Follow up and evaluation of the Victorian first-trimester combined screening programme for Down syndrome and trisomy 18.

OBJECTIVE: The objective of this study was to follow up and evaluate the statewide first-trimester combined screening programme for Down syndrome and trisomy 18 at Genetic Health Services Victoria, Australia. DESIGN: Retrospective population cohort. SETTING: Maternal Serum Screening Laboratory records. SAMPLE: All women screened between February 2000 and June 2002 (16,153 pregnancies). METHODS: Screening results were matched to Victorian perinatal and birth defect data via record linkage, with an ascertainment of 96.8% of pregnancy outcomes. Manual follow up with health professionals increased ascertainment to more than 99%. MAIN OUTCOME MEASURES: Fetal Down syndrome or trisomy 18, and combined screen results, to calculate test characteristics. RESULTS: Using a risk threshold of 1 in 300 at time of ultrasound, the sensitivities for standard first-trimester combined screening and augmented 13-week combined screening for Down syndrome were 87.3 and 90.5% and the false-positive rates (FPR) were 4.1 and 3.9%, respectively. The sensitivity for trisomy 18 was 66.7% (10/15, 95% CI 42.8-90.5%) with a 0.4% FPR and 15.2% positive predictive value (1 in 250 risk threshold). CONCLUSIONS: The combined use of record linkage and manual follow-up techniques was effective in ascertaining more than 99% of pregnancy outcomes for calculations of accurate test characteristics of the combined screen. The sensitivity for Down syndrome at Genetic Health is comparable to similar populations. However, the sensitivity for trisomy 18 is lower than that elsewhere, which may reflect the overall low birth prevalence of trisomy 18 and associated small numbers in this particular cohort.

Distal arthrogryposis type II: a family with varying congenital abnormalities.

Five family members with distal arthrogryposis in two generations are reported. Cleft lip and palate, micrognathia, ptosis, webbed neck, kyphoscoliosis, and short stature are seen in one or more affected family members. All individuals with distal arthrogryposis also have trismus. This family does not fit any of the recently proposed five subcategories of type II distal arthrogryposis, nor does it fit any other recognized autosomal dominant condition with distal contractures.

Limb deficiencies, chorion villus sampling, and advanced maternal age.

Record linkage between a prenatal diagnosis register and a congenital malformation register in the state of Victoria, Australia, has enabled further evaluation of the suggested association between limb deficiencies and early chorion villus sampling (CVS). We found 3 anomalies in this category after later CVS (i.e., 9 weeks and beyond), but our data suggest that advanced maternal age may be a risk factor for both terminal and all limb deficiencies. The data from Victoria are tabulated with data obtained from other registers. Different birth prevalence figures are obtained by different registers, therefore limiting comparisons between registers.

Two forms of ring 13 in a child with rhabdomyosarcoma.

Mosaicism for two forms of ring 13 was found in a child with embryonal rhabdomyosarcoma of the bladder, minor anomalies, and developmental delay. Her chromosome constitution was 46,XX,r(13)(p11q34)/46,XX,r del(13)(p11q14). Both cell lines were present in lymphocytes and fibroblasts. The cell line with the smaller ring chromosome predominated in both tissues. The child's manifestations reflect the presence of both cell lines.

A genetic follow-up study of 64 patients with the Pierre Robin complex.

A genetic follow-up study has been performed of 64 infants who were diagnosed as having Pierre Robin complex over a 23-year period in South Australia. Patients and their families were contacted, family history was obtained, and physical examinations were performed with an aim to detect heterogeneity and establish recurrence risks. In 16 deceased patients, detailed autopsy reports allowed the conclusion that 12 (70%) had an underlying syndrome. Twelve of the 47 living patients (26%) were diagnosed as having an underlying syndrome, the most common of which was Stickler syndrome (6 cases). In most cases separation of syndromic cases from the nonsyndromic cases was possible in the neonatal period. In the 34 patients without an underlying syndrome, study of pregnancy and birth details did not reveal any distinctive etiologic factors. There was no recurrence in sibs of this group of patients with nonsyndromic Pierre Robin complex.

Fragile X family with unusual digital and facial abnormalities, cleft lip and palate, and epilepsy.

We present a fragile X family with unusual clinical manifestations. These findings, which often occur in the X-linked FG syndrome, include minor limb anomalies, cleft lip and palate, characteristic facial appearance, gastrointestinal problems and epilepsy, and intellectual disability. In a total sample of 54 fra(X) families, the frequency of minor limb anomalies was estimated to be 32% in the affected males and 19% in the female heterozygotes. These anomalies tend to occur in several members of the same family, where some craniofacial abnormalities reported as characteristic of the FG syndrome have also been encountered. Possible mechanisms for the occurrence of these unusual manifestations in the fra(X) families are discussed.

Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K.

Ten patients with maxillonasal hypoplasia (Binder "syndrome"), who were prenatally exposed to phenytoin (usually in combination with other anticonvulsants), were identified retrospectively. In addition to their facial anomalies, 6 of the patients were radiographed neonatally and showed punctate calcification, characteristic of chondrodysplasia punctata. Evidence is presented that the facial abnormalities seen in these children are due to anticonvulsant-induced vitamin K deficiency, causing abnormal development of the cartilaginous nasal septum. We propose that early vitamin K supplementation of at-risk pregnancies may prevent the development of maxillonasal hypoplasia, which in some patients is severely disfiguring and causes great emotional distress. Correction of this facial defect requires surgical and dental treatment over a long period of time.

Strategies to find new genes involved in drug metabolism.

Pharmacogenomics is a field that is applying the new methods of molecular genetics to explain the genetic basis of an individual's reaction to drugs. One example from the literature of variations in a single gene being predictive of drug metabolism is described, in addition to methods of testing a gene to see if it is associated with poor metabolism of the drug. An explanation is given of why linkage and association studies are used. Candidate gene studies are most frequently used but whole-genome scans are also described. Case-control studies or transmission disequilibrium tests are used to investigate phenotype and genotype association.

Ultrasound and amniotic fluid alpha-fetoprotein in the prenatal diagnosis of spina bifida.

Amniotic fluid alpha-fetoprotein (AFP) assays and detailed ultrasound examinations were performed in 376 prenatal patients at risk for a neural tube defect (high-risk group). In addition, 2436 patients who underwent amniocentesis for other indications underwent preamniocentesis ultrasound screening and amniotic fluid AFP assays (low-risk group). There were 10 neural tube defects in the high-risk group (7 open and 3 closed) and 3 in the low-risk group (all open). Two of the 3 closed defects were detected prenatally. The predictive value of an elevated AFP level for an abnormal fetus was much higher in the high-risk (6 of 6, 100%) than in the low-risk group (1 of 6, 17%). When both ultrasound and AFP assay results were normal, the chance of a normal outcome was very high in both the high- and low-risk groups (99.7 and 100%, respectively). It was of particular interest that in the low-risk group, the likelihood of an abnormal outcome in women with elevated AFP and a normal ultrasonogram was low (0 of 5).

'Disorganization-like syndrome' with 47,XXY and unilateral narrowing of the common iliac artery.

We described a male infant with a spectrum of anomalies compatible with the diagnosis of 'disorganization-like syndrome'. The infant had a partial foot arising from the right buttock, an absent right kidney, and a shortened right leg with severe non-positional talipes equinovarus. The infant's karyotype was 47,XXY. The right common iliac artery was one half of the expected diameter. The limb reduction defect seen in this case of disorganization (Ds) may have had a vascular aetiology.

Binder's syndrome due to prenatal vitamin K deficiency: a theory of pathogenesis.

There is evidence that vitamin K-deficiency during human pregnancy can be caused by the therapeutic use of warfarin or phenytoin. The pregnancy histories of three cases of Binder's syndrome are reported. One was associated with warfarin exposure, one with phenytoin exposure and one with alcohol abuse. It is proposed that Binder's syndrome can be caused by prenatal exposure to agents that cause vitamin K-deficiency. Sprague-Dawley rats were treated from postnatal day 1 to 12 weeks with daily doses of warfarin (100 mg/kg) and concurrent vitamin K1 (10 mg/kg). This regimen creates a net extra-hepatic vitamin K-deficiency. The treated rats developed with a distinct facial appearance characterized by a markedly reduced snout. Histological examination showed that the normally non-calcified septal cartilage was extensively calcified. It is proposed that normal growth of the septal cartilage is necessary for the development of the profile of the nose and midface and that normal growth will only take place while the septal cartilage is uncalcified.

Randomized double-blind placebo-controlled crossover study to determine the effects of esomeprazole on inhibition of platelet function by clopidogrel.

BACKGROUND: Pharmacokinetic studies suggest that clopidogrel and esomeprazole are metabolized by similar hepatic enzymes; however, previous studies have not identified a biochemical interaction. OBJECTIVES: To determine whether addition of esomeprazole to patients receiving aspirin and clopidogrel reduces the antiplatelet effects of clopidogrel. PATIENT/METHODS: Patients with a history of an acute coronary syndrome who had previously received clopidogrel were recruited. Subjects were commenced on clopidogrel and randomized to one of two treatment arms (esomeprazole or placebo) for 6 weeks. Following a 2-week washout period for study medications, patients were crossed over onto the alternative treatment arm for a further 6 weeks. Platelet function tests were undertaken at baseline, following the first treatment period, after washout and following the second treatment period. RESULTS: Thirty-one patients were enrolled. Significant attenuation of clopidogrel's antiplatelet effects was seen with co-administration of esomeprazole compared with placebo. Vasodilator stimulated phosphoprotein (VASP), platelet aggregometry (area under the curve (AUC)) and VerifyNow results were 54.7% ± 2.8 platelet reactivity index (PRI), 66.3 ± 2.6 AUC units and 213.1 ± 14.1 platelet reactivity units (PRU) with esomeprazole vs. 47% ± 2.7 PRI, 59.7 ± 3.7 AUC units and 181.4 ± 14.6 PRU with placebo (P < 0.01 esomeprazole vs. placebo for all measures). There was no significant difference in platelet aggregometry (maximal aggregation) between the esomeprazole group (68.9% ± 2.7 units) and placebo-treated group (64.5% ± 4.1 units; P > 0.05). CONCLUSION: Esomeprazole when co-administered with aspirin and clopidogrel results in a significant attenuation of clopidogrel's antiplatelet effects.

Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients.

OBJECTIVES: To test the hypothesis that neuropsychiatric symptomatology is predictive of the success of seizure control in patients newly treated with antiepileptic drugs (AEDs), and that this predictive value adds to that provided by other clinical, imaging, and genomic factors in a multivariate model. METHODS: One hundred seventy newly treated patients with epilepsy completed the A-B Neuropsychological Assessment Scale (ABNAS) before commencing AED therapy and were prospectively followed up for 12 months. Patients were classified as nonresponsive if they had at least 1 seizure not explained by medication noncompliance or other significant provoking factors. RESULTS: Of the 138 patients in whom a drug response phenotype at 12 months was able to be determined, nonresponsive patients (n = 45) had a higher pretreatment ABNAS score than patients whose seizures were controlled (n = 93) (p = 0.007). A lesion on MRI was also associated with a higher risk of seizure recurrence (p = 0.003). On multivariate logistic regression, the ABNAS score, the MRI results, and a genomic classifier were all independently predictive of treatment outcome. For AED pharmacoresponse, this multivariate model had diagnostic values of 91% sensitivity, 64% specificity, 84% positive predictive, and 78% negative predictive values. The predictive value of the ABNAS score was validated in a second prospective cohort of 74 newly treated patients with epilepsy (p = 0.005). CONCLUSIONS: The ABNAS provides prognostic information regarding successful seizure control in patients newly treated with AEDs. Furthermore, these results demonstrate the multifactorial nature of the determinants of AED response, with neuropsychological, structural, and genomic factors all contributing to the complex response phenotype.

Sixteen New Cases Contributing to the Characterization of Patients with Distal 22q11.2 Microduplications.

The chromosome region 22q11.2 has long been recognized to be susceptible to genomic rearrangement. More recently, this genomic instability has been shown to extend distally (involving LCR22E-H) to the commonly deleted/duplicated region. To date, 21 index cases with 'distal' 22q11.2 duplications have been reported. We report on the clinical and molecular characterization of 16 individuals with distal 22q11.2 duplications identified by DNA microarray analysis. Two of the individuals have been partly described previously. The clinical phenotype varied among the patients in this study, although the majority displayed various degrees of developmental delay and speech disturbances. Other clinical features included behavioral problems, hypotonia, and dysmorphic facial features. Notably, none of the patients was diagnosed with a congenital heart defect. We found a high degree of inherited duplications. Additional copy number changes of unclear clinical significance were identified in 5 of our patients, and it is possible that these may contribute to the phenotypic expression in these patients as has been suggested recently in a 2-hit 'digenic' model for 16p12.1 deletions. The varied phenotypic expression and incomplete penetrance observed for distal 22q11.2 duplications makes it exceedingly difficult to ascribe pathogenicity for these duplications. Given the observed enrichment of the duplication in patient samples versus healthy controls, it is likely that distal 22q11.2 duplications represent a susceptibility/risk locus for speech and mild developmental delay.

Pharmacogenomics education: International Society of Pharmacogenomics recommendations for medical, pharmaceutical, and health schools deans of education.

Pharmacogenomics would be instrumental for the realization of personalized medicine in coming decades. Efforts are evident to clarify the potential bioethical, societal, and legal implications of key pharmacogenomics-based technologies projected to be soon introduced into the core practice of medicine. In sharp contrast, a lack of sufficient attention to educational aspects of pharmacogenomics, both for professionals and for society at large, is evident. In order to contribute to this discussion, a 'Pharmacogenomics Education Forum' was held on October 2, 2004 during the 3rd Annual Meeting of the International Society of Pharmacogenomics (ISP) at Santorini, Greece. The participants, members of the ISP Pharmacogenomics Education Forum, after deliberate discussions, proposed a document of 'Background Statement' and 'Recommendations and Call for Action' addressed to Deans of Education at Medical, Pharmaceutical, and Health Schools globally. This document has been considered by the education committee of the International Society of Pharmacogenomics and the result is presented here. We hope that this call would be listened to, and soon followed by beneficial action, ultimately leading to enhanced implementation of personalized medicine into core medical education and practice.

The creation of therapeutic orphans--or, what have we learnt from the Debendox fiasco?

The drug combination Debendox has been very widely used for the treatment of nausea and vomiting in pregnancy. Recently its manufacturer ceased world-wide production owing to the increasing costs of litigation associated with claims of teratogenicity. Teratogenicity claims were widespread in the media but the overwhelming scientific evidence was that Debendox was not teratogenic. In the interests of preventing other drugs (and drug companies) being subjected to similarly unfounded claims, the literature relating to the effects of Debendox on the fetus has been reviewed and evaluated against well known epidemiological principles of establishing causality. This evaluation consistently demonstrates that Debendox is not in fact teratogenic. It is recommended that appropriate professional bodies be more aware of the criteria by which causation is established and be prepared publicly to state their considered views of the effects of particular drugs in pregnancy.