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Background Proteus syndrome is an ultra-rare mosaic overgrowth disorder. Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention. This retrospective study seeks to quantify the radiographic features of Proteus syndrome-associated lung disease using computed tomography (CT) of the chest. The first method derives a Cystic Lung Score (CLS) by using a computer-aided diagnostic tool to quantify the fraction of cystic involvement of the lung. The second method yields a Clinician Visual Score (CVS), an observer reported scale of severity based on multiple radiographic features. The aim of this study was to determine if these measurements are associated with clinical symptoms, pulmonary function test (PFT) measurements, and if they may be used to assess progression of pulmonary disease. Results One hundred and thirteen imaging studies from 44 individuals with Proteus syndrome were included. Dyspnea and oxygen use were each associated with higher CLS ( p  = 0.001 and < 0.001, respectively) and higher CVS ( p  < 0.001 and < 0.001). Decreases in percent predicted FVC, FEV 1 , and DLCO each correlated with increased CLS and CVS. The annual increase of CLS in children, 5.6, was significantly greater than in adults, 1.6. ( p  = 0.03). The annual increase in CVS in children, 0.4, was similar to adults, 0.2 ( p  = 0.36). Conclusions Proteus syndrome-associated lung disease is progressive. The rate of cystic progression is increased in children. Increased scores in CLS and CVS were associated with clinical symptoms and decreased pulmonary function. Both methods were able to detect change over time and were associated with clinically meaningful outcomes which may enable their use in interventional studies.

A child's obesity is generally perceived by the public to be under the control of the child's parents. While the health consequences of childhood obesity are well understood, less is known about psychological and social effects of having an obese child on parents. We set out to characterize stigma and courtesy stigma experiences surrounding obesity among children with Bardet-Biedl syndrome (BBS), a multisystem genetic disorder, and their parents. Twenty-eight parents of children with BBS participated in semi-structured interviews informed by social stigmatization theory, which describes courtesy stigma as parental perception of stigmatization by association with a stigmatized child. Parents were asked to describe such experiences. Parents of children with BBS reported the child's obesity as the most frequent target of stigmatization. They perceived health care providers as the predominant source of courtesy stigma, describing interactions that resulted in feeling devalued and judged as incompetent parents. Parents of children with BBS feel blamed by others for their child's obesity and described experiences that suggest health care providers may contribute to courtesy stigma and thus impede effective communication about managing obesity. Health care providers may reinforce parental feelings of guilt and responsibility by repeating information parents may have previously heard and ignoring extremely challenging barriers to weight management, such as a genetic predisposition to obesity. Strategies to understand and incorporate parents' perceptions and causal attributions of their children's weight may improve communication about weight control.

Background Clinical outcome assessments are important tools for measuring the natural history of disease and efficacy of an intervention. The heterogenous phenotype and difficult to quantity features of Proteus syndrome present challenges to measuring clinical outcomes. To address these, we designed a global clinical assessment for Proteus syndrome, a rare mosaic overgrowth disorder. The Clinical Gestalt Assessment (CGA) aims to evaluate change over time in this phenotypically diverse disorder. Results We gathered paired serial photographs and radiographs obtained at 12-to-36-month intervals from our natural history study of Proteus syndrome. The chronologic order of each set was blinded and presented to clinicians familiar with overgrowth disorders. They were asked to determine the chronologic order and, based on that response, rate global clinical change using a seven-point scale (Much Worse, Worse, Minimally Worse, No Change, Minimally Improved, Improved, Much Improved). Following a pilot, we tested the inter-rater reliability of the CGA using eight cases rated by eight clinicians. Raters identified the correct chronologic order in 53 of 64 (83%) of responses. There was low inter-rater variance and poor to moderate reliability with an intraclass correlation coefficient of 0.46 (95% CI 0.24–0.75). The overall estimate of global change was Minimally Worse over time, which is an accurate reflection of the natural history of Proteus syndrome. Conclusions The CGA is a tool to evaluate clinical change over time in Proteus syndrome and may be a useful adjunct to measure clinical outcomes in prospective therapeutic trials.

In this work, we sought to delineate the prevalence of cardiothoracic imaging findings of Proteus syndrome in a large cohort at our institution. Of 53 individuals with a confirmed diagnosis of Proteus syndrome at our institution from 10/2001 to 10/2019, 38 individuals (men, n = 23; average age = 24 years) underwent cardiothoracic imaging (routine chest CT, CT pulmonary angiography and/or cardiac MRI). All studies were retrospectively and independently reviewed by two fellowship-trained cardiothoracic readers. Disagreements were resolved by consensus. Differences between variables were analyzed via parametric and nonparametric tests based on the normality of the distribution. The cardiothoracic findings of Proteus syndrome were diverse, but several were much more common and included: scoliosis from bony overgrowth (94%), pulmonary venous dilation (62%), band-like areas of lung scarring (56%), and hyperlucent lung parenchyma (50%). In addition, of 20 individuals who underwent cardiac MRI, 9/20 (45%) had intramyocardial fat, mostly involving the endocardial surface of the left ventricular septal wall. There was no statistically significant difference among the functional cardiac parameters between individuals with and without intramyocardial fat. Only one individual with intramyocardial fat had mildly decreased function (LVEF = 53%), while all others had normal ejection fraction.

Background The widespread use of next-generation sequencing has identified an important role for somatic mosaicism in many diseases. However, detecting low-level mosaic variants from next-generation sequencing data remains challenging. Results Here, we present a method for Position-Based Variant Identification (PBVI) that uses empirically-derived distributions of alternate nucleotides from a control dataset. We modeled this approach on 11 segmental overgrowth genes. We show that this method improves detection of single nucleotide mosaic variants of 0.01–0.05 variant allele fraction compared to other low-level variant callers. At depths of 600 × and 1200 ×, we observed > 85% and > 95% sensitivity, respectively. In a cohort of 26 individuals with somatic overgrowth disorders PBVI showed improved signal to noise, identifying pathogenic variants in 17 individuals. Conclusion PBVI can facilitate identification of low-level mosaic variants thus increasing the utility of next-generation sequencing data for research and diagnostic purposes.

Respecting the confidentiality of personal data contributed to genomic studies is an important issue for researchers using genomic sequencing in humans. Although most studies adhere to rules of confidentiality, there are different conceptions of confidentiality and why it is important. The resulting ambiguity obscures what is at stake when making tradeoffs between data protection and other goals in research, such as transparency, reciprocity, and public benefit. Few studies have examined why participants in genomic research care about how their information is used. To explore this topic, we conducted semi-structured phone interviews with 30 participants in two National Institutes of Health research protocols using genomic sequencing. Our results show that research participants value confidentiality as a form of control over information about themselves. To the individuals we interviewed, control was valued as a safeguard against discrimination in a climate of uncertainty about future uses of individual genome data. Attitudes towards data sharing were related to the goals of research and details of participants' personal lives. Expectations of confidentiality, trust in researchers, and a desire to advance science were common reasons for willingness to share identifiable data with investigators. Nearly, all participants were comfortable sharing personal data that had been de-identified. These findings suggest that views about confidentiality and data sharing are highly nuanced and are related to the perceived benefits of joining a research study.

Dubowitz syndrome is a rare disorder characterized by multiple congenital anomalies, cognitive delay, growth failure, an immune defect, and an increased risk of blood dyscrasia and malignancy. There is considerable phenotypic variability, suggesting genetic heterogeneity. We clinically characterized and performed exome sequencing and high-density array SNP genotyping on three individuals with Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister) and an unpublished patient (Patient 3). Given the siblings' history of bone marrow abnormalities, we also evaluated telomere length and performed radiosensitivity assays. In the siblings, exome sequencing identified compound heterozygosity for a known rare nonsense substitution in the nuclear ligase gene LIG4 (rs104894419, NM_002312.3:c.2440C>T) that predicts p.Arg814X (MAF:0.0002) and an NM_002312.3:c.613delT variant that predicts a p.Ser205Leufs*29 frameshift. The frameshift mutation has not been reported in 1000 Genomes, ESP, or ClinSeq. These LIG4 mutations were previously reported in the sibling sister; her brother had not been previously tested. Western blotting showed an absence of a ligase IV band in both siblings. In the third patient, array SNP genotyping revealed a de novo ∼ 3.89 Mb interstitial deletion at chromosome 17q24.2 (chr 17:62,068,463-65,963,102, hg18), which spanned the known Carney complex gene PRKAR1A. In all three patients, a median lymphocyte telomere length of ≤ 1st centile was observed and radiosensitivity assays showed increased sensitivity to ionizing radiation. Our work suggests that, in addition to dyskeratosis congenita, LIG4 and 17q24.2 syndromes also feature shortened telomeres; to confirm this, telomere length testing should be considered in both disorders. Taken together, our work and other reports on Dubowitz syndrome, as currently recognized, suggest that it is not a unitary entity but instead a collection of phenotypically similar disorders. As a clinical entity, Dubowitz syndrome will need continual re-evaluation and re-definition as its constituent phenotypes are determined.

Purpose PIK3CA -related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. Methods Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. Results Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of –7.2% (SD 16.0, p  = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p  = 0.48) ( n  = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. Conclusion This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS.

Purpose Secondary findings (SFs) are present in 1–4% of individuals undergoing genome/exome sequencing. A review of how SFs are disclosed and what outcomes result from their receipt is urgent and timely. Methods We conducted a systematic literature review of SF disclosure practices and outcomes after receipt including cascade testing, family and provider communication, and health-care actions. Of the 1,184 nonduplicate records screened we summarize findings from 27 included research articles describing SF disclosure practices, outcomes after receipt, or both. Results The included articles reported 709 unique SF index recipients/families. Referrals and/or recommendations were provided 647 SF recipients and outcome data were available for 236. At least one recommended evaluation was reported for 146 SF recipients; 16 reports of treatment or prophylactic surgery were identified. We found substantial variations in how the constructs of interest were defined and described. Conclusion Variation in how SF disclosure and outcomes were described limited our ability to compare findings. We conclude the literature provided limited insight into how the American College of Medical Genetics and Genomics (ACMG) guidelines have been translated into precision health outcomes for SF recipients. Robust studies of SF recipients are needed and should be prioritized for future research.

The Proteus syndrome affects some tissues and not others and is thought to be caused by a somatic mutation. Investigators found that the mutation is caused by activation of AKT1, an enzyme that mediates glucose metabolism, cell proliferation, and apoptosis. The Proteus syndrome is characterized by patchy or segmental overgrowth and hyperplasia of multiple tissues and organs, along with susceptibility to the development of tumors 1 , 2 (Figure 1). It is thought that Joseph Merrick, an Englishman who lived in the late 19th century and became the subject of the play and film The Elephant Man, had the Proteus syndrome. This uncommon syndrome (with an incidence of <1 case per 1 million population) has not been reported to recur in a family but has been reported in discordant monozygotic twins. 3 These observations support the hypothesis that the Proteus syndrome is caused . . .