Characteristics Associated with Tumor Development in Individuals Diagnosed with Beckwith–Wiedemann Spectrum: Novel Tumor-(epi)Genotype-Phenotype Associations in the BWSp Population

Duffy, Kelly A.; Getz, Kelly; Hathaway, Evan R; Byrne, Mallory E.; MacFarland, Suzanne P.; Kalish, Jennifer M.

doi:10.3390/genes12111839

Cited by 12 publications

(11 citation statements)

References 51 publications

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“…[16] They should be referred to a clinical geneticist, and an examination and molecular testing including 11p15.5 analysis in deoxyribonucleic acid (DNA) should be performed. [17][18][19] Baseline abdominal ultrasonography is advised to assess the presence of organomegaly. For significant ILO, the advice is to establish the underlying (epi)genetic cause and initiate surveillance while awaiting the test results.…”

Section: Discussionmentioning

confidence: 99%

Lateralized overgrowth as a guiding sign of abdominal neoplasms for pediatric orthopedic surgeons

Parada-Avendaño

Salvador²,

Garcia³

et al. 2023

Jt Dis Relat Surg

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The term hemihyperplasia, defined as the pathological growth process that involves an abnormal proliferation of cells, has been replaced with the term hemihypertrophy, defined as the increase in size of existing cells. [1] Recently, newly proposed terms have been used rather than these histopathological and nonclinical concepts, as asymmetric regional body overgrowth and lateralized overgrowth (LO), are used synonymously to indicate a significant increase in the length and/or girth of most or all of one side Objectives: This study aims to increase the awareness of the association between lateralized overgrowth (LO) and abdominal tumor among the pediatric orthopedic community and to evaluate its incidence in our center. Patients and methods: Between January 1997 and December 2021, a total of 166 patients with Wilms tumors and hepatoblastomas were retrospectively analyzed. Data including age, sex, initial clinical signs (hematuria, abdominal mass with or without general discomfort), type of asymmetric regional body overgrowth (isolated or in relation with any syndrome), and tumor stage at diagnosis were recorded. In addition, age at which asymmetric regional body overgrowth was described and age at the time of tumor diagnosis were noted. Results: Of a total of 166 patients, 133 were diagnosed with Wilms tumors (nephroblastomas) and 33 were diagnosed with hepatoblastomas. In 94% of the cases, the initial clinical signs were an abdominal mass and/or hematuria. Overall, five (3%) patients presented with LO. Four patients with Wilms tumor presented it at the initial clinical examinations. In three of these cases (2.3%), we found it isolated and, in the remaining patient (0.75%), it was associated with Beckwith-Wiedemann spectrum. Only one patient affected from hepatoblastoma (3%) presented with an isolated LO at the time of tumor diagnosis. Conclusion:Our study results show an incidence of LO in relation to intra-abdominal tumors of 3%. The latest updates recommend genetic testing to identify subgroups with a higher risk for tumor development that are more likely to benefit from tumor protocol surveillance.

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Section: Discussionmentioning

confidence: 99%

Lateralized overgrowth as a guiding sign of abdominal neoplasms for pediatric orthopedic surgeons

Parada-Avendaño

Salvador²,

Garcia³

et al. 2023

Jt Dis Relat Surg

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“…Similar to these studies, two of 55 patients (3.4%) in our ILO group also developed tumors; molecular testing was negative in two ILO patients with embryonal tumors, while three of four patients with atypical and classic phenotypes had pUPD11 and an IC1-GOM. Among the molecular subgroups of BWSp patients, the risk of tumor development was highest in patients with IC1-GOM (28%), 2.5% in IC2-LOM, and 16% in pUPD11 [ 2 , 12 , 26 ]; 152 patients with LO were evaluated for tumor frequency; in 34 patients who developed tumors, epigenetic alterations were detected in 61.8% pUPD11, 32% IC1-GOM, and 5.9% IC2-LOM [ 14 ]. Another study reported that the molecular subgroup with the highest tumor incidence was pUPD in LO patients [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…The fact that embryonal tumor risk is higher in BWSp patients, especially in LO, has increased the importance of both clinical diagnosis and the detection of methylation alterations in the 11p15.5 region in this group of patients [ 12 , 13 , 14 ]. On the other hand, Wilms tumor (WT) and other embryonal cancers associated with BWSp may be the first recognized manifestation of the syndrome.…”

Section: Introductionmentioning

confidence: 99%

Investigation of 11p15.5 Methylation Defects Associated with Beckwith-Wiedemann Spectrum and Embryonic Tumor Risk in Lateralized Overgrowth Patients

Tüysüz

Bozlak

Alkaya

et al. 2023

Cancers

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The Beckwith–Wiedemann spectrum (BWSp) ranges from isolated lateralized overgrowth (ILO) to classic phenotypes. In this broad clinical spectrum, an epigenetic alteration on chromosome 11p15.5 can be detected. The risk for embryonal tumors is high, especially in patients with lateralized overgrowth (LO). The aim of this study is to investigate epigenetic alterations in 11p15.5 and tumor risk in 87 children with LO. The methylation level of 11p15.5 was examined in the blood of all patients and in skin samples or buccal swabs from 40 patients with negative blood tests; 63.2% of patients were compatible with the ILO phenotype, 18.4% were atypical, and 18.4% were classic. The molecular diagnosis rate was 81.2% for the atypical and classic phenotypes, and 10.9% for the ILO phenotype. In patients with epigenetic alterations, LO was statistically significantly more severe than in test negatives. Tumors developed in six (6.9%) of the total 87 patients with LO; four belonged to the atypical or classical phenotype (12.5%) and two to ILO (3.5%). Three of the four patients with atypical/classical phenotypes had pUPD11, one had IC1-GOM alteration, and two ILO patients were negative. We conclude that LO patients should be monitored for tumor risk even if their epigenetic tests are negative.

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“…Mosaicism in the context of BWSp is well‐established and presents the primary challenge to obtaining the accurate molecular diagnosis within this population (Brioude et al, 2018; Brzezinski et al, 2017; Duffy, Getz, et al, 2021). While classically associated with pUPD11 or IC1‐GOM, the notion of mosaicism within the context of IC2‐LOM profiles established in blood was previously proposed (Brzezinski et al, 2017), although met with considerable criticism (Brioude et al, 2018).…”

Section: Potential Etiologies Of Clinical Variability With a Single F...mentioning

confidence: 99%

Familial Beckwith‐Wiedemann syndrome in a multigenerational family: Forty years of careful phenotyping

Best

Duffy

George

et al. 2022

American J of Med Genetics Pt A

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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.

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Characteristics Associated with Tumor Development in Individuals Diagnosed with Beckwith–Wiedemann Spectrum: Novel Tumor-(epi)Genotype-Phenotype Associations in the BWSp Population

Cited by 12 publications

References 51 publications

Lateralized overgrowth as a guiding sign of abdominal neoplasms for pediatric orthopedic surgeons

Lateralized overgrowth as a guiding sign of abdominal neoplasms for pediatric orthopedic surgeons

Investigation of 11p15.5 Methylation Defects Associated with Beckwith-Wiedemann Spectrum and Embryonic Tumor Risk in Lateralized Overgrowth Patients

Familial Beckwith‐Wiedemann syndrome in a multigenerational family: Forty years of careful phenotyping

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