ABSTRACT
PURPOSE: The current, 8th edition of the American Joint Committee on Cancer (AJCC) anatomic classification and staging model for uveal melanoma does not fully separate survival estimates for patients with advanced stages of the disease (e.g., IIIB and IIIC). Furthermore, some tumors in higher size categories have a smaller volume than tumors in lower categories. Therefore, we developed a novel model for prognostication of metastatic mortality based on estimations of tumor volume. DESIGN: Retrospective, multicenter case series of patients with uveal melanoma involving the choroid, ciliary body, or both. PARTICIPANTS: Six thousand five hundred twenty-eight consecutively registered patients treated at 3 tertiary ocular oncology centers on 2 continents between 1981 and 2022. METHODS: Data on survival, tumor size, and extent were collected for all 6528 patients. Tumor volume was estimated using a simple equation based on largest basal diameter and thickness. Volume-based size categories and stages were developed and validated in independent patient cohorts using competing risk analyses, and correlations with cytogenetic and cytomorphologic features were examined. MAIN OUTCOME MEASURE: Cumulative incidence of metastatic death. RESULTS: The 6528 patients were distributed over 7 stages based on estimated tumor volume and anatomic extent (V stages IA, IB, IIA, IIB, IIIA, IIIB, and IIIC), with a 15-year incidence of metastatic death ranging from 7% to 77%. A new category, V1min, and corresponding stage IA, were introduced, indicating an excellent prognosis. Metastatic mortality in V stage IIIC was significantly higher than that in V stage IIIB (P = 0.03), whereas incidence curves crossed for patients in AJCC stages IIIC vs. IIIB (P = 0.53). Univariable and multivariable competing risk regressions demonstrated higher Wald statistics for V stages compared with AJCC stages (1152 vs. 1038 and 71 vs. 17, respectively). The frequency of monosomy 3, gain of chromosome 8q, and epithelioid cytomorphologic features increased with tumor volume (R2 = 0.70, R2 = 0.50, and R2 = 0.71, respectively; P < 0.001) and showed similar correlations with both AJCC and V stages. CONCLUSIONS: Anatomic classification and staging of ciliary body and choroidal melanomas based on estimation of tumor volume improves prognostication of metastatic mortality. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Subject(s)
Choroid Neoplasms , Melanoma , Uveal Neoplasms , Humans , Melanoma/pathology , Neoplasm Staging , Retrospective Studies , Ciliary Body/pathology , Tumor Burden , Prognosis , Choroid Neoplasms/genetics , Choroid Neoplasms/pathologyABSTRACT
Beckwith-Wiedemann spectrum (BWSp) is caused by genetic and epigenetic alterations on chromosome 11 that regulate cell growth and division. Considering the diverse phenotypic landscape in BWSp, the characterization of the CDKN1C molecular subtype remains relatively limited. Here, we investigate the role of CDKN1C in the broader BWSp phenotype. Notably, patients with CDKN1C variants appear to exhibit a different tumor risk than other BWSp molecular subtypes. We performed a comprehensive literature review using the search term "CDKN1C Beckwith" to identify 113 cases of patients with molecularly confirmed CDKN1C-BWSp. We then assessed the genotype and phenotype in a novel cohort of patients with CDKN1C-BWSp enrolled in the BWS Research Registry. Cardinal and suggestive features were evaluated for all patients reported, and tumor risk was established based on available reports. The most common phenotypes included macroglossia, omphalocele, and ear creases/pits. Tumor types reported from the literature included neuroblastoma, acute lymphocytic leukemia, superficial spreading melanoma, and intratubular germ cell neoplasia. Overall, this study identifies unique features associated with CDKN1C variants in BWSp, enabling more accurate clinical management. The absence of Wilms tumor and hepatoblastoma suggests that screening for these tumors may not be necessary, while the neuroblastoma risk warrants appropriate screening recommendations.
ABSTRACT
Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, known vascular anomaly of Turner syndrome. However, previous studies have described other vascular malformations as a rare feature of Turner syndrome and suggested that vascular abnormalities in individuals with Turner syndrome may be more generalized. In this study, we describe two individuals with co-occurrence of Turner syndrome and vascular malformations with a lymphatic component. In these individuals, genetic testing of the lesional tissue revealed a somatic pathogenic variant in PIK3CA-a known and common cause of lymphatic malformations. Based on this finding, we conclude that the vascular malformations presented here and likely those previously in the literature are not a rare part of the clinical spectrum of Turner syndrome, but rather a separate clinical entity that may or may not co-occur in individuals with Turner syndrome.
Subject(s)
Cardiovascular Abnormalities , Lymphatic Abnormalities , Turner Syndrome , Vascular Malformations , Humans , Turner Syndrome/complications , Turner Syndrome/genetics , Mosaicism , Lymphatic Abnormalities/genetics , Vascular Malformations/complications , Vascular Malformations/genetics , Class I Phosphatidylinositol 3-Kinases/geneticsABSTRACT
Beckwith-Wiedemann Spectrum (BWSp) is an overgrowth and cancer predisposition disorder characterized by a wide spectrum of phenotypic manifestations including macroglossia, abdominal wall defects, neonatal hypoglycemia, and predisposition to embryonal tumors. In 1981, Best and Hoekstra reported four patients with BWSp in a single family which suggested autosomal dominant inheritance, but standard clinical testing for BWSp was not available during this time. Meticulous phenotyping of this family has occurred over the past 40 years of follow-up with additional family members being identified and samples collected for genetic testing. Genetic testing revealed a pathogenic mutation in CDKN1C, consistent with the most common cause of familial BWSp. CDKN1C mutations account for just 5% of sporadic cases of BWSp. Here, we report the variable presentation of BWSp across the individuals affected by the CDKN1C mutation and other extended family members spanning multiple generations, all examined by the same physician. Additional phenotypes thought to be atypical in patients with BWSp were reported which included cardiac abnormalities. The incidence of tumors was documented in extended family members and included rhabdomyosarcoma, astrocytoma, and thyroid carcinoma, which have previously been reported in patients with BWSp. These observations suggest that in addition to the inheritance of the CDKN1C variant, there are modifying factors in this family driving the phenotypic spectrum observed. Alternative theories are suggested to explain the etiology of clinical variability including diffused mosaicism, anticipation, and the presence of additional variants tracking in the family. This study highlights the necessity of long-term follow-up in patients with BWSp and consideration of individual familial characteristics in the context of phenotype and/or (epi)genotype associations.
Subject(s)
Astrocytoma , Beckwith-Wiedemann Syndrome , Humans , Beckwith-Wiedemann Syndrome/diagnosis , Beckwith-Wiedemann Syndrome/genetics , Beckwith-Wiedemann Syndrome/pathology , Extended Family , Phenotype , Genotype , Astrocytoma/genetics , Genomic ImprintingABSTRACT
DNA methylation, chromatin-binding proteins, and DNA looping are common components regulating genomic imprinting which leads to parent-specific monoallelic gene expression. Loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15 is the most common cause of the imprinting overgrowth disorder Beckwith-Wiedemann Syndrome (BWS). Here, we report a familial transmission of a 7.6 kB deletion that ablates the core promoter of KCNQ1. This structural alteration leads to IC2 LOM and causes recurrent BWS. We find that occupancy of the chromatin organizer CTCF is disrupted proximal to the deletion, which causes chromatin architecture changes both in cis and in trans. We also profile the chromatin architecture of IC2 in patients with sporadic BWS caused by isolated LOM to identify conserved features of IC2 regulatory disruption. A strong interaction between CTCF sites around KCNQ1 and CDKN1C likely drive their expression on the maternal allele, while a weaker interaction involving the imprinting control region element may impede this connection and mediate gene silencing on the paternal allele. We present an imprinting model in which KCNQ1 transcription is necessary for appropriate CTCF binding and a novel chromatin conformation to drive allele-specific gene expression.
Subject(s)
Beckwith-Wiedemann Syndrome/genetics , CCCTC-Binding Factor/metabolism , Chromosomes, Human, Pair 11 , KCNQ1 Potassium Channel/genetics , CCCTC-Binding Factor/physiology , Centromere , Chromosome Deletion , Female , Genomic Imprinting , Humans , Infant, Newborn , Transcription, GeneticABSTRACT
PURPOSE: Uveal melanoma (UM) is a rare disease and the most common primary intraocular malignancy in adults, with a high risk of metastases. Reliable prognostication systems are based on anatomic features, as in the tumor-node-metastasis staging of the American Joint Committee on Cancer (AJCC) system, or on genetic information, as in The Cancer Genome Atlas (TCGA) system. Prior evidence suggests that combining both systems may be beneficial. We evaluated the benefit of combining the TCGA and AJCC systems in a large cohort of patients. DESIGN: Retrospective case series of patients with UM. PARTICIPANTS: Nine hundred seventy-nine patients with a choroidal or ciliary body melanoma treated at the Wills Eye Hospital between 1998 and 2020, 94% of whom received eye-sparing treatment. METHODS: Tumors were classified into 4 TCGA groups based on chromosome copy number: A (disomy 3, normal 8q), B (disomy 3, any 8q gain), C (monosomy 3, 1 extra copy of 8q), and D (monosomy 3, multiple 8q gain). The eighth edition of the AJCC staging manual was used for AJCC staging. Cox regression and the log-rank test were used for survival analysis. MAIN OUTCOME MEASURE: Metastasis-free survival. RESULTS: Combining information of the 2 systems improved prognostication in intermediate groups: in TCGA group C, we saw an increased rate of metastasis in AJCC stage III (28%) compared with stage II (8.9%); the same was seen in AJCC stage II, going from TCGA group C (8.9%) to group D (46%), and in AJCC stage III, going from group C (28%) to group D (49%). In patients with AJCC stage II or III disease, loss of chromosome 3 and gain of 8q (TCGA groups C and D) significantly worsened the prognosis, with multiple 8q gain (TCGA group D) having a greater impact. CONCLUSIONS: Combining information from AJCC stages and TCGA groups yields a better predictive power even in this set of relatively small tumors. We propose that physicians take both systems into account whenever possible, especially in moderate-risk groups.
Subject(s)
Melanoma , Uveal Neoplasms , Adult , Chromosomes , Humans , Melanoma/pathology , Monosomy , Neoplasm Staging , Prognosis , Retrospective Studies , Uveal Neoplasms/pathologyABSTRACT
PURPOSE: Individuals with gray, blue, or green eyes have a higher chance of developing uveal melanoma (UM) than those with brown eyes. We wondered whether iris pigmentation might be related not only to predisposition to UM but also to its behavior; therefore, we compared the clinical, histopathologic, and genetic characteristics of UM between eyes with different colors. DESIGN: We determined iris color in a large cohort of patients enucleated for UM. Clinical and histopathologic tumor characteristics, chromosome status, and survival were compared among 3 groups on the basis of iris color. PARTICIPANTS: A total of 412 patients with choroidal/ciliary body UM, who had undergone primary enucleation at the Leiden University Medical Center, Leiden, The Netherlands, between 1993 and 2019, were divided into 3 groups based on iris color: gray/blue, green/hazel, and brown. The validation cohort included 934 patients with choroidal/ciliary body UM treated at Wills Eye Hospital (WEH). METHODS: Comparison of clinical, histopathologic, and genetic characteristics of UM in patients with different iris colors. MAIN OUTCOME MEASURES: Melanoma-related survival in UM patients, divided over 3 iris color groups, in relation to the tumor's chromosome 3 and 8q status. RESULTS: Moderate and heavy tumor pigmentations were especially seen in eyes with a brown iris (P < 0.001). Survival did not differ between patients with different iris colors (P = 0.27); however, in patients with a light iris, copy number changes in chromosome 3 and 8q had a greater influence on survival than in patients with a dark iris. Likewise, chromosome 3 and chromosome 8q status affected survival more among patients with lightly pigmented tumors than in patients with heavily pigmented tumors. The WEH cohort similarly showed a greater influence of chromosome aberrations in light-eyed individuals. CONCLUSIONS: Although iris color by itself did not relate to UM-related survival, chromosome 3 and 8q aberrations had a larger influence on survival in patients with a light iris than those with a brown iris. This suggests a synergistic effect of iris pigmentation and chromosome status in the regulation of oncogenic behavior of UM. Iris color should be taken into consideration when calculating a patient's risk for developing metastases.
Subject(s)
Melanoma , Uveal Neoplasms , Chromosome Aberrations , Chromosomes, Human, Pair 3/genetics , Eye Color/genetics , Humans , Iris/pathology , Melanoma/pathology , Prognosis , Uveal Neoplasms/pathologyABSTRACT
BACKGROUND: Beckwith-Wiedemann Syndrome (BWS) is characterised by overgrowth and tumour predisposition. While multiple epigenetic and genetic mechanisms cause BWS, the majority are caused by methylation defects in imprinting control regions on chromosome 11p15.5. Disease-causing methylation defects are often mosaic within affected individuals. Phenotypic variability among individuals with chromosome 11p15.5 defects and tissue mosaicism led to the definition of the Beckwith-Wiedemann Spectrum (BWSp). Molecular diagnosis of BWSp requires use of multiple sensitive diagnostic techniques to reliably detect low-level aberrations. METHODS: Multimodal BWS diagnostic testing was performed on samples from 1057 individuals. Testing included use of a sensitive qRT-PCR-based quantitation method enabling identification of low-level mosaic disease, identification of CNVs within 11p15.5 via array comparative genomic hybridisation or qRT-PCR, and Sanger sequencing of CDKN1C. RESULTS: A molecular diagnosis was confirmed for 27.4% of individuals tested, of whom 43.4% had mosaic disease. The presence of a single cardinal feature was associated with a molecular diagnosis of BWSp in 20% of cases. Additionally, significant differences in the prevalence of mosaic disease among BWS molecular subtypes were identified. Finally, the diagnostic yield obtained by testing solid tissue samples from individuals with negative blood testing results shows improved molecular diagnosis. CONCLUSION: This study highlights the prevalence of mosaic disease among individuals with BWSp and the increases in diagnostic yield obtained via testing both blood and solid tissue samples from affected individuals. Additionally, the results establish the presence of a molecular diagnosis in individuals with very subtle features of BWSp.
Subject(s)
Beckwith-Wiedemann Syndrome/diagnosis , Cyclin-Dependent Kinase Inhibitor p57/genetics , Genomic Imprinting/genetics , Mosaicism , Adolescent , Adult , Beckwith-Wiedemann Syndrome/genetics , Beckwith-Wiedemann Syndrome/pathology , Child , Child, Preschool , Comparative Genomic Hybridization/methods , DNA Copy Number Variations/genetics , DNA Methylation/genetics , Female , Genotype , Humans , Infant , Infant, Newborn , Male , Phenotype , Young AdultABSTRACT
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and 30% of all cases of CRC are believed to have a familial component and up to one-third of these (10%) are hereditary. Pathogenic germline variants in multiple genes have been associated with predisposition to hereditary CRC or polyposis. Lynch syndrome (LS) is the most common hereditary CRC syndrome, caused by variants in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 and is inherited in a dominant manner. Heritable conditions associated with colonic polyposis include familial adenomatous polyposis (FAP) associated with APC pathogenic variants, MUTYH-associated polyposis (MAP) caused by biallelic MUTYH pathogenic variants, and polymerase proofreading-associated polyposis (PPAP) caused by POLE or POLD1 pathogenic variants. Given the overlapping phenotypes of the cancer syndromes along with the limited sensitivity of using clinical criteria alone, a multigene panel testing approach to diagnose these conditions using next-generation sequencing (NGS) is effective and efficient. This technical standard is not recommended for use in the clinic for patient evaluation. Please refer to National Comprehensive Cancer Network (NCCN) clinical practice guidelines to determine an appropriate testing strategy and guide medical screening and management. This 2021 edition of the American College of Medical Genetics and Genomics (ACMG) technical standard supersedes the 2013 edition on this topic.
Subject(s)
Colorectal Neoplasms , Genetics, Medical , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Genetic Testing , Genomics , Germ-Line Mutation/genetics , Humans , United StatesABSTRACT
PURPOSE: Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder. METHODS: We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed. RESULTS: We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing. CONCLUSION: Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.
Subject(s)
Intellectual Disability , Mediator Complex/genetics , Mental Retardation, X-Linked , Retinitis Pigmentosa , Adult , Cholestasis , Cleft Palate , Female , Genes, X-Linked , Humans , Intellectual Disability/genetics , Mental Retardation, X-Linked/genetics , Phenotype , Young AdultABSTRACT
OBJECTIVE: The objective of this study was to describe molecular findings and phenotypic features among individuals referred for prenatal Beckwith-Wiedemann syndrome (BWS) testing. METHODS: Molecular diagnostic testing was performed using a sensitive quantitative real-time PCR-based assay capable of detecting mosaic methylation to the level of 3% at IC1 and IC2. Sanger sequencing of CDKN1C was performed in cases with normal methylation. RESULTS: Of the 94 patients tested, a molecular diagnosis was identified for 25.5% of cases; 70.9% of diagnosed cases had loss of methylation at IC2, 4.2% had gain of methylation at IC1, 12.5% had paternal uniparental isodisomy, and 12.5% had CDKN1C loss-of-function variants. Methylation level changes in prenatal cases were significantly greater than changes identified in cases tested after birth. Cases with a prenatal molecular diagnosis had a significantly greater number of BWS-associated phenotypic features. The presence of either macroglossia or placentomegaly was most predictive of a BWS diagnosis. CONCLUSION: Our results support the consensus statement advocating BWS molecular testing for all patients with one or more BWS-associated prenatal features and suggest that low-level mosaic methylation changes may be uncommon among prenatal BWS diagnoses.
Subject(s)
Beckwith-Wiedemann Syndrome/diagnosis , Cyclin-Dependent Kinase Inhibitor p57/analysis , Prenatal Diagnosis/methods , Adult , Cyclin-Dependent Kinase Inhibitor p57/isolation & purification , Female , Humans , Molecular Diagnostic Techniques/methods , Molecular Diagnostic Techniques/statistics & numerical data , Pregnancy , Prenatal Diagnosis/trendsABSTRACT
BACKGROUND: Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith-Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large-scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. METHODS: Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). RESULTS: Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low-level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. CONCLUSIONS: Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low-level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing-based approaches and detecting a cancer predisposition may modify treatment.
Subject(s)
Beckwith-Wiedemann Syndrome/blood , DNA Methylation/genetics , Genomic Imprinting/genetics , Hepatoblastoma/blood , Wilms Tumor/blood , Adolescent , Adult , Beckwith-Wiedemann Syndrome/genetics , Beckwith-Wiedemann Syndrome/pathology , Child , Child, Preschool , Chromosomes, Human, Pair 11/genetics , Female , Genetic Predisposition to Disease , Germ-Line Mutation/genetics , Hepatoblastoma/genetics , Hepatoblastoma/pathology , Humans , Infant , Male , Neoplasm Proteins/genetics , Wilms Tumor/genetics , Wilms Tumor/pathology , Young AdultABSTRACT
BACKGROUND: While there is evidence that parental exposure to medical radiation is associated with increased risk of sporadic bilateral retinoblastoma in offspring, this association has not been confirmed. Additionally, the relationship between paternal and maternal exposures and sporadic unilateral retinoblastoma has not been fully investigated. PROCEDURE: Data were obtained from two large multicenter case-control studies of retinoblastoma. For the paternal analyses, 268 bilateral cases, 155 unilateral cases, and 358 controls were included. For the maternal analyses, 298 bilateral cases, 184 unilateral cases, and 404 controls were included. Logistical regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) to evaluate the associations between parental exposures to medical radiation and sporadic retinoblastoma, while adjusting for potential confounders. RESULTS: Paternal exposure to medical radiation was not significantly associated with sporadic bilateral retinoblastoma in offspring. However, increasing paternal exposure to gonadal radiation was associated with increased risk of unilateral retinoblastoma (P-trend = .03). Maternal history of upper and lower gastrointestinal (GI) series was associated with bilateral retinoblastoma (OR = 1.9, 95% CI: 1.1-3.2 and OR = 6.9, 95% CI: 2.9-16.4, respectively). However, there was no association between maternal exposure to medical radiation and unilateral retinoblastoma in offspring. CONCLUSION: Our investigation adds to the evidence that medical radiation exposure in fathers as well as mothers prior to pregnancy may increase the risk of germline alterations leading to the development of retinoblastoma in their offspring. However, our findings could point to a more complex etiological framework for this important pediatric malignancy.
Subject(s)
Maternal Exposure/adverse effects , Paternal Exposure/adverse effects , Prenatal Exposure Delayed Effects/etiology , Radiation Exposure/adverse effects , Retinal Neoplasms/etiology , Retinoblastoma/etiology , Adult , Case-Control Studies , Child , Female , Follow-Up Studies , Humans , Male , Pregnancy , Prenatal Exposure Delayed Effects/pathology , Prognosis , Retinal Neoplasms/pathology , Retinoblastoma/pathology , Risk FactorsABSTRACT
Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate treatment contribute to a high risk of neurocognitive impairment. HI represents a heterogeneous group of disorders characterized by dysregulated insulin secretion by the pancreatic beta cells, which in utero, may result in somatic overgrowth. There are at least nine known monogenic forms of HI as well as several syndromic forms. Molecular diagnosis allows for prediction of responsiveness to medical treatment and likelihood of surgically-curable focal hyperinsulinism. Timely genetic mutation analysis has thus become standard of care. However, despite significant advances in our understanding of the molecular basis of this disorder, the number of patients without an identified genetic diagnosis remains high, suggesting that there are likely additional genetic loci that have yet to be discovered.
Subject(s)
Congenital Hyperinsulinism/genetics , Congenital Hyperinsulinism/physiopathology , Child , Congenital Hyperinsulinism/metabolism , Epigenesis, Genetic , Genetic Testing , Humans , Infant , Mutation , Philadelphia , SyndromeABSTRACT
Beckwith-Wiedemann syndrome (BWS) is the most common epigenetic overgrowth and cancer predisposition disorder. Due to both varying molecular defects involving chromosome 11p15 and tissue mosaicism, patients can present with a variety of clinical features, leading to the newly defined Beckwith-Wiedemann spectrum (BWSp). The BWSp can be further divided into three subsets of patients: those presenting with classic features, those presenting with isolated lateralized overgrowth (ILO) and those not fitting into the previous two categories, termed atypical BWSp. Previous reports of patients with BWS have focused on those with the more recognizable, classic features, and limited information is available on those who fit into the atypical and ILO categories. Here, we present the first cohort of patients recruited across the entire BWSp, describe clinical features and molecular diagnostic characteristics, and provide insight into practical diagnosis and management recommendations that we have gained from this cohort.
Subject(s)
Beckwith-Wiedemann Syndrome/diagnosis , Beckwith-Wiedemann Syndrome/therapy , Beckwith-Wiedemann Syndrome/genetics , DNA Methylation , Female , Genotype , Humans , Infant , Male , PhenotypeABSTRACT
PURPOSE: Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder characterized by lateralized overgrowth, macroglossia, abdominal wall defects, congenital hyperinsulinism, and predisposition to embryonal tumors. One of the molecular etiologies underlying BWS is paternal uniparental isodisomy of chromosome 11p15.5 (pUPD11). About 8% of pUPD11 cases are due to genome-wide paternal uniparental isodisomy (GWpUPD). About 30 cases of live-born patients with GWpUPD have been described, most of whom were mosaic and female. We present male patients with BWS due to GWpUPD, elucidate the underlying mechanism, and make recommendations for management. METHODS: Three male patients with GWpUPD underwent clinical and molecular evaluation by single-nucleotide polymorphism (SNP) microarrays in different tissues. Previously published cases of GWpUPD were reviewed. RESULTS: SNP microarray demonstrated a GWpUPD cell population with sex chromosomes XX and biparental cell population with sex chromosomes XY, consistent with dispermic androgenetic chimerism. CONCLUSION: SNP microarray is necessary to distinguish GWpUPD cases and the underlying mechanisms. The percentage of GWpUPD cell population within a specific tissue type correlated with the amount of tissue dysplasia. Males with BWS due to GWpUPD are important to distinguish from other molecular etiologies because the mechanism indicates risk for germ cell tumors and autosomal recessive diseases in addition to other BWS features.
Subject(s)
Beckwith-Wiedemann Syndrome/etiology , Uniparental Disomy/genetics , Chimerism , Chromosomes, Human, Pair 11/genetics , DNA Methylation/genetics , Genomic Imprinting/genetics , Genotype , Humans , Infant , Infant, Newborn , Male , Mosaicism , Phenotype , Polymorphism, Single Nucleotide/genetics , Uniparental Disomy/diagnosis , Uniparental Disomy/physiopathologyABSTRACT
PURPOSE: The Cancer Genome Atlas (TCGA) classification has been validated for uveal melanoma (UM) prognostication. We applied TCGA classification to UM biopsied using fine-needle aspiration biopsy (FNAB) to determine the predictability for metastasis and death. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with UM treated with plaque radiotherapy at Wills Eye Hospital, Philadelphia, Pennsylvania, from October 1, 2008, through December 31, 2018, who completed genetic analysis of chromosomes 3 and 8 after FNAB. METHODS: Tumors were classified as A, B, C, or D and were compared using the chi-square test, Fisher exact test, analysis of variance, and Kaplan-Meier analysis. MAIN OUTCOME MEASURES: Metastasis and death. RESULTS: Six hundred fifty-eight UM patients were categorized accordingly as TCGA class A (n = 342 [52%]), B (n = 91 [14%]), C (n = 118 [18%]), and D (n = 107 [16%]). More advanced tumor classification revealed older mean patient age (56 vs. 53 vs. 60 vs. 63 years, respectively; P < 0.001), worse presenting visual acuity (20/20-20/50: 81% vs. 67% vs. 71% vs. 66%, respectively; P < 0.001), greater distance from the optic disc (3.5 vs. 4.9 vs. 5.7 vs. 5.3 mm, respectively; P < 0.001), larger tumor basal diameter (10.3 vs. 12.9 vs. 13.9 vs. 15.3 mm, respectively; P < 0.001), and greater tumor thickness (4.3 vs. 6.1 vs. 6.6 vs. 7.5 mm, respectively; P < 0.001). After mean follow-up (47.6 vs. 47.6 vs. 42.9 vs. 28.7 months, respectively; P < 0.001), more advanced TCGA class was associated with increased risk of metastasis (3% vs. 10% vs. 25% vs. 41%, respectively; P < 0.001) and death (1% vs. 0% vs. 3% vs. 9%, respectively; P < 0.001). Compared with class A, the 5-year hazard ratio for metastasis increased at 4.1 (B vs. A; P = 0.01), 10.1 (C vs. A; P < 0.001), and 30.0 (D vs. A; P < 0.001). The 5-year hazard ratio for death increased at 3.1 (C vs. A; P = 0.11) and 13.7 (D vs. A; P < 0.001) with no deaths in class B. CONCLUSIONS: Grouping of UM using TCGA classification predicts the risk of melanoma-related metastasis and death.
Subject(s)
Melanoma/genetics , Uveal Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Chromosomes, Human, Pair 3/genetics , Chromosomes, Human, Pair 8/genetics , Female , Humans , Kaplan-Meier Estimate , Male , Melanoma/classification , Middle Aged , Neoplasm Metastasis , Retrospective Studies , Uveal Neoplasms/classificationABSTRACT
Inactivating mutations in the genes encoding the two subunits of the pancreatic beta-cell KATP channel, ABCC8 and KCNJ11, are the most common finding in children with congenital hyperinsulinism (HI). Interpreting novel missense variants in these genes is problematic, because they can be either dominant or recessive mutations, benign polymorphisms, or diabetes mutations. This report describes six novel missense variants in ABCC8 and KCNJ11 that were identified in 11 probands with congenital HI. One of the three ABCC8 mutations (p.Ala1458Thr) and all three KCNJ11 mutations were associated with responsiveness to diazoxide. Sixteen family members carried the ABCC8 or KCNJ11 mutations; only two had hypoglycemia detected at birth and four others reported symptoms of hypoglycemia. Phenotype testing of seven adult mutation carriers revealed abnormal protein-induced hypoglycemia in all; fasting hypoketotic hypoglycemia was demonstrated in four of the seven. All of six mutations were confirmed to cause dominant pathogenic defects based on in vitro expression studies in COSm6 cells demonstrating normal trafficking, but reduced responses to MgADP and diazoxide. These results indicate a combination of in vitro and in vivo phenotype tests can be used to differentiate dominant from recessive KATP channel HI mutations and personalize management of children with congenital HI.
Subject(s)
Congenital Hyperinsulinism/diagnosis , Congenital Hyperinsulinism/genetics , Genetic Association Studies , Genetic Predisposition to Disease , KATP Channels/genetics , Mutation , Alleles , DNA Mutational Analysis , Female , Gene Frequency , Genotype , Humans , Infant , KATP Channels/chemistry , Male , Pedigree , Phenotype , Structure-Activity RelationshipABSTRACT
Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with a heterogeneous phenotypic spectrum. There is an increased prevalence of monozygotic twinning in BWS. Given the epigenetic nature and phenotypic spectrum that defines BWS, twins are often discordant for clinical features, and clinicians are faced with the challenge of diagnosing and managing these twins. We present a cohort of multiple pregnancies in which one or more child from each pregnancy was diagnosed with BWS. We conducted a chart review of monochorionic and dichorionic gestations. Clinical scores for monochorionic twins demonstrated phenotypic discordance between the proband and twin. Based on linear regression analysis, a higher clinical score in the proband correlated with larger phenotypic discordance between twin siblings. Despite phenotypic discordance, however, we observed a consistent additive clinical score for a pregnancy (proband's plus twin's scores from a pregnancy). This idea of a finite degree of affectedness for a pregnancy implies a finite number of epigenetically affected cells. This further corroborates the idea that timing of monozygotic monochorionic twinning correlates with the disruption of establishment and/or maintenance of imprinting. The difference in clinical score between a proband and their twin may be due to diffused mosaicism, whereby there is an asymmetric distribution of affected cells among the multiple fetuses in a monozygotic monochorionic pregnancy, leading to a spectrum of variably affected phenotypes. Based on these findings, we recommend an algorithm for a conservative approach to clinically evaluate all children in a monozygotic multiple gestation affected by BWS.
Subject(s)
Beckwith-Wiedemann Syndrome/diagnosis , Diseases in Twins/diagnosis , Genomic Imprinting , Phenotype , Twins, Dizygotic , Twins, Monozygotic , Algorithms , Beckwith-Wiedemann Syndrome/genetics , Beckwith-Wiedemann Syndrome/pathology , Cohort Studies , DNA Methylation , Disease Management , Diseases in Twins/genetics , Diseases in Twins/pathology , Female , Humans , Infant , Male , Mosaicism , Pregnancy , Severity of Illness IndexABSTRACT
Beckwith-Wiedemann syndrome (BWS) is a genetic syndrome associated with overgrowth and cancer predisposition, including predisposition to Wilms tumor (WT). Patients with BWS and BWS spectrum are screened from birth to age 7 years for BWS-associated cancers. However, in some cases a BWS-associated cancer may be the first recognized manifestation of the syndrome. We describe 12 patients diagnosed with BWS after presenting with a WT. We discuss the features of BWS in these patients and hypothesize that earlier detection of BWS by attention to its subtler manifestations could lead to earlier detection of children at risk for associated malignancies.