Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients.

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis.

Segmental Maternal UPD6 with Prenatal Growth Restriction.

We report a child with segmental maternal uniparental isodisomy of chromosome 6, involving most of the long arm distal to 6q16, detected by SNP microarray. Clinical features include prenatal growth restriction, global developmental delay, and severe gastro-esophageal reflux disease. Maternal uniparental disomy (UPD) of chromosome 6 has previously been reported to cause intrauterine growth restriction. Paternal UPD of this chromosome is well known to cause transient neonatal diabetes mellitus. We discuss reported cases of maternal UPD of chromosome 6 and consider whether our patient's features may be due to disordered imprinting or unmasking of an autosomal recessive condition.

Communication and information-giving in high-risk breast cancer consultations: influence on patient outcomes.

This longitudinal study aimed to document (i) the information-giving and patient-communication styles of clinical geneticists and genetic counsellors (consultants) in familial breast cancer clinics and (ii) assess the effect of these styles on women's knowledge, whether their expectations were met, satisfaction, risk perception and psychological status. A total of 158 women from high-risk breast cancer families completed self-report questionnaires at 2 weeks preconsultation and 4 weeks postconsultation. The consultations were audiotaped, transcribed and coded. Multivariate logistic regressions showed that discussing prophylactic mastectomy (P=0.00) and oophorectomy (P=0.01) led to women having significantly more expectations met; discussing genetic testing significantly decreased anxiety (P=0.03) and facilitating understanding significantly decreased depression (P=0.05). Receiving a summary letter of the consultation significantly lowered anxiety (P=0.01) and significantly increased the accuracy of perceived risk (P=0.02). Women whose consultant used more supportive communications experienced significantly more anxiety about breast cancer at the 4 weeks follow-up (P=0.00). These women were not significantly more anxious before genetic counselling. In conclusion, this study found that consultants vary in the amount of information they give and the way they communicate; and this variation can result in better or worse psychosocial outcomes. Greater use of supportive and counselling communications appeared to increase anxiety about breast cancer. Identifying methods to assist consultants to address emotional issues effectively may be helpful.

Telemedicine and clinical genetics: establishing a successful service.

There is a surprising lack of published experience on the use of videoconferencing in clinical genetics. Patients were randomly allocated to either a telegenetic (cases) or face-to-face (control) conventional clinic. The telegenetic consultation was done by videoconferencing, using ISDN lines at 384 kbit/s. Evaluation by the doctor and counsellor took place immediately after each appointment. The patient was asked to evaluate the appointment by telephone questionnaire about four weeks after the event. Forty-two patients were invited to participate and 33 (79%) returned their consent forms. Four patients declined to participate and were seen in ordinary face-to-face clinics. Preliminary results showed that the assessment of the telegenetics consultations by doctors, counsellors and patients was very favourable, and they responded positively when asked if they would be happy to use telemedicine in the future. For use in selected consultations, videoconferencing does appear to fulfil a useful role in clinical genetics.

Long-term outcomes of genetic counseling in women at increased risk of developing hereditary breast cancer.

This multicenter study evaluated the impact of genetic counseling in 218 women at risk of developing hereditary breast cancer. Women were assessed prior to counseling and 12-month post-counseling using self-administered, mailed questionnaires. Compared to baseline, breast cancer genetics knowledge was increased significantly at follow-up, and greater increases in knowledge were associated with educational level. Breast cancer anxiety decreased significantly from baseline to follow-up, and these decreases were associated with improvements in perceived risk. A significant decrease in clinical breast examination was observed at the 12-month follow-up. Findings suggest that women with a family history of breast cancer benefit from attending familial cancer clinics as it leads to increases in breast cancer genetics knowledge and decreases in breast cancer anxiety. The lowered rates of clinical breast examination indicate that the content of genetic counseling may need to be reviewed to ensure that women receive and take away the right message.

Intention to undergo prophylactic bilateral mastectomy in women at increased risk of developing hereditary breast cancer.

PURPOSE: To assess intention to undergo prophylactic bilateral mastectomy and psychologic determinants in unaffected women at increased risk of developing hereditary breast cancer. PATIENTS AND METHODS: Three hundred thirty-three women who were awaiting their initial appointments for risk assessment, advice about surveillance, and prophylactic options at one of 14 familial cancer clinics participated in a cross-sectional, questionnaire-based survey. RESULTS: Nineteen percent of women would consider and 47% would not consider a prophylactic mastectomy, should genetic testing identify a mutation in a breast cancer-predisposing gene, whereas 34% were unsure and 1% had already undergone a prophylactic mastectomy. In a bivariate analysis, women at a moderately increased risk of developing breast cancer had the highest proportion of subjects reporting that they would consider a prophylactic mastectomy (25%), compared with women at high risk (16%) (chi(2) = 7.79; P =.051). In multivariate analyses, consideration of prophylactic mastectomy strongly correlated with high levels of breast cancer anxiety (odds ratio [OR] = 17.4; 95% confidence interval [CI], 4.35 to 69.71; P =. 0001) and overestimation of one's breast cancer risk (OR = 3.01; 95% CI, 1.43 to 6.32; P =.0036), whereas there was no association with objective breast cancer risk (P =.60). CONCLUSION: A significant proportion of women at increased risk of developing hereditary breast cancer would consider prophylactic mastectomy. Although prophylactic mastectomy may be appropriate in women at high risk of developing breast cancer, it is perhaps less so in those who have a moderately increased risk. Such moderate-risk women are likely to benefit from interventions aimed at reducing breast cancer anxiety and correcting exaggerated breast cancer risk perceptions.

Clinical findings in a patient with FGFR1 P252R mutation and comparison with the literature.

We report on a patient with the skeletal findings of Jackson-Weiss syndrome, who manifests only mild craniofacial anomalies. Molecular analysis of her fibroblast growth factor receptor 1 gene (FGFR1) identified a heterozygous P252R missense mutation, previously only reported with FGFR1-Pfeiffer syndrome like manifestations. Mutations in the immunoglobulin-like, II-III (IgII-III) linker region of FGFR1 and FGFR3 molecules may present as a skeletal dysplasia affecting the appendicular skeleton including, brachydactyly, short broad middle phalanges, phalangeal epiphyseal coning and broad halluces. This communication is a further example of the phenomenon of an activated FGFR molecule resulting in overlapping manifestations in FGFR syndromes.

Macrocephaly--cutis marmorata telangiectatica congenita: report of five patients and a review of the literature.

Cutis marmorata telangiectatica congenita (CMTC) is a cutaneous disorder often accompanied by additional anomalies, most commonly segmental overgrowth. Recently a clinically discrete condition has been described comprising CMTC and congenital macrocephaly together with pre- and post-natal macrosomia, segmental overgrowth, central nervous system malformations, connective tissue abnormalities and intellectual handicap. We describe the natural history of macrocephaly-CMTC (M-CMTC) syndrome in a further five patients including the oldest reported patient, a 22 year old. The addition of our five patients brings the total number of reported patients to 28 and now makes it possible to more accurately delineate the phenotype and the frequency of clinical manifestations. We add some further clinical associations to those previously described, including anomalies of the growth of hair and teeth, neuronal migration defects, dislocated hips and stridor. We discuss potential genetic mechanisms that might account for the pleiotropic manifestations of this apparently rare segmental overgrowth disorder.

The management of familial breast cancer.

Epidemiological studies over the past several decades have consistently supported the concept that a proportion of breast cancers develop as the result of an inherited familial predisposition. However, until recently our understanding and knowledge of the underlying genetic processes involved have been limited. Current advances in molecular biology have shown that hereditary breast cancer may arise as the result of mutations of several specific gene loci including BRCA1, BRCA2, ATM gene, PTEN and p53. Several other less frequently occurring predisposition genes such as the androgen receptor gene (AR), the HNPCC genes and the oestrogen receptor gene may also be involved, but to a lesser extent. It is estimated that approximately 5-10% of all breast cancers involve one of these inherited predisposition genes, with BRCA1 and BRCA2 accounting for up to 90% of this group. Mutation analysis is complex in nature and is presently in a developmental and evolving phase, for which reason genetic testing should be offered on a selective basis and through genetic counselling clinics. This report reviews the current knowledge and roles of the various predisposition genes and discusses the management implications for both affected and nonaffected members of breast cancer families. Comprehensive and informative counselling is critical for women with an inherited predisposition to breast cancer and this has led to the evolution of familial cancer clinics involving a multi-disciplinary specialist team approach. Familial cancer clinics can provide individuals with information about their risk of developing breast cancer and offer advice regarding the various management options presently available.

Attitudes toward prophylactic oophorectomy and screening utilization in women at increased risk of developing hereditary breast/ovarian cancer.

OBJECTIVES: The aim of this study was to evaluate ovarian cancer screening uptake and attitudes toward prophylactic oophorectomy in women at risk of developing hereditary breast/ovarian cancer. STUDY METHODS: Ninety-five unaffected women, who approached 1 of 14 familial cancer clinics for advice about their breast/ovarian cancer risk and surveillance and prophylactic options, were assessed in a cross-sectional design when they attended the clinic. RESULTS: Among high-risk women ages 30 and over who had not had a prophylactic oophorectomy, 48% reported ever having had an ovarian ultrasound, and among women ages 50 and over 23% had had a serum CA 125 test. Twenty-three percent of women would consider, and 27% would not consider, a prophylactic oophorectomy should the genetic test indicate a germline mutation associated with hereditary breast/ovarian cancer, while 38% were unsure. Twelve percent had already undergone a prophylactic oophorectomy. Interest in prophylactic oophorectomy was associated with increased breast/ovarian cancer anxiety (chi(2) = 5.14, P = 0.023), but not objective cancer risk (chi(2) = 0.40, P = 0.53). CONCLUSION: Findings demonstrate that breast/ovarian cancer anxiety, rather than objective risk, is the major factor which determines women's attitude to prophylactic oophorectomy. Women are likely to benefit from interventions aimed at reducing breast/ovarian cancer anxiety. Research on the impact of prophylactic oophorectomy would be helpful in the development of educational strategies and decision aids to assist women who are trying to make a decision under conditions of uncertainty.

The genetic basis of breast cancer and its clinical implications.

While it has long been recognized that a proportion of breast cancer cases are the result of an inherited familial predisposition, precise knowledge of the underlying genetic processes has been lacking. Recent advances in molecular biology, however, have shown that hereditary breast cancer may eventuate as a result of mutations on several specific gene loci including BRCA1, BRCA2, ATM gene, PTEN and p53. Several other less frequently occurring predisposition genes such as the androgen receptor gene (AR), the HNPCC genes and the oestrogen receptor gene may also be involved, but to a lesser extent. Overall, approximately 5-10% of all breast cancers are thought to involve one of these inherited predisposition genes, with BRCA1 and BRCA2 being responsible for as much as 90% of this group. Because of the complex nature of genetic testing, mutation analysis is not presently routinely available outside genetic counselling clinics. In this review the current knowledge and role of each predisposition gene is outlined and the management implications of genetic testing for members of breast cancer families for both affected and non-affected members are discussed. The need to provide comprehensive counselling for women with an inherited predisposition to breast cancer has seen the evolution of the familial cancer clinic, involving a multidisciplinary specialist team approach. Familial cancer clinics will provide individuals with information about their risk of developing breast cancer and offer advice regarding further management strategies. It is important that surgeons, who have traditionally played a key role in breast cancer treatment, remain cognizant of these advances in genetic molecular biology, and in so doing continue to remain key participants in the conduct of breast cancer management.

Acute hepatitis and Brucella melitensis infection: clinicopathological findings.

The clinical and pathological findings in a patient who had acute hepatitis caused by Brucella melitensis are described. Antibiotic therapy induced a good clinical and biochemical response, although a relapse occurred. Brucellosis must be considered in the differential diagnosis of pyrexia of unknown origin, particularly if associated hepatic involvement is present. A careful occupational and travel history is essential.

A study of sterilization containers.

The introduction of rigid sterilization container systems in the U.S. marketplace has brought about many questions regarding how they should be used and whether or not they provide a "total system for aseptic practice." Questions have even been raised as to whether the rigid container is a better system than the established cloth and non-woven methods of wrapping. The purpose of this article is to share the results of a study which was conducted to closely examine the use of containers. The focus of the study was to determine whether an inner wrap should be used, whether there were problems at the sterile field with presentation of instruments, and whether the container configuration caused problems in processing, sterilization, storage, or use at the field. No attempt was made to compare various systems.