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ArXiv Apr 2024Individuals with suspected rare genetic disorders often undergo multiple clinical evaluations, imaging studies, laboratory tests and genetic tests, to find a possible...
Individuals with suspected rare genetic disorders often undergo multiple clinical evaluations, imaging studies, laboratory tests and genetic tests, to find a possible answer over a prolonged period of time. Addressing this "diagnostic odyssey" thus has substantial clinical, psychosocial, and economic benefits. Many rare genetic diseases have distinctive facial features, which can be used by artificial intelligence algorithms to facilitate clinical diagnosis, in prioritizing candidate diseases to be further examined by lab tests or genetic assays, or in helping the phenotype-driven reinterpretation of genome/exome sequencing data. Existing methods using frontal facial photos were built on conventional Convolutional Neural Networks (CNNs), rely exclusively on facial images, and cannot capture non-facial phenotypic traits and demographic information essential for guiding accurate diagnoses. Here we introduce GestaltMML, a multimodal machine learning (MML) approach solely based on the Transformer architecture. It integrates facial images, demographic information (age, sex, ethnicity), and clinical notes (optionally, a list of Human Phenotype Ontology terms) to improve prediction accuracy. Furthermore, we also evaluated GestaltMML on a diverse range of datasets, including 528 diseases from the GestaltMatcher Database, several in-house datasets of Beckwith-Wiedemann syndrome (BWS, over-growth syndrome with distinct facial features), Sotos syndrome (overgrowth syndrome with overlapping features with BWS), NAA10-related neurodevelopmental syndrome, Cornelia de Lange syndrome (multiple malformation syndrome), and KBG syndrome (multiple malformation syndrome). Our results suggest that GestaltMML effectively incorporates multiple modalities of data, greatly narrowing candidate genetic diagnoses of rare diseases and may facilitate the reinterpretation of genome/exome sequencing data.
PubMed: 38711434
DOI: No ID Found -
Cureus Apr 2024Beckwith-Wiedemann syndrome (BWS) is a rare genomic imprinting disorder that affects multiple systems. Major features can manifest as large birth weight, anterior...
Beckwith-Wiedemann syndrome (BWS) is a rare genomic imprinting disorder that affects multiple systems. Major features can manifest as large birth weight, anterior abdominal wall defects, macroglossia, hyperinsulinism, organomegaly hemihypertrophy, and renal abnormalities. Characteristic facies manifested as midface hypoplasia, infraorbital creases, facial nevus simplex, and anterior linear ear lobe creases/posterior helical ear pits, with a predisposition to tumor development. This case report describes a Saudi infant born at 38+5 weeks gestation via elective cesarean section to a 33-year-old G3P2+0 mother, with a family history of type 1 diabetes and Down syndrome. Prenatal ultrasound revealed an anterior abdominal wall defect. Postnatally, the infant exhibited macrosomia, macroglossia, and omphalocele. Genetic testing confirmed paternal disomy of the imprinted region in 11p15.5. The infant underwent successful omphalocele repair but experienced respiratory distress, and seizures on the third day of life. Intubation, ventilation, and antiepileptic treatment were initiated. Subsequent investigations revealed right upper lobe collapse, neonatal seizures on electroencephalogram (EEG), and thin corpus callosum on magnetic resonance imaging (MRI). Feeding difficulties led to elective partial glossectomy at two months of age. During her hospital stay two days post surgery, the infant developed persistent hypoglycemia requiring high glucose infusion rates. Extensive endocrine evaluation revealed high insulin and cortisol levels. Subcutaneous octreotide was administered with minimal response. After 15 days of careful glucose tapering, the infant's blood glucose stabilized, reaching feeding targets. The patient was discharged with follow-up appointments. This comprehensive case highlights the complexity of managing severe relapsing hypoglycemia in an infant with BWS.
PubMed: 38707113
DOI: 10.7759/cureus.57588 -
International Journal of Molecular... Mar 2024Beckwith-Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, stemming from various genetic and epigenetic changes. This study delves into the...
Beckwith-Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, stemming from various genetic and epigenetic changes. This study delves into the role of upregulation in BWS, focusing on insulin-like growth factor pathways, which are poorly known in this syndrome. We examined the IGF2R, the primary receptor of IGF2, WNT, and autophagy/lysosomal pathways in BWS patient-derived lymphoblastoid cell lines, showing different genetic and epigenetic defects. The findings reveal a decreased expression and mislocalization of IGF2R protein, suggesting receptor dysfunction. Additionally, our results point to a dysregulation in the AKT/GSK-3/mTOR pathway, along with imbalances in autophagy and the WNT pathway. In conclusion, BWS cells, regardless of the genetic/epigenetic profiles, are characterized by alteration of the IGF2R pathway that is associated with the perturbation of the autophagy and lysosome processes. These alterations seem to be a key point of the molecular pathogenesis of BWS and potentially contribute to BWS's characteristic overgrowth and cancer susceptibility. Our study also uncovers alterations in the WNT pathway across all BWS cell lines, consistent with its role in growth regulation and cancer development.
Topics: Humans; Autophagy; Beckwith-Wiedemann Syndrome; Cell Line; Glycogen Synthase Kinase 3; Neoplasms
PubMed: 38612397
DOI: 10.3390/ijms25073586 -
Frontiers in Pediatrics 2024Fetal Wilms tumor (WT) is extremely rare, but with advances in fetal imaging, more cases are being reported. The management of these cases remains challenging. Herein,...
Fetal Wilms tumor (WT) is extremely rare, but with advances in fetal imaging, more cases are being reported. The management of these cases remains challenging. Herein, we present the case of a full-term female infant diagnosed antenatally at 32 weeks of gestation with a right solid renal mass detected on routine prenatal ultrasound without polyhydramnios. At birth, the infant was healthy, with no evidence of dysmorphic features or abnormal laboratory tests to suggest a predisposition syndrome. Her family history was also unremarkable. A successful radical right nephrectomy was performed on day 2 of life revealing a classic WT. She received vincristine as adjuvant chemotherapy without any complications. At the age of 1 month, the infant developed isolated lateralized overgrowth of the right lower limb suspicious of Beckwith-Wiedemann syndrome. At the latest follow-up of 4 years, the child is healthy and disease-free with conserved asymmetry of lower limbs. The case provides insights into the challenging diagnosis and treatment of fetal WT. A review of the literature suggests that the presence of polyhydramnios is a worse prognostic factor while the combination of best supportive care and surgery remains the best management. Fetal WT can be associated with predisposition syndromes; however, their first manifestations can develop after the diagnosis of cancer has been made, as in our patient. We propose starting active surveillance programs and genetic testing for any case of fetal WT.
PubMed: 38562132
DOI: 10.3389/fped.2024.1334544 -
Children (Basel, Switzerland) Mar 2024The study's aim was to determine the prevalence of depression and anxiety in children with Beckwith-Wiedemann syndrome (BWS) and their effects on social relationships...
The study's aim was to determine the prevalence of depression and anxiety in children with Beckwith-Wiedemann syndrome (BWS) and their effects on social relationships and family acceptance. The Pediatric Symptom Checklist-35 items (PSC-35), Screen for Child Anxiety Related Emotional Disorders (SCARED), and the Vineland Adaptive Behavior Scale Second Edition (VABS-II) were administered to the children. The parental Acceptance Rejection/Control Questionnaire (PARQ/Control) and Zarit Burden Inventory (ZBI) were administered to parents. In total, 6 patients and 10 parents were included. Patients showed a significant presence of internalizing behavior in PSC-35 (mean, 7.66 ± 3.67), anxiety symptoms (SCARED: mean, 46.33 ± 17.50) and socialization difficulties (mean, 90.83 ± 10.09). Parents reported a perceived good acceptance (mean, 56.33 ± 1.03) and a moderate control (mean, 24.17 ± 1.83), but the burden level was ranked moderate to severe (mean, 59.33 ± 16.78). It was found that the severity of the burden level reported by parents was related to internalizing behavior (OR = 2.000; 95% CI = 0.479-3.521; = 0.022) and anxiety symptoms (SCARED total score: OR = 3.000; 95% CI = 1.479-4.521; = 0.005) of children. During psychological counseling in the context of BWS treatment, it is important to identify specific resources that can support patients and families in dealing with stress and identify any critical areas that could hinder the adaptation process.
PubMed: 38539377
DOI: 10.3390/children11030342 -
Surgical Case Reports Mar 2024Beckwith-Wiedemann syndrome (BWS) is a genomic imprinting disorder caused by diverse genetic and/or epigenetic disorders of chromosome 11p15.5. BWS presents with a...
BACKGROUND
Beckwith-Wiedemann syndrome (BWS) is a genomic imprinting disorder caused by diverse genetic and/or epigenetic disorders of chromosome 11p15.5. BWS presents with a variety of clinical features, including overgrowth and an increased risk of embryonal tumors. Notably however, reports of patients with BWS and breast tumors are rare, and the association between these conditions is still unclear. Insulin-like growth factor-2 (IGF2) expression is known to be associated with the development of various cancers, including breast cancer, and patients with BWS with specific subtypes of molecular defects are known to show characteristic clinical features and IGF2 overexpression.
CASE PRESENTATION
A 17-year-old girl who had been diagnosed with BWS based on an umbilical hernia, hyperinsulinemia, and left hemihypertrophy at birth, visited our department with a gradually swelling left breast. Her left breast was markedly larger than her right breast on visual examination. Imaging examinations showed two tumors measuring about 10 cm each in the left breast, and she was diagnosed with juvenile fibroadenoma following core needle biopsy. The two breast tumors were removed surgically and the patient remained alive with no recurrence. The final diagnosis was juvenile fibroadenoma without malignant findings. Immunohistochemical staining using IGF2 antibody revealed overexpression of IGF2 in the cytoplasm of ductal epithelial cells. Because of her clinical features and IGF2 overexpression, molecular defects of 11p15.5 including a possible genetic background of paternal uniparental disomy of chromosome 11 or hypermethylation of imprinting center 1 was suspected.
CONCLUSIONS
In this case, overexpression of IGF2 suggested a possible relationship between BWS and breast tumors. Moreover, the characteristic clinical features and IGF2 staining predicted the subtype of 11p15.5 molecular defects in this patient.
PubMed: 38514513
DOI: 10.1186/s40792-024-01865-2 -
Plastic and Reconstructive Surgery.... Mar 2024Beckwith-Wiedemann syndrome (BWS) is a complex congenital overgrowth disorder necessitating a multidisciplinary approach for effective management. A 5-year-old Saudi...
Beckwith-Wiedemann syndrome (BWS) is a complex congenital overgrowth disorder necessitating a multidisciplinary approach for effective management. A 5-year-old Saudi girl with BWS received comprehensive care involving various specialists, including a plastic surgeon who performed a keyhole technique tongue reduction to address macroglossia. The intervention resulted in significant improvements in speech and quality of life, with no postoperative complications. Intensive speech therapy further enhanced speech development. This case report emphasizes the importance of a multidisciplinary approach and the critical role of the plastic surgeon in managing BWS patients with macroglossia to achieve optimal outcomes.
PubMed: 38463705
DOI: 10.1097/GOX.0000000000005635 -
Genes & Development Mar 2024Maternal inactivation of genes encoding components of the subcortical maternal complex (SCMC) and its associated member, PADI6, generally results in early embryo...
A maternal-effect variant causes nuclear and cytoplasmic abnormalities in oocytes, as well as failure of epigenetic reprogramming and zygotic genome activation in embryos.
Maternal inactivation of genes encoding components of the subcortical maternal complex (SCMC) and its associated member, PADI6, generally results in early embryo lethality. In humans, SCMC gene variants were found in the healthy mothers of children affected by multilocus imprinting disturbances (MLID). However, how the SCMC controls the DNA methylation required to regulate imprinting remains poorly defined. We generated a mouse line carrying a missense variant that was identified in a family with Beckwith-Wiedemann syndrome and MLID. If homozygous in female mice, this variant resulted in interruption of embryo development at the two-cell stage. Single-cell multiomic analyses demonstrated defective maturation of mutant oocytes and incomplete DNA demethylation, down-regulation of zygotic genome activation (ZGA) genes, up-regulation of maternal decay genes, and developmental delay in two-cell embryos developing from mutant oocytes but little effect on genomic imprinting. Western blotting and immunofluorescence analyses showed reduced levels of UHRF1 in oocytes and abnormal localization of DNMT1 and UHRF1 in both oocytes and zygotes. Treatment with 5-azacytidine reverted DNA hypermethylation but did not rescue the developmental arrest of mutant embryos. Taken together, this study demonstrates that PADI6 controls both nuclear and cytoplasmic oocyte processes that are necessary for preimplantation epigenetic reprogramming and ZGA.
Topics: Animals; Child; Female; Humans; Mice; CCAAT-Enhancer-Binding Proteins; Cytoplasm; DNA Methylation; Embryonic Development; Genomic Imprinting; Oocytes; Ubiquitin-Protein Ligases; Zygote
PubMed: 38453481
DOI: 10.1101/gad.351238.123 -
Archives of Endocrinology and Metabolism Feb 2024Beckwith-Wiedemann syndrome (BWS) is a common genetic congenital disease characterized by somatic overgrowth and its broad clinical spectrum includes pre- and post-natal...
Beckwith-Wiedemann syndrome (BWS) is a common genetic congenital disease characterized by somatic overgrowth and its broad clinical spectrum includes pre- and post-natal macrosomia, macroglossia, visceromegaly, increased risk of neonatal hypoglycemia, and development of embryonic tumors. BWS occurs due to genetic/epigenetic changes involving growth-regulating genes, located on region 11p15, with an important genotype-phenotype correlation. Congenital adrenal hyperplasia (CAH) comprises a spectrum of autosomal recessive diseases presenting a variety of clinical manifestations due to a deficiency in one of the enzymes involved in cortisol secretion. Early diagnosis based on newborn screening prevents the adrenal crisis and early infant death. However, high 17-hydroxyprogesterone (17-OHP) levels can occur in newborns or premature infants without CAH, in situations of stress due to maternal or neonatal factors. Here, we report new cases of false-positive diagnosis of 21-hydroxylase deficiency during newborn screening - two girls and one boy with BWS. Methylation-specific multiplex ligation-dependent probe amplification revealed a gain of methylation in the H19 differentially methylated region. Notably, all three cases showed a complete normalization of biochemical changes, highlighting the transient nature of these hormonal findings that imitate the classical form of CAH. This report sheds light on a new cause of false-positive 21-hydroxylase deficiency diagnosis during newborn screening: Beckwith-Wiedemann syndrome.
Topics: Male; Infant; Female; Humans; Infant, Newborn; Beckwith-Wiedemann Syndrome; Adrenal Hyperplasia, Congenital; DNA Methylation; Neonatal Screening
PubMed: 38427811
DOI: 10.20945/2359-4292-2022-0395 -
JPRAS Open Mar 2024Thigh lift surgery is generally performed in patients with severe weight loss outcomes, particularly those undergoing bariatric surgery. However, there are other...
Thigh lift surgery is generally performed in patients with severe weight loss outcomes, particularly those undergoing bariatric surgery. However, there are other congenital malformation conditions that may require the same treatment, such as Beckwith Wideman syndrome.
PubMed: 38375434
DOI: 10.1016/j.jpra.2023.12.004