.7%. Repeat thoracotomy for recurrent metastases was performed in one patient. The disease-free interval, the size of metastases, the type of pulmonary resection, and the location and the stage of primary cancer had no apparent influence on survival, but the survival rate at 4 years was 25% for patients with high carcinoembryonic antigen (CEA) level versus 80% for those with low CEA level. We conclude that, at least when the number of metastases is less than two, resection of colorectal lung metastasis is safe and effective.