Search

Clinical geneticists and syndromologists have traditionally focused on identifying syndromes in children. However, there is a growing acknowledgment of the need to describe adult phenotypes. This article provides an overview of the evolving phenotypes of rare genetic syndromes into adulthood, elucidating its challenges, opportunities, and future perspectives. The clinical phenotypes of four adults with Costello syndrome are described to illustrate these aspects. Phenotypic and genotypic data from four individuals broaden the spectrum of Costello syndrome in adulthood and highlight the high variability in neurocognitive outcome. The clinical data align with previous findings and established genotype-phenotype correlations. Interestingly, two individuals presented with recurrent cancers (bladder cancer and neuroblastoma). Further studies are imperative to provide reliable information for counselling and management to enable comprehensive understanding of the evolving features of rare syndromic diseases and special health issues into adulthood. [ABSTRACT FROM AUTHOR]

Many conspiracy theories and worst-case scenarios have been produced about the COVID-19 pandemic. With a reductionist approach, this new coronavirus disease outbreak has been regrettably confined to the simple matter that humans are exposed to viral pathogens of certain wild animals. However, the global reasons and outcomes of the present outbreak should not simply be correlated with the physiologies of a group of animals but with human activities subject to wanton consumption, interference with living spaces, intense commercialization and, particularly, dietary habits. Thus, reconceptualizing pandemics as a multidimensional “ecological crisis” posing a threat to the future of human and nonhuman beings rather than a “disease” endangering human welfare seems to become the sole prerequisite for a significant policy shift in the relationship between humans and animals. With this in mind, the eponymous protagonist of the novel, Elizabeth Costello, a vegetarian like her creator, gives the traces of an ecological philosophy which reinforces the notion that it is not the sheer scientific productivity driven by the rationalization but the reconsideration of animal-human interactions that can prevent post-pandemic era from recurring outbreaks. In the novel, through her understanding of environmental ethics, J. M. Coetzee’s vegetarian and writer protagonist provides discussions that help rethinking literature as one of the guiding disciplines that can offer new insights into the natural habitat of animals. This study intends to handle how Coetzee’s thoughts on vegetarianism and human-animal interactions can become an ethical model for the future world in dire need of a post-pandemic paradigm shift.

RAS GTPases are ubiquitous GDP/GTP-binding proteins that function as molecular switches in cellular signalling and control numerous signalling pathways and biological processes. Pathogenic mutations in RAS genes severely affect cellular homeostasis, leading to cancer when occurring in somatic cells and developmental disorders when the germline is affected. These disorders are generally termed as RASopathies and among them Costello syndrome (CS) is a distinctive entity that is caused by specific HRAS germline mutations. The majority of these mutations affect residues 12 and 13, the same sites as somatic oncogenic HRAS mutations. The hallmarks of the disease include congenital cardiac anomalies, impaired thriving and growth, neurocognitive impairments, distinctive craniofacial anomalies, and susceptibility to cancer. Adult patients often present signs of premature aging including reduced bone mineral density and osteoporosis. Using a CS mouse model harbouring a Hras G12V germline mutation, we aimed at determining whether this model recapitulates the patients’ bone phenotype and which bone cells are driving the phenotype when mutated. Our data revealed that Hras G12V mutation induces bone loss in mice at certain ages. In addition, we identified that bone loss correlated with an increased number of osteoclasts in vivo and Hras G12V mutations increased osteoclastogenesis in vitro. Last, but not least, mutant osteoclast differentiation was reduced by treatment in vitro with MEK and PI3K inhibitors, respectively. These results indicate that Hras is a novel regulator of bone homeostasis and an increased osteoclastogenesis due to Hras G12V mutation contributes to bone loss in the Costello syndrome.

What is happening in literary culture that critics and scholars believe the way we read novels today is troubled? Writer-critics like Zadie Smith have argued that the value of the novel be reconsidered according to an earlier tradition of realism, which evokes an increasingly complex world by which readers can be roused to ethical knowledge of other people. Smith’s formulation tells a story about the way we connect the reality of the novel and our own reality, a story of which literary scholars have begun to question the very possibility. This essay engages a debate between Dorothy Hale (2020) and Timothy Bewes (2022) that has significant consequences for reading, if Bewes is correct to question critical approaches that treat literature as an object of analysis and to theorise, instead, that the contemporary novel has its own, unapprehendable ‘thought’. But if thought is unapprehendable, how can criticism survive? Answering this question, I read J.M. Coetzee’s Elizabeth Costello (2003) as a novel that foregrounds thought, not, I argue, as in Bewes’s negative formulation but necessarily as a positive power that manifests a life. In this case, realism and criticism survive as precisely the nonsubjective thinking of impossibility required for less troubling times. [ABSTRACT FROM AUTHOR]

Background: Data on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description. Objectives: To describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype–genotype correlations. Methods: We performed a 10‐year, large, prospective, multicentric, collaborative dermatological and genetic study. Results: Thirty‐one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and 'cobblestone' papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS. Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype–genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S). Conclusions and Relevance: This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS. [ABSTRACT FROM AUTHOR]

A large hepatic mixed echoic mass occupying the left fetal abdomen was identified at 266/7 weeks. The mass showed peripheral and internal vascularity. Other ultrasound findings included edema of the fetal head and face, macrosomia, shortened long bones, abnormal posture of hands, small stomach, polyhydramnios and biventricular hypertrophy. Fetal magnetic resonance imaging confirmed a hypervascular mass replacing the lateral left hepatic lobe, suggestive of a congenital hemangioma. The fetus was delivered by cesarean section at 282/7 weeks. The baby was stabilized at day 3 of life, and underwent successful selective tumor embolization. The baby remained stable for 3 days, then deteriorated with a progressive thickening of the myocardium. The child then passed away on day 11 from severe progressive hypertrophic cardiomyopathy, with almost complete obliteration of the left ventricular cavity; an autopsy was declined. Postnatal investigations reported a de novo heterozygous pathogenic HRAS variant (NM_005343.3(HRAS): c.35_36 delinsTT, p.Gly21Val), previously reported in 8 cases associated with the early, lethal form of Costello syndrome.