Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome

Laurin-Sandrow syndrome (LSS) is a rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. The genetic basis of LSS is currently unknown. LSS shows phenotypic overlap with Haas-type polysyndactyly (HTS) regarding the digital phenotype. Here we report on five unrelated families with overlapping microduplications encompassing the Sonic hedgehog (SHH) limb enhancer ZPA regulatory sequence (ZRS) on chromosome 7q36. Clinically, the patients show polysyndactyly phenotypes and various types of lower limb malformations ranging from syndactyly to mirror image polydactyly with duplications of the fibulae. We show that larger duplications of the ZRS region (>80 kb) are associated with HTS, whereas smaller duplications (<80 kb) result in the LSS phenotype. On the basis of our data, the latter can be clearly distinguished from HTS by the presence of mirror image polysyndactyly of the feet with duplication of the fibula. Our results expand the clinical phenotype of the ZRS-associated syndromes and suggest that smaller duplications (<80 kb) are associated with a more severe phenotype. In addition, we show that these small microduplications within the ZRS region are the underlying genetic cause of Laurin-Sandrow syndrome

Design Characteristics Influence Performance of Clinical Prediction Rules in Validation: A Meta-Epidemiological Study

BACKGROUND: Many new clinical prediction rules are derived and validated. But the design and reporting quality of clinical prediction research has been less than optimal. We aimed to assess whether design characteristics of validation studies were associated with the overestimation of clinical prediction rules' performance. We also aimed to evaluate whether validation studies clearly reported important methodological characteristics. METHODS: Electronic databases were searched for systematic reviews of clinical prediction rule studies published between 2006 and 2010. Data were extracted from the eligible validation studies included in the systematic reviews. A meta-analytic meta-epidemiological approach was used to assess the influence of design characteristics on predictive performance. From each validation study, it was assessed whether 7 design and 7 reporting characteristics were properly described. RESULTS: A total of 287 validation studies of clinical prediction rule were collected from 15 systematic reviews (31 meta-analyses). Validation studies using case-control design produced a summary diagnostic odds ratio (DOR) 2.2 times (95% CI: 1.2-4.3) larger than validation studies using cohort design and unclear design. When differential verification was used, the summary DOR was overestimated by twofold (95% CI: 1.2 -3.1) compared to complete, partial and unclear verification. The summary RDOR of validation studies with inadequate sample size was 1.9 (95% CI: 1.2 -3.1) compared to studies with adequate sample size. Study site, reliability, and clinical prediction rule was adequately described in 10.1%, 9.4%, and 7.0% of validation studies respectively. CONCLUSION: Validation studies with design shortcomings may overestimate the performance of clinical prediction rules. The quality of reporting among studies validating clinical prediction rules needs to be improved

The creatine kinase system and pleiotropic effects of creatine

The pleiotropic effects of creatine (Cr) are based mostly on the functions of the enzyme creatine kinase (CK) and its high-energy product phosphocreatine (PCr). Multidisciplinary studies have established molecular, cellular, organ and somatic functions of the CK/PCr system, in particular for cells and tissues with high and intermittent energy fluctuations. These studies include tissue-specific expression and subcellular localization of CK isoforms, high-resolution molecular structures and structure–function relationships, transgenic CK abrogation and reverse genetic approaches. Three energy-related physiological principles emerge, namely that the CK/PCr systems functions as (a) an immediately available temporal energy buffer, (b) a spatial energy buffer or intracellular energy transport system (the CK/PCr energy shuttle or circuit) and (c) a metabolic regulator. The CK/PCr energy shuttle connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases). Thus, diffusion limitations of ADP and ATP are overcome by PCr/Cr shuttling, as most clearly seen in polar cells such as spermatozoa, retina photoreceptor cells and sensory hair bundles of the inner ear. The CK/PCr system relies on the close exchange of substrates and products between CK isoforms and ATP-generating or -consuming processes. Mitochondrial CK in the mitochondrial outer compartment, for example, is tightly coupled to ATP export via adenine nucleotide transporter or carrier (ANT) and thus ATP-synthesis and respiratory chain activity, releasing PCr into the cytosol. This coupling also reduces formation of reactive oxygen species (ROS) and inhibits mitochondrial permeability transition, an early event in apoptosis. Cr itself may also act as a direct and/or indirect anti-oxidant, while PCr can interact with and protect cellular membranes. Collectively, these factors may well explain the beneficial effects of Cr supplementation. The stimulating effects of Cr for muscle and bone growth and maintenance, and especially in neuroprotection, are now recognized and the first clinical studies are underway. Novel socio-economically relevant applications of Cr supplementation are emerging, e.g. for senior people, intensive care units and dialysis patients, who are notoriously Cr-depleted. Also, Cr will likely be beneficial for the healthy development of premature infants, who after separation from the placenta depend on external Cr. Cr supplementation of pregnant and lactating women, as well as of babies and infants are likely to be of benefit for child development. Last but not least, Cr harbours a global ecological potential as an additive for animal feed, replacing meat- and fish meal for animal (poultry and swine) and fish aqua farming. This may help to alleviate human starvation and at the same time prevent over-fishing of oceans

Clinical Presentation, Surgical Treatment, and Outcome in Radial Polydactyly

Radial polydactyly or thumb duplication' is the most common congenital upper limb anomaly (CULA') affecting the thumb. The clinical presentation is highly diverse, ranging from an extra thumb floating on a skin bridge to complicated thumb triplications with triphalangeal, deviating, and hypoplastic components. Radial polydactyly can be classified into one of 7 osseous presentations using the Wassel classification, with type IV (45%), type II (20%), and type VII (15%) occurring most frequently. When faced with a radial polydactyly case, hand surgeons specialised in congenital anomalies must weigh the preoperative functional potential and degree of hypoplasia of both thumbs in order to decide whether to resect one thumb and reconstruct the other (resection and reconstruction'), excise a central part of both thumbs and unite the lateral tissues into one thumb (the Bilhaut procedure'), transfer the better-developed distal tissues of one thumb onto the better-developed proximal tissues of the other (on-top plasty'), or discard both severely hypoplastic thumbs and pollicise the index finger. Mere excision of the hypoplastic thumb is rarely indicated since it often requires subsequent revision surgery. Even after being treated by experienced surgeons, about 15% of patients with polydactyly will need additional procedures to correct residual and/or new problems such as deviation from the longitudinal axis and joint instability. Nevertheless, radial polydactyly patients usually achieve unimpaired everyday hand function postoperatively. Zusammenfassung Die radiale Polydaktylie, auch Doppeldaumen genannt, ist die haufigste angeborene den Daumen betreffende Fehlbildung der oberen Extremitat. Das klinische Erscheinungsbild weist eine gro ss e Variationsbreite auf, von einem nur an einer dunnen Hautbrucke flottierenden Daumenanhangsel bis hin zum Dreifach-Daumen mit dreigliedrigen, deviierenden und hypoplastischen Anteilen. Die Wassel-Klassifikation, bei der die radiale Polydaktylie anhand der knochernen Situation eingeteilt wird, unterscheidet 7 Typen, wobei der Typ IV mit 45%, der Typ II mit 20% und der Typ VII mit 15% am haufigsten vorkommen. Bei der Planung der chirurgischen Behandlung der radialen Polydaktylie gilt es fur den mit angeborenen Fehlbildungen vertrauten Handchirurgen abzuwagen, ob einer der beiden Daumen und ggf. welcher ein gro ss eres funktionelles Potenzial hat bzw. welcher weniger gut ausgebildet ist. In Betracht kommen die Resektion des einen und Rekonstruktion des anderen Daumens, die Resektion der einander zugewandten zentralen Anteile beider Daumen mit anschlie ss endem Zusammenfugen der beiden au ss eren Anteile zu einem Daumen (Bilhaut-Operation), die Transposition des besser entwickelten distalen Anteils des einen auf den besser entwickelten proximalen Anteils des anderen Daumens (on-top-plasty) und die Entfernung beider ausgepragt hypoplastischer Daumen mit anschlie ss ender Pollizisation des Zeigefingers. Das blo ss e Abschneiden ist selten indiziert, da es oft spatere Revisionsoperationen notig macht. Selbst in der Hand des Erfahrenen bedurfen 15% der Patienten mit einer radialen Polydaktylie weiterer Eingriffe zur Behandlung verbliebener und/oder neu aufgetretener Probleme, z.B. bei Achsabweichungen oder Gelenkinstabilitaten. Dennoch erlangen Patienten mit einer radialen Polydaktylie in der Regel eine fur den Alltagsgebrauch uneingeschrankte Handfunktion

A clinically weighted approach to outcome assessment in radial polydactyly

Currently available outcome assessment systems for radial polydactyly are mainly based on expert opinion. The aim of this study was to develop an outcome assessment system based on clinical data. We performed linear regression analysis on data from a multicentre study of 121 patients with radial polydactyly types II, IV and VII to develop a clinically weighted outcome assessment system. Items were weighted according to their influence on overall functional and aesthetic outcome in the regression analysis. Active flexion, scar appearance and prominence at amputation site were the main items influencing overall functional and aesthetic outcome (beta = 0.393, beta = 0.326 and beta = 0.288, respectively). Palmar abduction, metacarpophalangeal joint deviation and nail appearance influenced overall functional and aesthetic outcome the least (beta = -0.002, beta = -0.104 and beta = 0.070, respectively). Our proposed assessment system for radial polydactyly reflects the way clinicians value individual aspects of outcome as determinants of overall outcome and helps guide future treatment and evaluation of outcome