Search

SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction ( IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Whole-exome sequencing ( WES) has transformed our ability to detect mutations causing rare diseases. FORGE (Finding Of Rare disease GEnes) and Care4Rare Canada are nation-wide projects focused on identifying disease genes using WES and translating this technology to patient care. Rare forms of epilepsy are well-suited for WES and we retrospectively selected FORGE and Care4Rare families with clinical descriptions that included childhood-onset epilepsy or seizures not part of a recognizable syndrome or an early-onset encephalopathy where standard-of-care investigations were unrevealing. Nine families met these criteria and a diagnosis was made in seven, and potentially eight, of the families. In the eight families we identified mutations in genes associated with known neurological and epilepsy disorders: ASAH1, FOLR1, GRIN2A (two families), SCN8A, SYNGAP1 and SYNJ1. A novel and rare mutation was identified in KCNQ2 and was likely responsible for the benign seizures segregating in the family though additional evidence would be required to be definitive. In retrospect, the clinical presentation of four of the patients was considered atypical, thereby broadening the phenotypic spectrum of these conditions. Given the extensive clinical and genetic heterogeneity associated with epilepsy, our findings suggest that WES may be considered when a specific gene is not immediately suspected as causal. [ABSTRACT FROM AUTHOR]

BACKGROUND: Concentrated platelets (CP) when combined with calcified thrembin produces a platelet gel which has been used to achieve hemostasis and can modulate bone growth and wound healing. The availability of bovine thrombin (BT) in Europe is limited due to the possibility of disease transmission and the reports of antibody development to Factor V has questioned its use by some physicians in the United States. The objective of this study was an in vitro evaluation of the SmartPRePÔ (Harvest Technologies, Plymouth, MA) to simultaneously produce an autologous CP and procoagulant(AP) within 15 minutes of collection from a small blood sample. METHODS: Blood was obtained from a range of donors under conditions representative of expected clinical use based upon a gender-based blood process protocol. An additional (4 ml of blood) was collected into a serum separator tube(SST). Both samples were processed in the SmartPRePÔ System. The serum supernatant was combined with 10% CaCl in a 3:1 ratio which becomes the AP. The CP was reacted with the AP at both room temperature and 37°C at a 10:1 ratio and the time to gel determined. The system was tested utilizing cancellous bone to determine handling characteristics. RESULTS: The table compares the gel times using both bovine thrembin(BT) and AP. The material was demonstrated to gel cancellous bone in less than 5 minutes. Clinical trials are in progress in Europe using the SmartPRePÔ to prepare a platelet gel using the autologous procoagulant. CONCLUSION: In comparison to bovine thrembin the AP takes longer to gel but eliminates the exposure to bovine proteins. However, the additional time is not clinically significant. AP can simultaneously be prepared with CP. AP will produce a gel that can be used as a matrix to shape or model allograft, autograft or synthetic bone. [ABSTRACT FROM AUTHOR]