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Intrachromosomal amplification of chromosome 21 (iAMP21) identifies a high-risk subtype of acute lymphoblastic leukaemia (ALL), requiring intensive treatment to reduce their relapse risk. Improved understanding of the genomic landscape of iAMP21-ALL will ascertain whether these patients may benefit from targeted therapy. We performed whole-exome sequencing of eight iAMP21-ALL samples. The mutation rate was dramatically disparate between cases (average 24.9, range 5–51) and a large number of novel variants were identified, including frequent mutation of the RAS/MEK/ERK pathway. Targeted sequencing of a larger cohort revealed that 60% (25/42) of diagnostic iAMP21-ALL samples harboured 42 distinct RAS pathway mutations. High sequencing coverage demonstrated heterogeneity in the form of multiple RAS pathway mutations within the same sample and diverse variant allele frequencies (VAFs) (2–52%), similar to other subtypes of ALL. Constitutive RAS pathway activation was observed in iAMP21 samples that harboured mutations in the predominant clone (⩾35% VAF). Viable iAMP21 cells from primary xenografts showed reduced viability in response to the MEK1/2 inhibitor, selumetinib, in vitro. As clonal (⩾35% VAF) mutations were detected in 26% (11/42) of iAMP21-ALL, this evidence of response to RAS pathway inhibitors may offer the possibility to introduce targeted therapy to improve therapeutic efficacy in these high-risk patients.

The aim of this study was to investigate the social, contextual and situational factors that influence football coaches' behaviour in competition. Twelve English youth professional coaches were observed over a five-month period using the Coach Analysis and Intervention System (CAIS). Two sets of interpretive interviews were subsequently utilized to identify the underlying processes and motivations for their behaviour. Using the work of Goffman as a lens to probe the data, it is suggested that coaching behaviour during games was largely performative, with the coaches' behaviours dependent on social pressures and constraints. It is thus contended that the outcome was a form of ‘traditional coaching’ employed as impression management, as opposed to behaviours linked to pedagogical principles or the needs of athletes.

A screening programme to detect fragile X syndrome has been operating in New South Wales, Australia, since 1984. The aim of this programme is to find previously unidentified individuals with the syndrome so that their extended families can be properly informed of the risks before making decisions about childbearing. 14 225 individuals attending adult and child facilities for the intellectually handicapped have been screened, of whom 8172 have been offered testing for the fragile X syndrome with a 79% uptake of the service. 253 probands were found, and in the extended families 818 females at 25-100% risk of being carriers were interviewed and counselled. Continuing contact was maintained and prenatal diagnosis was offered. The effect of the programme was assessed in a subgroup of 90 individuals, most of whom were appreciative of the service and felt that they had been adequately informed. The influence of knowing the diagnosis and its genetic implications were also assessed, the main consequences being a 26% reduction in births and a 61% uptake of prenatal diagnosis. Improved techniques for diagnosis of fragile X have benefited the families identified and counselled, suggesting that systematic screening for fragile X should be an essential component of community genetic services.

In 3 families with the fragile-X [fra(X)] syndrome, we have identified a minimum of 4 recombinations in 9 meioses between the syndrome locus and the coagulation Factor IX gene. Two Factor IX intragenic restriction fragment length polymorphisms (RFLPs), produced with TaqI and XmnI, were used as markers. In lod score calculations, incomplete penetrance of the fra(X) mutation in males and females was taken into account by the computer program LIPED. The cumulative maximum lod score calculated from these data and from data previously reported was 2.75 at a recombination frequency of 20% (θ = 0.20). This indicates that the genetic distance between the Factor IX gene and the fra(X) locus is too great for Factor IX probes to be used alone for carrier detection in the fra(X) syndrome. Additional polymorphic loci more tightly linked to the fra(X) syndrome locus are required.

A case is reported of the difficulties associated with late free toe transfer for thumb reconstruction after an initial reverse radial forearm flap.

A new series of 96 pedigrees with the fra(X) syndrome was analysed using complex segregation analysis with pointers, defining affection as any degree of mental impairment. These families were found to exhibit the same segregation pattern as the first series of 110 pedigrees (Sherman et al. 1984). The best estimate for penetrance of mental impairment in males was 79% and in females was 35% for the combined data. Again, there was little evidence for sporadic cases among affected males.

SINCE OUR description in 1961, with Dr. A. Hunter, of two children with an inborn error of histidine metabolism, 18 other cases have been reported (Table). Two thirds of the patients are girls. The youngest patient is 1 month of age and the oldest is 13 years. The mental abilities and speech development of the three patients under 1 year of age are difficult to assess accurately. Thirteen of the 17 patients have speech defects. The degree of mental retardation varies greatly from four normal-looking healthy children with definite evidence of the biochemical anomaly to six retarded children with IQs of about 50. The remaining seven have IQs of 65 to 85. The emerging clinical picture, when symptomatology is present, consists of a speech defect, mental retardation of mild to moderate degree, light-colored hair and eyes, and, possibly, growth retardation. Positive results of urinary tests with ferric chloride or Phenistix

IT is known that the ultra-violet wave-lengths responsible for producing vasodilatation or erythema penetrate only a short way into human skin1,2. These studies, however, do not by themselves exclude a direct action of ultra-violet light on the blood vessels as the cause of the characterstic erythema, for they have shown that a small fraction (up to 20 per cent) of these wave–lengths is able to penetrate through the avascular epidermis to the vascular corium. Further evidence that the effect of ultra–violet light on the skin blood-vessels is an indirect one would therefore seem of interest.