Clinical and molecular features of 66 patients with musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14).

BACKGROUND: Musculocontractural Ehlers-Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated. METHODS: We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations. RESULTS: Sixty-six patients in 48 families (33 males/females; 0-59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype-phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE. CONCLUSION: This first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.

Positive Minimal Residual Disease of FLT3-ITD before Hematopoietic Stem Cell Transplantation Resulted in a Poor Prognosis of an Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) patients with fms-related tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) often have a poor prognosis, even after hematopoietic stem cell transplantation (HSCT). We report a case of AML with FLT3-ITD identified upon initial diagnosis, who received HSCT at complete remission after 3 consecutive chemotherapies. However, the patient relapsed when the same FLT3-ITD clone emerged, and finally died. Retrospective analysis revealed an allelic ratio of FLT3-ITD/wild type of 1.1 and 0.0096 upon initial diagnosis and before HSCT, respectively. The detection of any minimal residual FLT3-ITD clone before HSCT is useful in the treatment of AML with FLT3-ITD.

Role of Class III phosphoinositide 3-kinase in the brain development: possible involvement in specific learning disorders.

Class III phosphoinositide 3-kinase (PIK3C3 or mammalian vacuolar protein sorting 34 homolog, Vps34) regulates vesicular trafficking, autophagy, and nutrient sensing. Recently, we reported that PIK3C3 is expressed in mouse cerebral cortex throughout the developmental process, especially at early embryonic stage. We thus examined the role of PIK3C3 in the development of the mouse cerebral cortex. Acute silencing of PIK3C3 with in utero electroporation method caused positional defects of excitatory neurons during corticogenesis. Time-lapse imaging revealed that the abnormal positioning was at least partially because of the reduced migration velocity. When PIK3C3 was silenced in cortical neurons in one hemisphere, axon extension to the contralateral hemisphere was also delayed. These aberrant phenotypes were rescued by RNAi-resistant PIK3C3. Notably, knockdown of PIK3C3 did not affect the cell cycle of neuronal progenitors and stem cells at the ventricular zone. Taken together, PIK3C3 was thought to play a crucial role in corticogenesis through the regulation of excitatory neuron migration and axon extension. Meanwhile, when we performed comparative genomic hybridization on a patient with specific learning disorders, a 107 Kb-deletion was identified on 18q12.3 (nt. 39554147-39661206) that encompasses exons 5-23 of PIK3C3. Notably, the above aberrant migration and axon growth phenotypes were not rescued by the disease-related truncation mutant (172 amino acids) lacking the C-terminal kinase domain. Thus, functional defects of PIK3C3 might impair corticogenesis and relate to the pathophysiology of specific learning disorders and other neurodevelopmental disorders. Acute knockdown of Class III phosphoinositide 3-kinase (PIK3C3) evokes migration defects of excitatory neurons during corticogenesis. PIK3C3-knockdown also disrupts axon outgrowth, but not progenitor proliferation in vivo. Involvement of PIK3C3 in neurodevelopmental disorders might be an interesting future subject since a deletion mutation in PIK3C3 was detected in a patient with specific learning disorders (SLD).

Verification of risk scores to predict i.v. immunoglobulin resistance in incomplete Kawasaki disease.

BACKGROUND: A recent study indicated the efficacy of the addition of prednisolone to i.v. immunoglobulin (IVIG) as initial treatment in patients with higher risk of IVIG resistance. Several different risk scores for predicting IVIG resistance have been proposed, mainly based on typical Kawasaki disease (KD) patients. We investigated the utility of the risk scores to predict IVIG resistance in incomplete KD. METHODS: Clinical records of incomplete KD patients who received a single dose of IVIG between 2005 and 2012 at Kochi Health Sciences Center were retrospectively reviewed. Patients were classified into an IVIG-responsive group and an IVIG-resistant group. The Kobayashi, Egami, and Sano risk scores were calculated for each patient and the proportion of high-risk patients was compared between the two groups for each risk score. RESULTS: For 51 incomplete KD patients, Kobayashi (66.7% vs 47.6%, P = 0.253), Egami (55.6% vs 38.1%, P = 0.274), and Sano (57.1% vs 10.8%, P = 0.068) risk scores identified a higher proportion of high-risk patients in the IVIG-resistant group compared with the IVIG-responsive group, but significant difference was not observed. Sano risk score had the highest OR (6.19; 95%CI: 1.00-38.26). CONCLUSIONS: The proportion of patients identified as being at high risk for IVIG resistance using the Kobayashi, Egami, and Sano risk scores, respectively, was not significantly different between the IVIG-responsive group and the IVIG-resistant group for incomplete KD. Among the three risk scores, the Sano risk score has the best ability to predict IVIG resistance in incomplete KD.

Importance of Milk Expression for Preterm Infants.

Mothers of preterm infants may find it difficult to express breast milk. There is a low breast milk rate among preterm infants at discharge at our hospital, and here we tested the hypothesis that milk expression factors were the cause of the low rate. The study subjects were born before 33 gestational weeks at our hospital between March 2005 and June 2014. Nutritional evaluation was performed at discharge and noted whether breast milk, infant formula, or a mix of the 2 was being given. We compared the group given breast milk or the mix versus the group given formula. Of the 337 infants, 40 cases were excluded. Data from 297 infants were analyzed. The mean (SD) gestational age and birth weight were 29.5 (2.4) weeks and 1,230 (391) g, respectively. At discharge, 26 (8.8% ), 102 (33.3% ), and 174 (57.9% ) infants were given breast milk, formula, and the mix, respectively. A multivariate logistic regression analysis showed that the first milk expression (h) was the risk factor for the formula group: adjusted odds ratio (95% confidence interval) 1.06 (1.02-1.09) and p=0.002. Delayed first milk expression could affect the low breast milk rate at discharge. Improvement of milk expression should be achieved to promote breastfeeding.

Survival and Neurodevelopmental Outcomes of Very Low Birth Weight Infants in a Regional Core Hospital in Kochi, Japan.

We sought to clarify the survival and neurodevelopmental outcomes of very low birth weight infants (VLBWIs) and to identify risk factors for death or neurodevelopmental impairment (NDI) in VLBWIs at our hospital. The total study population was 217 infants born in 2005-2012 weighing 1,500 g. We compared their outcomes with those from previous reports analyzed the causes of death. Risk factors for death after discharge or NDI were evaluated by a multivariate logistic regression analysis. The incidences of death or NDI reported revealed in this study and the database of Neonatal Research Network of Japan were 25.3% and 19.6% (p＝0.039), respectively. The main causes of death before discharge were intraventricular hemorrhage, sepsis, and persistent pulmonary hypertension of the newborn. The significant risk factors for death after discharge or NDI were early gestational age (weeks) and periventricular leukomalacia (adjusted odds ratio [95% confidence interval, p-value], 0.72 [0.54-0.94, 0.017] and 6.90 [1.35-38.25, 0.021], respectively). These factors must be addressed in order to improve treatment strategies for VLBWIs.

Erythroblastosis of the Donor Twin of Twin Anemia-Polycythemia Sequence.

Twin anemia-polycythemia sequence (TAPS) is a group of disorders in monochorionic twins characterized by a large intertwin hemoglobin difference without amniotic fluid discordance. Reticulocyte count is used to diagnose this condition, but little is known about the role of erythroblasts, which are the prior stage of reticulocytes. In the present case of TAPS, the 25-yr-old Japanese mother showed no signs of oligohydramnios or polyhydramnios throughout gestation. The twins were born at 36 weeks and 6 days, weighing 2,648g and 1,994g. The intertwin hemoglobin difference in umbilical cord blood was (21.1－5.0＝) 16.1g/dL and the donor twin showed signs of chronic anemia, including myocardial hypertrophy and pericardial effusion. Erythroblastosis of the donor twin was prolonged (53,088.5, 42,114.8 and 44,217.9/µL on days 0, 1 and 2, respectively). Erythroblastosis, which indicates chronic anemia, is also a good diagnostic indicator of TAPS.

Changes in the features of invasive pneumococcal disease after introduction of the seven-valent pneumococcal conjugate vaccine in a regional core hospital of Kochi, Japan.

Since the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) in 2007, invasive pneumococcal disease has declined, but the incidence of Streptococcus pneumoniae serotype 19A has risen worldwide. The present study examined changes in the features of invasive pneumococcal disease since the introduction of the PCV7 in Kochi, Japan. Pediatric cases of invasive pneumococcal disease were investigated before and after vaccine introduction (January 2008 to December 2013). Cases of invasive pneumococcal disease tended to decrease after PCV7 introduction. In addition, before introduction of the vaccine, most serotypes causing invasive pneumococcal disease were those included in the vaccine. However, after the introduction, we found cases infected by serotypes not covered by vaccine. Penicillin-resistant S. pneumoniae was the predominant serotype causing invasive pneumococcal disease before introduction of the PCV7, and the susceptibility of this serotype to antibiotics improved after vaccine introduction. Serotype isolates identified after vaccine introduction were also relatively susceptible to antibiotic therapy, but decreased susceptibility is expected.

Ventriculoperitoneal shunt outcomes among infants.

Ventriculoperitoneal shunts (VPSs) are used for the treatment of hydrocephalus. Here we analyzed the outcomes of VPS placements in 24 infants to determine the risk factors for shunt failure. The infants had undergone the initial VPS operation in our hospital between March 2005 and December 2013. They were observed until the end of January 2014. We obtained Kaplan-Meier curves and performed a multivariate Cox regression analysis of shunt failure. Of the 24 cases, the median (range) values for gestational age, birth weight, and birth head circumference (HC) were 37 (27-39) wks, 2,736 (686-3,788) g, and 35.3 (23.0-45.3) cm, respectively. The total number of shunt procedures was 45. Shunt failure rates were 0.51/shunt and 0.0053/shunt/year. Shunt infection rates were 0.13/shunt and 0.0014/shunt/year. The Kaplan-Meier analysis revealed an increased risk for shunt failure in infants <1 month old or in the HC >90%tile. The Cox regression analysis yielded hazard ratios (HRs) of 2.93(95% confidence interval (CI), 0.96-10.95, p=0.059) for age <1 month, and 4.46 (95%CI:1.20-28.91, p=0.023) for the HC >90%tile. The multivariate Cox regression analysis showed adjusted HRs of 17.56 (95%CI:2.69-202.8, p=0.001) for age <1 month, and 2.95 (95%CI:0.52-24.84, p=0.228) for the HC >90%tile. Our findings thus revealed that the risk factors for shunt failure in infants include age <1 month at the initial VPS placement.

Reliability of a rapid test for the clinical diagnosis of influenza A/H1N1 2009.

BACKGROUND: The rapid diagnosis of a pandemic influenza A/H1N1 2009 (H1N1pdm) virus infection is required in ambulatory care settings, since early identification can prevent further transmission. However, the sensitivity of rapid influenza diagnostic tests (RIDTs) is still questionable, and specific indicators for H1N1pdm and/or false-negative results by RIDTs have not been clearly determined. METHODS: From June to December 2009, nasal swabs from 324 patients at Kochi Health Science Center were used for the diagnosis of infection by RIDT and reverse transcription polymerase chain reaction. RESULTS: The sensitivity of the RIDT was determined to be 80.0% and the specificity 97.1%. Multivariate analysis revealed that the frequencies of contagiousness and headache were significant in patients with H1N1pdm infection, in addition to common symptoms of respiratory infection. These data indicated that the H1N1pdm virus had high infectivity and was harmful to the endocranial environment. In the false-negative group, the time interval between onset and consultation was 5.5 ± 6.5 h (median ± interquartile range), which was significantly shorter than the 11.5 ± 7.0 h in the true-positive group. The sensitivity of the RIDT was significantly low during the time-period within 3 h from onset (56.0%); however after 4 h the sensitivity was determined to be >80%. These data indicated that the concentration of the virus in nasal swabs was elevated over the course of the disease. CONCLUSIONS: We have demonstrated that the RIDT is reliable for the diagnosis of H1N1pdm infection. Taking into consideration the time interval between onset and consultation and other features of H1N1pdm, such as contagiousness and headache, it may be necessary to re-test RIDT-negative cases later.

Minimally Conjoined Omphalopagus Twins with a Body Stalk Anomaly.

Introduction This report will discuss a case of minimally conjoined omphalopagus twins (MCOTs) with a body stalk anomaly (BSA). Case Report We experienced monochorionic diamniotic (MD) twins born at 31 weeks. One infant was suspicious of BSA before birth, and another infant was normal. But normal infant had anal atresia with small intestine which was inserted behind the umbilicus. Twins had very short common umbilicus and infant with BSA had intestinal conjunction, two appendixes at the site of the colon, and a blind-ending colon. We diagnosed MCOTs. Discussion On the basis of the Spencer hypothesis, the etiology of MCOTs was that MD twins shared a yolk sac. However, this could not explain the presence of a BSA. It is necessary to consider the possible reasons for a singleton BSA. In addition, intestinal fusion occurred unequally in this case, although two appendixes were found in the same place, which might have occurred because of the balanced fusion.