Array comparative genomic hybridization for diagnosis of developmental delay: an exploratory cost-consequences analysis.

A major application of array comparative genomic hybridization (aCGH) is to define a specific cause in children with undiagnosed learning and developmental disability (LDD). Medical notes for 46 consecutive patients selected for aCGH analysis by clinical dysmorphologists were abstracted for clinical investigations related to LDD and a cost-consequences analysis was performed. aCGH analysis was completed in 36 cases and five diagnostic chromosomal anomalies were identified (13.8%). The number of investigations undertaken on each child varied. With aCGH estimated to cost 590 British Pound per case, if aCGH had been undertaken after negative standard initial tests for LDD investigation, the additional cost would be 2399 British Pound per positive case. If the cost of aCGH was reduced to 256 British Pound per case (approximately 350 Euro), aCGH becomes cost neutral. All chromosomal anomalies detected by aCGH had a de Vries score of > or =5. If aCGH had only been used for individuals with a score of > or =5, the sensitivity increased to 21.7% yielding a cost of 1087 British Pound per positive case identified. Pre-selection of cases for aCGH based on de Vries criteria has a major economic impact on introducing aCGH into clinical practice. Prospective studies are required to explore the long-term costs and consequences of aCGH and identify when aCGH may provide the most benefit at least cost.

Interaction of air ions and bactericidal vapours to control micro-organisms.

AIMS: The aim of this study was to investigate the antibacterial activity of candles containing specific-antibacterial compounds, such as essential oils and their constituent compounds. The importance of the ionization products from the flame and the aerial concentration of the volatile compounds were investigated. METHODS AND RESULTS: Agar plates inoculated with Escherichia coli (DH5alpha) or Staphylococcus aureus (NCTC strain number 8532) were exposed in a large air-tight chamber to candle flames combined with the volatile bactericidal compounds beta-pinene and orange oil. A steady decline in E. coli numbers was observed over time because of the effect of a candle flame. This was significantly increased by the addition of volatile oils. The number of S. aureus colonies was not reduced by a plain candle, but significant reductions were caused following exposure to beta-pinene and orange oil candles. As aerial concentration of the volatiles was increased the viability of E. coli and S. aureus declined. Ionization products from the flame made a significant contribution to the observed effects, as intercepting the ions on a grounded grid over the agar plates allowed at least 20% more cells to survive. CONCLUSIONS: This study demonstrates the antibacterial properties of ionization products from a candle flame, and that this effect can be significantly increased by the addition of specific-antibacterial compounds, such as orange oil and beta-pinene. The role of both the ionization products from the candle flame and the concentration of volatile compounds released are important to the effect. SIGNIFICANCE AND IMPACT OF THE STUDY: The technique described here offers a new and novel technique for reducing the concentration of bacteria on surfaces.

Two unique patients with trisomy 18 mosaicism and molecular marker studies.

We report two unusual patients with trisomy 18 mosaicism presenting with minor anomalies and failure to thrive in the first year of life. Chromosome analysis showed trisomy 18 in 30/30 peripheral blood lymphocytes in both children. Analysis of skin fibroblasts in the first child showed normal female chromosomes in 30/30 cells, and the fibroblast karyotype in the second child showed mosaicism for tetrasomy 18p, trisomy 18, and normal female chromosomes (karyotype 47,XX, +i(18)(p10)[47]/47,XX, +18[9] /46,XX[4]). Trisomy 18 commonly results from nondisjunction at maternal meiosis II (MII). Nondisjunction at maternal MII has also been postulated to be the initial step in the formation of tetrasomy 18p. In our second case, the additional chromosome 18 was the result of maternal nondisjunction at MII, consistent with this hypothesis. In the first case, nondisjunction at maternal meiosis I (MI) was responsible for the extra chromosome 18.

De novo deletion of chromosome 18q in a baby with harlequin ichthyosis.

Harlequin ichthyosis, (MIM 242500), is a rare, autosomal recessive skin disorder due to an inborn error of epidermal keratinization. The gene for this condition has not been localized. We present a case of HI in which there was a de novo deletion of chromosome 18q: the karyotype was 46, XY, del(18)(q21.3). We postulate that the gene for HI may lie at, or distal to 18q21.3 and that the deletion observed in this case may have unmasked this autosomal recessive disorder.

Screening for submicroscopic chromosome rearrangements in children with idiopathic mental retardation using microsatellite markers for the chromosome telomeres.

Recently much attention has been given to the detection of submicroscopic chromosome rearrangements in patients with idiopathic mental retardation. We have screened 27 subjects with mental retardation and dysmorphic features for such rearrangements using a genetic marker panel screening. The screening was a pilot project using markers from the subtelomeric regions of all 41 chromosome arms. The markers were informative for monosomy in both parents at 3661902 loci (40.6%, 95% confidence interval 37.0-44.2%) in the 22 families where DNA was available from both parents. In two of the 27 subjects, submicroscopic chromosomal aberrations were detected. The first patient had a 5-6 Mb deletion of chromosome 18q and the second patient had a 4 Mb deletion of chromosome 1p. The identification of two deletions in 27 cases gave an aberration frequency of 7.5% without adjustment for marker informativeness (95% confidence interval 1-24%) and an estimated frequency of 18% if marker informativeness for monosomy was taken into account. This frequency is higher than previous estimates of the number of subtelomeric chromosome abnormalities in children with idiopathic mental retardation (5-10%) although the confidence interval is overlapping. Our study suggests that in spite of the low informativeness of this pilot screening, submicroscopic chromosome aberrations may be a common cause of dysmorphic features and mental retardation.

Paternally inherited duplications of 11p15.5 and Beckwith-Wiedemann syndrome.

We present a three generation family in which a father and son have a balanced chromosome translocation between the short arms of chromosomes 5 and 11 (karyotype 46,XY,t(5;11)(p15.3;p15.3)). Two family members have inherited the unbalanced products of this translocation and are trisomic for chromosome 11p15.3-->pter and monosomic for chromosome 5p15.3-->pter (karyotype 46,XY,der(5)t(5;11)(p15.3;p15.3)pat). Paternally derived duplications of 11p15.5 are associated with Beckwith-Wiedemann syndrome (BWS) and both family members trisomic for 11p15.5 had prenatal overgrowth (birth weights >97th centile), macroglossia, coarse facial features, and broad hands. We review the clinical features of BWS patients who have a paternally derived duplication of 11p15.5 and provide evidence for a distinct pattern of dysmorphic features in those with this chromosome duplication. Interestingly, our family is the fifth unrelated family to be reported with a balanced reciprocal translocation between the short arms of chromosomes 5 and 11. The apparently non-random nature of this particular chromosome translocation is suggestive of sequence homology between the two chromosome regions involved in the translocation.

A case of mosaic trisomy 2 diagnosed at amniocentesis in an abnormal fetus and confirmed in multiple fetal tissues.

Pseudomosaicism for trisomy 2 is a relatively common finding at amniocentesis. However, genuine trisomy 2 mosaicism is extremely rare. As a result, very few cases have been described and little information is available with which to counsel the parents of an affected fetus. We describe a case of mosaic trisomy 2 diagnosed at amniocentesis in a fetus with multiple anomalies on ultrasound scan. Following termination of pregnancy, the fetus was found to have mild dysmorphic features, together with an absent gall bladder, cystic left kidney, a 13th left rib and mild unilateral talipes. The presence of trisomy 2 cells was confirmed by both standard cytogenetic analysis and fluorescent in-situ hybridisation techniques in multiple fetal tissues, as well as in the cord and placenta.

A case of Angelman syndrome arising as a result of a de novo Robertsonian translocation.

A male child has been identified with Angelman syndrome. He has been shown to carry a de novo Robertsonian 15/15 translocation where both chromosome 15s have been derived from the father. Consequently the disease in this instance is due to paternal uniparental disomy.

Rubinstein-Taybi syndrome with deletions of FISH probe RT1 at 16p13.3: two UK patients.

We report two patients with Rubinstein-Taybi syndrome out of a total of 16 tested who have a deletion of the region visualised by the cosmid probe RT1. These results further confirm this as a locus for Rubinstein-Taybi syndrome.

A disease-associated germline deletion maps the type 2 neurofibromatosis (NF2) gene between the Ewing sarcoma region and the leukaemia inhibitory factor locus.

RFLP typing of members of a neurofibromatosis type 2 (NF2) family suggested that affected individuals were hemizygous at the neurofilament heavy chain (NEFH) locus, possibly as a result of a disease-associated deletion. Conventional karyotyping revealed no evidence for a deletion and all or a majority of the affected family members were heterozygous for closely linked markers which mapped proximal to the NEFH locus (D22S1 and D22S56) and for the distal marker D22S32. FISH analysis confirmed a disease-associated germinal deletion on 22q which encompassed the NEFH locus, which is known to be very closely linked to NF2, but did not extend as far as the proximal Ewing sarcoma region or the distal leukaemia factor (LIF) locus. PFGE analysis with a LIF cosmid subclone identified patient-specific NotI and MluI fragments and suggested that the deletion is about 700 kb in length. Although this large deletion could be expected to eliminate a considerable fraction, and possibly all of the NF2 gene, the resulting phenotype is the mild, so-called Gardner subtype of NF2. The deletion should provide a useful mapping resource for characterising the chromosomal region containing the NF2 locus.

The 5q--syndrome: an underdiagnosed form of macrocytic anaemia.

Since the description in 1974 of the 5q--syndrome, only 29 cases have been reported. Over a 3 1/2 year period cytogenetic culture of bone marrow submitted from 344 patients being investigated for a blood disorder revealed nine patients with anomalies of chromosome 5. In five of these patients (samples arising from 37 patients being investigated for refractory macrocytic or aplastic anaemia) the 5q-syndrome was diagnosed. The clinical and haematological findings of this syndrome are reviewed and attention is drawn to the importance of reviewing megakaryocytic numbers and morphology in refractory macrocytic anaemia if the diagnosis is to be considered. The diagnosis is compatible with prolonged survival and establishing it prevents repeated and unnecessary investigation.

Mechanics of the syrinx in Gallus gallus. II. Electromyographic studies of ad libitum vocalizations.

Records of electrical activity in the tracheal muscles of domestic chickens were obtained for a variety of ad libitum vocalizations. Primary attention was given to an analysis of events during the most complex call, crowing. Three pairs of muscles, Mm, tracheohyoideus, tracheolateralis, and sternotrachealis, can affect the configuration of a chicken's syrinx. The firing patterns of the three muscle pairs are related to their different abilities to affect the tension of the syringeal membranes. The influence of M. tracheohyoideus is most indirect and imprecise, and its role the least clearly defined. It appears to adjust the position of the trachea so that the syrinx is isolated from unpredictable and/or undesireable consequences of nuchal position and tracheal elasticity, and also helps draw the glottis caudad, thereby deepening the pharyngeal chamber. The other two muscles interact to control the tension of the vocal membranes. M. sternotrachealis relaxes the membranes by drawing the drum of the trachea caudad, or, via the syringeal ligament, by rotating the pessulus cranioventrad, or both. M. tracheolateralis tenses the membranes and/or prevents caudal movement of the orgin of M. sternotrachedalis, a necessity if the syringeal ligament is to rotate the pessulus. Vocalization depends on both syringeal configuration and appropriated air flow. Hence, tracheal muscles, syrinx, air sacs, and ventilatory muscles cooperate to form a vocal system. Cooperation elicits a surprising degree of redundancy. At least one call, a high pitched wail, may be produced by two very different techniques.