Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry

Purpose: The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controversial. The aim of this study was to explore features of breast cancers arising in Lynch syndrome families. Experimental Design: This observational study involved 107 cases of breast cancer identified from the Colorectal Cancer Family Registry (Colon CFR) from 90 families in which (a) both breast and colon cancer co-occurred, (b) families met either modified Amsterdam criteria, or had at least one early-onset (<50 years) colorectal cancer, and (c) breast tissue was available within the biospecimen repository for mismatch repair (MMR) testing. Eligibility criteria for enrollment in the Colon CFR are available online. Breast cancers were reviewed by one pathologist. Tumor sections were stained for MLH1, PMS2, MSH2, and MSH6, and underwent microsatellite instability testing. Results: Breast cancer arose in 35 mutation carriers, and of these, 18 (51%) showed immunohistochemical absence of MMR protein corresponding to the MMR gene mutation segregating the family. MMR-deficient breast cancers were more likely to be poorly differentiated (P = 0.005) with a high mitotic index (P = 0.002), steroid hormone receptor–negative (estrogen receptor, P = 0.031; progesterone receptor, P = 0.022), and to have peritumoral lymphocytes (P = 0.015), confluent necrosis (P = 0.002), and growth in solid sheets (P < 0.001) similar to their colorectal counterparts. No difference in age of onset was noted between the MMR-deficient and MMR-intact groups. Conclusions: MMR deficiency was identified in 51% of breast cancers arising in known mutation carriers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lacking

Linkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome)

Abstract Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.

Contributors to life satisfaction in parents of an adult child with Down syndrome

Aim: This study investigated: (1) concurrent relationships between measures of family life and parental satisfaction with life in parents of an adult with Down syndrome and (2) influence of early family functioning on current parental satisfaction. Method: Sixty-two families were interviewed using a semi-structured interview, and responded to a series of questionnaires related to family functioning when their child with Down syndrome was between 7 and 15 years. Fifteen years later parents were asked to provide data on their current situation, including mental health, and satisfaction and difficulties with respect to care-giving in relation to their adult child. Results: Over half the families provided data to the second phase of the study. Life circumstances were appreciably worse for a small group of families than had been the case 15 years previously; however, these changes were generally unrelated to their parenting role. Overall, parents reported experiencing satisfaction from their care-giving role and did not report high levels of difficulties emanating from this role. Conclusions: Most parents demonstrated good levels of personal functioning, although there was a small group for whom this was not the case. Earlier functioning did not make a strong contribution to current levels of life satisfaction.

Home monitoring for infants at risk of the sudden infant death syndrome

This study evaluates the effectiveness and social implications of home monitoring of 31 infants at risk of sudden infant death syndrome (SIDS). Thirteen siblings of children dying of SIDS, nine near miss SIDS infants and nine preterm infants with apnoea persisting beyond 40 weeks post conceptual age were monitored from a mean age of 15 days to a mean of 10 months. Chest movement detection monitors were used in 27 and thoracic impedance monitors in four. Genuine apnoeic episodes were reported by 21 families, and 13 infants required resuscitation. Apnoeic episodes occurred in all nine preterm infants but in only five (38%) of the siblings of SIDS (P<0.05). Troublesome false alarms were a major problem occurring with 61% of the infants and were more common with the preterm infants than the siblings of SIDS. All but two couples stated that the monitor decreased anxiety and improved their quality of life. Most parents accepted that the social restrictions imposed by the monitor were part of the caring process but four couples were highly resentful of the changes imposed on their lifestyle. The monitors used were far from ideal with malfunction occurring in 17, necessitating replacement in six, repair in six and cessation of monitoring in three. The parents became ingenious in modifying the monitors to their own individual requirements Although none of these 31 ‘at risk’ infants died the study sample was far too small to conclude whether home monitoring prevented any cases of SIDS.

Further evidence for linkage of Gilles de la Tourette syndrome (GTS) susceptibility loci on chromosomes 2p11, 8q22 and 11q23-24 in South African Afrikaners

Utilizing DNA samples from 91 Afrikaner nuclear families with one or more affected children, five genomic regions on chromosomes 2p, 8q, 11q, 20q, and 21q that gave evidence for association with GTS in previous case-control association studies were investigated for linkage and association with GTS. Highly polymorphic markers with mean heterozygosity of 0.77 were typed and resulting genotypes evaluated using single marker transmission disequilibrium (TDT), single marker haplotype relative risk (HRR), and multi-marker "extended" TDT and HRR methods. Single marker TDT analysis showed evidence for linkage or association, with p-values near 0.05, for markers D2S139, GATA28F12, and D11S1377 on chromosomes 2p11, 8q22 and 11q23-24, respectively. Extended, two-locus TDT and HRR analysis provided further evidence for linkage or association on chromosome 2 with p-values of 0.007 and 0.025, and chromosome 8 with p-values of 0.059 and 0.013, respectively. These results provide important additional evidence for the location of GTS susceptibility loci.

Quantitative electroencephalographic comodulation : an investigation of patterns in chronic fatigue syndrome

Introduction. This is a pilot study of quantitative electro-encephalographic (QEEG) comodulation analysis, which is used to assist in identifying regional brain differences in those people suffering from chronic fatigue syndrome (CFS) compared to a normative database. The QEEG comodulation analysis examines spatial-temporal cross-correlation of spectral estimates in the resting dominant frequency band. A pattern shown by Sterman and Kaiser (2001) and referred to as the anterior posterior dissociation (APD) discloses a significant reduction in shared functional modulation between frontal and centro-parietal areas of the cortex. This research attempts to examine whether this pattern is evident in CFS. Method. Eleven adult participants, diagnosed by a physician as having CFS, were involved in QEEG data collection. Nineteen-channel cap recordings were made in five conditions: eyes-closed baseline, eyes-open, reading task one, math computations task two, and a second eyes-closed baseline. Results. Four of the 11 participants showed an anterior posterior dissociation pattern for the eyes-closed resting dominant frequency. However, seven of the 11 participants did not show this pattern. Examination of the mean 8-12 Hz amplitudes across three cortical regions (frontal, central and parietal) indicated a trend of higher overall alpha levels in the parietal region in CFS patients who showed the APD pattern compared to those who did not have this pattern. All patients showing the pattern were free of medication, while 71% of those absent of the pattern were using antidepressant medications. Conclusions. Although the sample is small, it is suggested that this method of evaluating the disorder holds promise. The fact that this pattern was not consistently represented in the CFS sample could be explained by the possibility of subtypes of CFS, or perhaps co-morbid conditions. Further, the use of antidepressant medications may mask the pattern by altering the temporal characteristics of the EEG. The results of this pilot study indicate that further research is warranted to verify that the pattern holds across the wider population of CFS sufferers.

Understanding the literacy difficulties of students with Asperger's syndrome in middle years' classrooms

Among the students in Australian classrooms who are experiencing learning difficulties are increasing numbers of children who have been diagnosed with Asperger's syndrome. Although the general cognitive and language abilities of these students are comparable with most of their peers, they experience significant difficulties with social communication, social interactions and social-emotional/behavioural functioning. Despite indications that there are features inherent in Asperger's syndrome that are likely to have a negative effect on the development of advanced literacy skills, studies to date have primarily focused on social-emotional/behavioural challenges. Without effective literacy skills, however, students' access to educational and career opportunities may be curtailed. This article reviews features of Asperger's syndrome that appear to have a negative impact upon the development of advanced literacy skills and suggests ways in which inclusive classroom teachers could support the development of their learners.

Towards self-authorship in child care students : implications for working with children and their families

Using self authorship as a theoretical framework, this chapter examines the relationship between personal epistemology and beliefs about children’s learning for students studying to be child care workers in Australia. Scenario-based interviews were used to investigate how students’ views of knowledge, identity and relationships with others were related to beliefs about how children learn. Implications for vocational education are discussed.