Genomic and clinical characterization of a familial GIST kindred intolerant to imatinib.

Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome sequencing of the germline and tumor. Affected individuals with GIST harbored a germline variant found within exon 13 of the KIT gene (c.1965T>G; p.Asn655Lys, p.N655K) and a variant in the MSR1 gene (c.877 C > T; p.Arg293*, pR293X). Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, which resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies, and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.

Audiological phenotyping evaluation in KBG syndrome: Description of a multicenter review.

OBJECTIVES: Our objective was to reinforce clinical knowledge of hearing impairment in KBG syndrome. KBG syndrome is a rare genetic disorder due to monoallelic pathogenic variations of ANKRD11.The typical phenotype includes facial dysmorphism, costal and spinal malformation and developmental delay. Hearing loss in KBG patients has been reported for many years, but no study has evaluated audiological phenotyping from a clinical and an anatomical point of view. METHODS: This French multicenter study included 32 KBG patients with retrospective collection of data on audiological features, ear imaging and genetic investigations. RESULTS: We identified a typical audiological profil in KBG syndrome: conductive (71%), bilateral (81%), mild to moderate (84%) and stable (69%) hearing loss, with some audiological heterogeneity. Among patients with an abnormality on CT imaging (55%), ossicular chain impairment (67%), fixation of the stapes footplate (33%) and inner-ear malformations (33%) were the most common abnormalities. CONCLUSION: We recommend a complete audiological and radiological evaluation and an ENT-follow up in all patients presenting with KBG Syndrome. Imaging evaluation is necessary to determine the nature of lesions in the middle and inner ear.

SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients.

BACKGROUND: Individuals with pathogenic variants in SATB2 display intellectual disability, speech and behavioral disorders, dental abnormalities and often features of Pierre Robin sequence. SATB2 encodes a transcription factor thought to play a role in bone remodeling. The primary aim of our study was to systematically review the skeletal manifestations of SATB2-associated syndrome. For this purpose, we performed a non-interventional, multicenter cohort study, from 2017 to 2018. We included 19 patients, 9 females and 10 males ranging in age from 2 to 19 years-old. The following data were collected prospectively for each patient: clinical data, bone markers and calcium and phosphate metabolism parameters, skeletal X-rays and bone mineral density. RESULTS: Digitiform impressions were present in 8/14 patients (57%). Vertebral compression fractures affected 6/17 patients (35%). Skeletal demineralization (16/17, 94%) and cortical thinning of vertebrae (15/17) were the most frequent radiological features at the spine. Long bones were generally demineralized (18/19). The distal phalanges were short, thick and abnormally shaped. C-telopeptide (CTX) and Alkaline phosphatase levels were in the upper normal values and osteocalcin and serum procollagen type 1 amino-terminal propeptide (P1NP) were both increased. Vitamin D insufficiency was frequent (66.7%). CONCLUSION: We conclude that SATB2 pathogenic variants are responsible for skeletal demineralization and osteoporosis. We found increased levels of bone formation markers, supporting the key role of SATB2 in osteoblast differentiation. These results support the need for bone evaluation in children and adult patients with SATB2-associated syndrome (SAS).

Better Understanding of the Metamorphosis of Pregnancy (BUMP): protocol for a digital feasibility study in women from preconception to postpartum.

The Better Understanding the Metamorphosis of Pregnancy (BUMP) study is a longitudinal feasibility study aimed to gain a deeper understanding of the pre-pregnancy and pregnancy symptom experience using digital tools. The present paper describes the protocol for the BUMP study. Over 1000 participants are being recruited through a patient provider-platform and through other channels in the United States (US). Participants in a preconception cohort (BUMP-C) are followed for 6 months, or until conception, while participants in a pregnancy cohort (BUMP) are followed into their fourth trimester. Participants are provided with a smart ring, a smartwatch (BUMP only), and a smart scale (BUMP only) alongside cohort-specific study apps. Participant centric engagement strategies are used that aim to co-design the digital approach with participants while providing knowledge and support. The BUMP study is intended to lay the foundational work for a larger study to determine whether participant co-designed digital tools can be used to detect, track and return multimodal symptoms during the perinatal window to inform individual level symptom trajectories.

Stapes surgery in osteogenesis imperfecta: retrospective analysis of 18 operated ears.

PURPOSE: To evaluate short and long term results of stapes surgery in patients with osteogenesis imperfecta (OI), METHODS: Retrospective case series of 18 primary stapes surgeries performed on 11 hearing-impaired OI patients with evidence of stapes fixation, in a Tertiary referral center. We analysed pre-operative and post-operative hearing results at 1 month and at least 1 year RESULTS: The main operative findings were stapes fixation, thickened footplate and fragile or fractured stapes crura. No revision surgery was necessary. Hearing improvement was achieved in 94% of the cases. We obtained an air-bone gap closure to within 10 dB in 46% of the cases and to within 15 dB in 92% of the cases at 1-year follow-up. The mean hearing gain in air conduction (at 0.5, 1, 2 and 4 kHz) was 18.4 dB at 1 month and 22.4 dB at 1 year. CONCLUSION: Stapes surgery in OI gives good results with few complications in our series. A hearing gain is often obtained in spite of the sensorineural hearing loss caused by the natural progression of the disease.

Key characteristics of basal cell carcinoma with large subclinical extension.

BACKGROUND: Basal cell carcinoma with large subclinical extension (BCC-LSE) is a tumour whose extensive spread becomes apparent during Mohs surgery histopathology review. Not recognizing BCC-LSE preoperatively may result in a greater number of Mohs layers and in larger than anticipated postoperative defects. OBJECTIVE: To evaluate the characteristics of BCC-LSE. METHODS: This retrospective study reviewed BCC treated with Mohs surgery at a single academic surgical centre between March 2007 and February 2012. A total of 2044 cases met the criteria of BCC-LSE, which was defined as a lesion requiring at least three Mohs stages and a final surgical margin (difference between preoperative and postoperative measurements in either vertical or horizontal dimensions) of ≥1 cm. RESULTS: In adjusted multivariable analysis, male sex (P = 0.05), Fitzpatrick skin type I (P = 0.002), history of prior BCC (P = 0.003) and subtypes of basosquamous, metatypical, micronodular, infiltrative, morpheaform and sclerosing (P = 0.005) remained significant BCC-LSE predictors. CONCLUSIONS: Demographic factors, including personal history of BCC, skin type, anatomic location, gender and age, in addition to tumour histologic subtype assessed through incisional biopsy, can help predict occurrence of BCC-LSE and assist physicians in optimizing preoperative assessment of surgical time and complexity.

Implication of non-coding PAX6 mutations in aniridia.

There is an increasing implication of non-coding regions in pathological processes of genetic origin. This is partly due to the emergence of sophisticated techniques that have transformed research into gene expression by allowing a more global understanding of the genome, both at the genomic, epigenomic and chromatin levels. Here, we implemented the analysis of PAX6, whose coding loss-of-function variants are mainly implied in aniridia, by studying its non-coding regions (untranslated regions, introns and cis-regulatory sequences). In particular, we have taken advantage of the development of high-throughput approaches to screen the upstream and downstream regulatory regions of PAX6 in 47 aniridia patients without identified mutation in the coding sequence. This was made possible through the use of custom targeted resequencing and/or CGH array to analyze the entire PAX6 locus on 11p13. We found candidate variants in 30 of the 47 patients. 9/30 correspond to the well-known described 3' deletions encompassing SIMO and other enhancer elements. In addition, we identified numerous different variants in various non-coding regions, in particular untranslated regions. Among these latter, most of them demonstrated an in vitro functional effect using a minigene strategy, and 12/21 are thus considered as causative mutations or very likely to explain the phenotypes. This new analysis strategy brings molecular diagnosis to more than 90% of our aniridia patients. This study revealed an outstanding mutation pattern in non-coding PAX6 regions confirming that PAX6 remains the major gene for aniridia.

IL11RA-related Crouzon-like autosomal recessive craniosynostosis in 10 new patients: Resemblances and differences.

By describing 10 new patients recruited in centres for Human Genetics, we further delineate the clinical spectrum of a Crouzon-like craniosynostosis disorder, officially termed craniosynostosis and dental anomalies (MIM614188). Singularly, it is inherited according to an autosomal recessive mode of inheritance. We identified six missense mutations in IL11RA, a gene encoding the alpha subunit of interleukin 11 receptor, 4 of them being novel, including 2 in the Ig-like C2-type domain. A subset of patients had an associated connective tissue disorder with joint hypermobility and intervertebral discs fragility. A smaller number of teeth anomalies than that previously reported in the two large series of patients evaluated in dental institutes points toward an ascertainment bias.

MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype.

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.

Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

Ultrasonic motor-induced geometric distortions in magnetic resonance images.

Ultrasonic motors (USMs) are common actuators that can be safely used in the magnetic resonance imaging (MRI) environment. However, lack of MRI compatibility results in issues such as image distortion. This fact led researchers to shift focus from USMs to pneumatic and hydraulic actuators in development of surgical robots. The aim is to quantify and compensate the geometric distortion of MR images as generated by the presence of USMs. An ultrasonic motor was positioned in three orientations with respect to the bore axis. The induced distortions were compared across four image sequences. To reduce the distortions, three artifact reduction methods were employed. Geometric distortion is the only artifact in image slices farther from the motor. The various motor orientations lead to different distortions, with the lowest distortion for the z orientation. The maximum measured distortion of ten pixels occurred. This maximal distortion is equal to a 1-cm displacement of the displayed points relative to their actual locations and it is beyond the acceptable level for medical display standards. Bandwidth reduction reduced the distortion, with a 50% reduction for a doubled bandwidth. In conclusion, USMs can be preferred alternative because accurate targeting of pathologies can occur in free distorted images.

The association of severe encephalopathy and question mark ear is highly suggestive of loss of MEF2C function.

Auriculocondylar syndrome and isolated question mark ear result from dysregulation of the endothelin 1-endothelin receptor type A signaling pathway. Animal models have highlighted the role of the transcription factor MEF2C as an effector of this pathway. We report heterozygous MEF2C loss-of-function as a possible cause of question mark ear associated with intellectual deficiency.

Obesity conveys poor outcome in patients with hepatocellular carcinoma treated by transarterial chemoembolization.

PURPOSE: The purpose of this retrospective study was to evaluate the impact of obesity on radiologic outcomes in patients with hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE). MATERIALS AND METHODS: A total of 100 TACE procedures performed in 57 patients (42 men, 15 women) with a mean age of 62 years±8.4 (SD) (range: 39-83 years) were retrospectively reviewed. The 1-2-month follow-up computed tomography or magnetic resonance imaging examinations was assessed for new or residual disease and radiologic response using mRECIST criteria. Patients were categorized into two groups according to body mass index (BMI). Patients with BMI<25kg/m2 were further referred as to low BMI patients and those with BMI≥25kg/m2 as high BMI patients. Outcomes were compared between the two groups. RESULTS: Low and high BMI patients were similar in regard to age, gender, HCC etiology and stage, and pre-procedure disease burden. TACE for high BMI, compared to low BMI, patients resulted in lower complete response (39% vs. 66%) and higher progressive disease (21% vs. 5%) rates (P=0.04), and higher rates of residual disease (63% vs. 39%, P=0.02) and new lesions in untreated liver (39% vs. 18%, P=0.04) on 1-2-month follow-up imaging. CONCLUSIONS: High BMI is associated with significantly more residual disease, new lesions, and progressive disease in patients with HCC treated by TACE.

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.

Fetal phenotypes in otopalatodigital spectrum disorders.

Otopalatodigital spectrum disorders (OPDSD) include OPD syndromes types 1 and type 2 (OPD1, OPD2), Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.

Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey.

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.