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.
Biallelic mutations in DNAJC21 cause features overlapping with Dyskeratosis congenita and Shwachman‐Diamond syndrome.
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.
Identification of a homozygous truncating PIEZO2 mutation in three affected siblings from a consanguineous family showing short stature, scoliosis, gross motor impairment, a progressive form of contractures involving the distal joints and deficits in proprioception and touch sensation.
Objective
To evaluate the effectiveness of 200 mg of daily vaginal natural progesterone to prevent preterm birth in women with preterm labour.
Design
Multicentre, randomised, double‐blind, ...placebo‐controlled trial.
Setting
Twenty‐nine centres in Switzerland and Argentina.
Population
A total of 385 women with preterm labour (240/7 to 336/7 weeks of gestation) treated with acute tocolysis.
Methods
Participants were randomly allocated to either 200 mg daily of self‐administered vaginal progesterone or placebo within 48 hours of starting acute tocolysis.
Main outcome measures
Primary outcome was delivery before 37 weeks of gestation. Secondary outcomes were delivery before 32 and 34 weeks, adverse effects, duration of tocolysis, re‐admissions for preterm labour, length of hospital stay, and neonatal morbidity and mortality. The study was ended prematurely based on results of the intermediate analysis.
Results
Preterm birth occurred in 42.5% of women in the progesterone group versus 35.5% in the placebo group (relative risk RR 1.2; 95% confidence interval 95% CI 0.93–1.5). Delivery at <32 and <34 weeks did not differ between the two groups (12.9 versus 9.7%; RR 1.3; 95% CI 0.7–2.5 and 19.7 versus 12.9% RR 1.5; 95% CI 0.9–2.4, respectively). The duration of tocolysis, hospitalisation, and recurrence of preterm labour were comparable between groups. Neonatal morbidity occurred in 44 (22.8%) cases on progesterone versus 35 (18.8%) cases on placebo (RR: 1.2; 95% CI 0.82–1.8), whereas there were 4 (2%) neonatal deaths in each study group.
Conclusion
There is no evidence that the daily administration of 200 mg vaginal progesterone decreases preterm birth or improves neonatal outcome in women with preterm labour.
Both RBP1 and the highly related protein BCAA play a role in the induction of growth arrest and cellular senescence via mechanisms involving transcriptional repression. While investigating the ...transcriptional repression activities of RBP1, we observed a genetic link between RBP1 and SIR2. Further work uncovered an interaction between RBP1 family proteins and the mammalian homologue of SIR2, SIRT1. Interestingly, the HDAC-dependent transcriptional repression domain of RBP1 proteins, termed R2, is necessary and sufficient for the interaction with SIRT1. In vitro and in vivo binding studies indicated that the p33(ING1b) and p33(ING2) subunits of the mSIN3A/HDAC1 complex are responsible for the recruitment of SIRT1 to the R2 domain. To investigate the biological relevance of this interaction, we used the sirtuin activator resveratrol and the sirtuin inhibitor sirtinol in transcriptional repression assays and demonstrated that SIRT1 activity negatively regulates R2-mediated transcriptional repression activity. We therefore propose a novel mechanism of class I HDAC regulation by a class III HDAC. Explicitly, SIRT1 is recruited by ING proteins and inhibits R2-associated mSIN3A/HDAC1 transcriptional repression activity.
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.
Although the function of posttranscriptional processes in regulating the expression of genes involved in muscle fiber formation (myogenesis) is well accepted, the mechanisms by which these effects ...are mediated remain elusive. Here, we uncover such a mechanism and show that during myogenesis, a fraction of the posttranscriptional regulator human antigen R (HuR) is cleaved in a caspase-dependent manner in both cell culture and animal models. Disruption of caspase activity in cultured myoblasts or knocking out the caspase-3 gene in mice significantly reduced HuR cleavage and the cytoplasmic accumulation of HuR in muscle fibers. The non-cleavable isoform of HuR, HuRD226A, failed to reestablish the myogenic potential of HuR-depleted myoblasts. HuR cleavage generates two fragments: HuR-cleavage product 1 (HuR-CP1) (24 kDa) and HuR-CP2 (8 kDa). Here, we show that one of these fragments (HuR-CP1) binds to the HuR import factor transportin-2 (TRN2) allowing HuR to accumulate in the cytoplasm. As this cytoplasmic accumulation is required for the promyogenic function of HuR, our data support a model, whereby during the transition phase from myoblasts to myotubes, a proportion of HuR is cleaved to generate HuR-CP1. By interfering with the TRN2-mediated import of HuR, this CP helps non-cleaved HuR accumulate in the cytoplasm thus promoting myogenesis.
Background. To describe an accurate approach, hemostatic procedures and uterine repair in patients with anterior placenta percreta. Methods. A total of 68 patients with anterior placenta percreta ...were included. A large retrovesical and parametrial dissection was performed in all cases. Hemostasis was achieved with selective vascular ligature or with surgical myometrial compression. The anterior wall defect was repaired using a myometrial suture, fibrin glue and polyglycolic mesh. Finally, a nonadherent cellulose layer was applied over this reconstruction. Hysteroscopy and T2 magnetic resonance imaging (MRI) were performed as a reconstruction control at 90 days after discharge. Results. Elective surgery was performed in 49 patients and emergency surgery in 19. In 59 midline incisions were performed and in nine lower transverse incisions. Forty-nine patients underwent fundal hysterotomy and 19 transplacental segmental uterine approaches. The uteri of 50 patients with anterior placenta percreta were repaired. Of the 18 hysterectomies performed in this series, 16 were indicated due to massive destruction and two were secondary to coagulopathies. The following surgical complications developed: pelvic hemorrhage (one), coagulopathies (two), uterine infection (three), low ureteral ligations (two), iatrogenic foreign bodies (two) and collection (three). Uterine conservation was highly significant between the upper and lower invasion areas. Ten pregnancies were reported after the repair, resulting in uncomplicated cesarean delivery. Conclusion. This approach has allowed an adequate uterine repair in patients with anterior placenta percreta. Based on these results it is valid to assume that a functional and anatomic uterine repair has been successfully performed.
Objective
To analyse life‐threatening obstetric complications that occurred in public hospitals in Argentina.
Design
Multicentre collaborative cross‐sectional study.
Setting
Twenty‐five hospitals ...included in the Perinatal Network of Buenos Aires Metropolitan Area.
Population
Women giving birth in participating hospitals during a 1‐year period.
Methods
All cases of severe maternal morbidity (SMM) and maternal mortality (MM) during pregnancy (including miscarriage and induced abortion), labour and puerperium were included. Data were collected prospectively.
Main outcome measures
Identification criteria, main causes and incidence of SMM; case‐fatality rates, morbidity–mortality index and effective intervention's use rate.
Results
A total of 552 women with life‐threatening conditions were identified: 518 with SMM, 34 with MM. Identification criteria for SMM were case‐management (48.9%), organ dysfunction (15.2%) and mixed criteria (35.9%). Incidence of SMM was 0.8% (95% confidence interval 95% CI 0.73–0.87%) and hospital maternal death ratio was 52.3 per 100 000 live births (95% CI 35.5–69.1). Main causes of MM were abortion complications and puerperal sepsis; main causes of SMM were postpartum haemorrhage and hypertension. Overall case‐fatality rate was 6.2% (95% CI 4.4–8.6): the highest due to sepsis (14.8%) and abortion complications (13.3%). Morbidity‐mortality index was 15:1 (95% CI 7.5–30.8). Use rate of known effective interventions to prevent or treat main causes of MM and SMM was 52.3% (95% CI 46.9–57.7).
Conclusions
This study describes the importance of life‐threatening obstetric complications that took place in public hospitals with comprehensive obstetric care and the low utilisation of known effective interventions that may decrease rates of SMM and MM. It also provides arguments that justify the need to develop a surveillance system for SMM.
Abstract Objectives With medical improvements in pediatrics, the role of tracheotomy has evolved. The aim of this study was to specify the indications for and complications of tracheotomy performed ...on children in a teaching hospital containing a level-3 maternity department and pediatric intensive care unit. Material and methods A retrospective study was conducted in pediatric tracheotomies performed from 2004 to 2014. Indications, early and late complications and the number and timing of decannulations were collated. Results Fifty-seven patients were included. Tracheotomy was motivated by upper airway obstruction in 39 children (68%) (median age, 4.9 months) or the need for prolonged ventilation in 18 children (32%) (median age, 6 months). There were 4 early complications (7%) (2 decannulations, including 1 fatal; an obstructive plug, responsible for another death; and 1 pneumothorax during an EXIT procedure), and 15 secondary complications requiring further surgery (26%). Twenty-seven patients (47%) were decannulated, with a mean tracheotomy duration of 26 months. In 9 cases (33% of decannulations), persistence of tracheocutaneous fistula required surgical repair. Conclusion Tracheotomy for infection is almost a thing of the past; tracheotomy for airway obstruction is also likely to decrease, thanks to medical treatment (for hemangioma) and surgical techniques (for congenital stenosis). Tracheotomy for prolonged ventilation, on the other hand, remains. Complications of tracheotomy in children are rare but potentially serious, requiring care in a specialized center within a multidisciplinary team with defined care protocols.
Background. To describe an accurate approach, hemostatic procedures and uterine repair in patients with anterior placenta percreta.
Methods. A total of 68 patients with anterior placenta percreta ...were included. A large retrovesical and parametrial dissection was performed in all cases. Hemostasis was achieved with selective vascular ligature or with surgical myometrial compression. The anterior wall defect was repaired using a myometrial suture, fibrin glue and polyglycolic mesh. Finally, a nonadherent cellulose layer was applied over this reconstruction. Hysteroscopy and T2 magnetic resonance imaging (MRI) were performed as a reconstruction control at 90 days after discharge.
Results. Elective surgery was performed in 49 patients and emergency surgery in 19. In 59 midline incisions were performed and in nine lower transverse incisions. Forty‐nine patients underwent fundal hysterotomy and 19 transplacental segmental uterine approaches. The uteri of 50 patients with anterior placenta percreta were repaired. Of the 18 hysterectomies performed in this series, 16 were indicated due to massive destruction and two were secondary to coagulopathies. The following surgical complications developed: pelvic hemorrhage (one), coagulopathies (two), uterine infection (three), low ureteral ligations (two), iatrogenic foreign bodies (two) and collection (three). Uterine conservation was highly significant between the upper and lower invasion areas. Ten pregnancies were reported after the repair, resulting in uncomplicated cesarean delivery.
Conclusion. This approach has allowed an adequate uterine repair in patients with anterior placenta percreta. Based on these results it is valid to assume that a functional and anatomic uterine repair has been successfully performed.
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