Evaluation of keyhole-pattern reduction glossoplasty for macroglossia in beckwith-wiedemann syndrome: A multidimensional analysis of postoperative course and outcomes.

The aim of this study was to evaluate the postoperative course and long-term functional and aesthetic outcomes in patients with Beckwith-Wiedemann syndrome (BWS) following surgical reduction of macroglossia, using multiple questionnaires. Patients with BWS who underwent keyhole reduction for macroglossia were included in this study. The postoperative course for each patient was recorded, and multiple questionnaires were administered to evaluate aesthetic concerns, oral incompetence or feeding difficulties, sleep-disordered breathing symptoms, and speech. Nine patients underwent ten reduction glossoplasty surgeries. The mean age at surgery was 22 months. The postoperative course for each case was uneventful, except for one patient who had wound dehiscence. The questionnaires revealed significant improvements in tongue appearance, feeding, drooling, facial appearance, and psychosocial outcomes. There was also a significant reduction in sleep-disordered breathing symptoms after surgery. Keyhole reduction glossoplasty is a safe and effective procedure for the treatment of macroglossia in BWS patients, with excellent functional and aesthetic outcomes and a low complication rate.

Beckwith-Widemann Macroglossia: The Role of Surgical Tongue Reduction.

Objective: This review was conducted to define the natural history of unoperated Beckwith-Wiedemann syndrome (BWS) macroglossia and the effect of tongue reduction surgery upon breathing, eating, speaking and dentoskeletal development in individuals having BWS. Design: This is a retrospective study of medical records. SETTING: All patients were evaluated and treated in one of two Children's Hospitals by an ACPA approved Craniofacial Team. PATIENTS/PARTICIPANTS: Medical records were reviewed of 526 individuals having a diagnosis of BWS and evaluated in-person by a single craniofacial surgeon between 1986 and 2014 in conjunction with a series of multi-disciplinary craniofacial team colleagues. 28 individuals were excluded having had multiple tongue reductions elsewhere. 498 individuals comprise the "pre tongue-reduction group". The "post tongue-reduction group" consists of 391 individuals who underwent surgical tongue reduction by one surgeon using one technique between 1986 and 2014. MAIN OUTCOME MEASURES: The primary outcome measure was change in anterior dental occlusion following tongue reduction surgery. Tongue reduction surgery was performed on the assumption that it would improve dentoskeletal relationships. Secondary outcome measures were: breathing, feeding/swallowing, and speech. Results: A significant difference (p<0.001) over time between the two groups was found with less anterior occlusal abnormality in the tongue reduction group. Tongue reduction surgery had no mortality and minimal morbidity for breathing, feeding/swallowing, and speech and can ameliorate obstructive sleep apnea. Conclusions: Surgical tongue reduction for BWS macroglossia is recommended for the infant or child in primary dentition with a grossly abnormal anterior tooth/jaw relationship and/or obstructive sleep apnea.

Beckwith-Wiedemann syndrome with multiple hepatic and cutaneous hemangiomas in a female patient of Albanian origin: Diagnostic and therapeutic considerations.

We describe a 2-month-old female infant with macroglossia, macrosomia, omphalocele, neonatal hypoglycemia, earlobe creases, low nasal bridge, midface retrusion, syndromic facies and multiple cutaneous and hepatic hemangiomas (HH). Genetic evaluation confirmed the diagnosis of Beckwith-Wiedemann Syndrome (BWS) with mosaic uniparental disomy 11 as the underlying genetic mechanism suggested by partial hypermethylation of H19/IGF2:IG-DMR and partial hypomethylation of KCNQ1OT1:TSS-DMR on chromosome 11p15.5. Pediatric endocrinology and cardiology assessments were normal. No malignant liver or renal tumors were detected during the follow-up period. Treatment with propranolol was started for the multiple HH, according to international recommendations. At 3-, 6-, and 9-month follow up, a gradual decrease in the size of the hemangiomas and AFP levels was observed, without side effects. This is the fifth case in the literature combining HH and BWS, and among these, the third case with this specific genetic defect suggesting a possible association between HH and BWS caused by 11 paternal uniparental disomy [upd(11)pat]. The case also highlights that if treatment is warranted, then oral propranolol can be used for the management of infantile HH in BWS patients similarly to non-BWS patients.

Pediatric cancer incidence among individuals with overgrowth syndromes and overgrowth features: A population-based assessment in seven million children.

BACKGROUND: Overgrowth syndromes (e.g., Beckwith-Wiedemann) are associated with an increased risk of pediatric cancer, although there are few population-based estimates of risk. There are also limited studies describing associations between other overgrowth features (e.g., hepatosplenomegaly) and pediatric cancer. Therefore, cancer risk among children with these conditions was evaluated with data from a large, diverse population-based registry linkage study. METHODS: This study includes all live births in Texas during the years 1999-2017. Children with overgrowth features and syndromes were identified from the Texas Birth Defects Registry; children with cancer were identified by linkage to the Texas Cancer Registry. Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between each overgrowth syndrome/feature and cancer, which were adjusted for infant sex and maternal age. RESULTS: In the total birth cohort (n = 6,997,422), 21,207 children were identified as having an overgrowth syndrome or feature. Children with Beckwith-Wiedemann syndrome were 42 times more likely to develop pediatric cancer (95% CI, 24.20-71.83), with hepatoblastoma being the most common, followed by Wilms tumor. The presence of any isolated overgrowth feature was associated with increased cancer risk (HR, 4.70; 95% CI, 3.83-5.77); associations were strongest for hepatosplenomegaly (HR, 23.04; 95% CI, 13.37-39.69) and macroglossia (HR, 11.18; 95% CI, 6.35-19.70). CONCLUSIONS: This population-based assessment confirmed prior findings that children with either overgrowth syndromes or features were significantly more likely to develop cancer. Overall, this study supports recommendations for cancer surveillance in children with these conditions and may also inform future research into cancer etiology.

Associations between the timing of tongue reduction surgery, (Epi)genotype, and dentoskeletal development in patients with Beckwith-Wiedemann syndrome.

Tongue reduction surgery is often pursued to manage the adverse effects of macroglossia in patients with Beckwith-Wiedemann syndrome (BWS). This study characterized dental outcomes in patients with BWS based on surgical timing and molecular diagnosis. A retrospective study was designed to include patients with BWS over the age of two who had clinical or radiographic documentation of dental development. Patients were grouped by history of tongue reduction surgery and surgical timing (early: <12 months). One hundred three patients were included (55 no tongue reduction, 18 early, 30 late). Patients who underwent late surgery had lower odds of class I occlusion (OR 0.11, 95% CI 0.02-0.58, p = 0.009) and higher odds of anterior open bite (OR 7.5, 95% CI 1.14-49.4, p = 0.036). Patients with clinical diagnoses and negative molecular testing had anterior open bite less frequently than patients with imprinting center 2 loss of methylation and paternal uniparental isodisomy of 11p15.5 (p = 0.009). Compared to reference values, patients who had tongue reductions had an increased mandibular plane angle (32.0 ± 4.5° versus 36.9 ± 5.0°, p = 0.001), indicative of hyperdivergent growth. The results of this study help to understand the complex nature of dentoskeletal growth in BWS and shed insight on how surgical timing and molecular diagnosis influence prognosis.

Syndromic forms of congenital hyperinsulinism.

Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and persistent hypoglycemia in infancy and childhood. The majority of cases in which a genetic cause can be identified have monogenic defects affecting pancreatic ß-cells and their glucose-sensing system that regulates insulin secretion. However, CHI/HH has also been observed in a variety of syndromic disorders. The major categories of syndromes that have been found to be associated with CHI include overgrowth syndromes (e.g. Beckwith-Wiedemann and Sotos syndromes), chromosomal and monogenic developmental syndromes with postnatal growth failure (e.g. Turner, Kabuki, and Costello syndromes), congenital disorders of glycosylation, and syndromic channelopathies (e.g. Timothy syndrome). This article reviews syndromic conditions that have been asserted by the literature to be associated with CHI. We assess the evidence of the association, as well as the prevalence of CHI, its possible pathophysiology and its natural course in the respective conditions. In many of the CHI-associated syndromic conditions, the mechanism of dysregulation of glucose-sensing and insulin secretion is not completely understood and not directly related to known CHI genes. Moreover, in most of those syndromes the association seems to be inconsistent and the metabolic disturbance is transient. However, since neonatal hypoglycemia is an early sign of possible compromise in the newborn, which requires immediate diagnostic efforts and intervention, this symptom may be the first to bring a patient to medical attention. As a consequence, HH in a newborn or infant with associated congenital anomalies or additional medical issues remains a differential diagnostic challenge and may require a broad genetic workup.

Mesothelial Inclusion Cyst in an Infant with Beckwith-Weidemann Syndrome.

Mesothelial inclusion cysts are rare benign tumors not frequently reported in the literature. When reported, they are primarily found in adults. One report from 2006 reports an association with Beckwith-Weideman syndrome, but no other reported cases discuss this correlation. We describe a case of an infant with Beckwith-Weideman syndrome who, in the setting of omphalocele repair, was found to have hepatic cysts with pathology revealing mesothelial inclusion cysts.

Concurrent Hepatoblastoma and Wilms Tumor Leading to Diagnosis of Beckwith-Wiedemann Syndrome.

Beckwith-Wiedemann syndrome (BWS) is an epigenetic overgrowth disorder and cancer predisposition syndrome caused by imprinting defects of chromosome 11p15.5-11p15.4. BWS should be considered in children with atypical presentations of embryonal tumors regardless of clinical phenotype. Risk of malignancy correlates with specific molecular subgroups of BWS making molecular subclassification important for appropriate cancer screening. We report the first case of concurrent embryonal tumors in a phenotypically normal child, leading to the diagnosis of BWS with paternal uniparental disomy and describe the molecular classification of BWS as it relates to malignancy risk, along with approach to management.

[Preterm with Macroglossia and Persistent Hypoglycemia - Beckwith-Wiedemann Syndrome]. / Frühgeborenes mit Makroglossie und persistierender Hypoglykämie ­ Beckwith-Wiedemann-Syndrom.

Beckwith-Wiedemann syndrome (BWS) is a genetic disease with phenotypic variability and the following signs: macroglossia, asymmetry, lateralised overgrowth, overgrowth of the internal organs, abdominal wall defects, neonatal hypoglycemia and increased risk of embryonic tumours. The prevalence is reported as being between 1 in 10,000 and 1 in 21,000 live births. The disease is caused by molecular changes in gene clusters on the short arm of chromosome 11 region P15.5. We present the case of a female, born preterm at 32 0/7 weeks. A UPD(11)pat-mutation was diagnosed postnatally. The particular feature of her case was an early tongue reduction surgery which was necessary because of drinking and breathing difficulties. Long-lasting hypoglycemia was difficult to treat.

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

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.

Fetal Micro and Macroglossia: Defining Normal Fetal Tongue Size.

OBJECTIVES: Abnormal fetal tongue size is a phenotypic feature of various syndromes including Beckwith-Wiedemann, Pierre-Robin, oromandibular limb hypoplasia, chromosomal aberrations, etc. Current data regarding normal fetal tongue size are limited. Hence, micro/macroglossia are subjectively determined. The aim of the study was to construct a contemporary fetal tongue nomogram and to assess its clinical contribution. METHODS: A prospective cross-sectional study was performed in well dated, low risk, singleton pregnancies. Fetal tongues were measured by 5 trained sonographers. Highest quality images were selected. Intra- and interobserver variability was assessed. Tongue length, width, area, and circumference 1st to 99th centiles were calculated for each gestational week. Based on the normal tongue size charts, we created a Tongue Centile Calculator. RESULTS: Over 18 months, 664 tongue measurements were performed. A cubic polynomial regression model best described the correlation between tongue size and gestational age. The correlation coefficient (r2 ) was 0.934, 0.932, 0.925, and 0.953 for tongue length, width, area, and circumference, respectively (P < .001). Intra- and interobserver variability had high interclass correlation coefficients (>0.9). Using the new charts, we were able to identify 2 cases of macroglossia, subsequently diagnosed with Beckwith-Wiedemann, and 4 cases of microglossia, 3 associated with Pierre-Robin sequence, and 1 associated with persistent buccopharyngeal membrane. CONCLUSIONS: We present novel fetal tongue size charts from 13 to 40 weeks of gestation. Clinical application of these nomograms may be beneficial in the prenatal diagnosis of syndromes or malformations associated with abnormal fetal tongue size.

Etiological diagnosis of macroglossia: Systematic review and diagnostic algorithm.

BACKGROUND: The objective of this literature review was to list the different etiologies of macroglossia reported in the literature, to identify characteristics that might guide diagnosis, and to create a diagnostic algorithm. METHODS: The bibliographic search was carried out between October 2019 and July 2020 in the PubMed research base using the keywords "macroglossia" (MESH) and/or "tongue enlargement". RESULTS: Of the 1711 references identified, 615 articles were excluded, and 1096 abstracts were reviewed. We classified the different etiologies identified according to their mechanism and whether they were congenital or acquired. The etiologies are divided into the following categories: genetic malformation syndromes, non-syndromic congenital malformations, endocrinopathies, neuromuscular diseases, storage disorders, infectious, inflammatory, traumatic, and iatrogenic diseases. CONCLUSION: Based on this review, we propose a diagnostic algorithm for macroglossia according to the characteristics described. The most common diagnoses among acquired causes were amyloidosis (13.7%), endocrinopathies (8.8%), myopathies (4%) and tongue tumors (6.7%). The most common congenital causes were aneuploidy, lymphatic malformations, and Beckwith-Wiedemann syndrome, which is the main cause of congenital macroglossia, even if it appears isolated.

Metastatic Phyllodes Tumor in a Patient With Beckwith-Wiedemann Syndrome.

Beckwith-Wiedemann syndrome (BWS) is an epigenetic disorder of imprinting on the chromosome 11p15 region that presents with clinical features, such as macroglossia, abdominal wall defects, neonatal hypoglycemia, hemihypertrophy, and embryonal tumors. Phyllodes tumors (PTs) are rare fibroepithelial tumors that account for 0.3% to 1% of breast tumors and present in women aged 35 to 55 years. Here we describe a rare case of metastatic malignant phyllodes tumor in a 27-year-old woman with BWS and uniparental disomy (UPD) of chromosome 11p15.5. To our knowledge, this is the first case report in literature to describe metastatic malignant phyllodes tumor in a woman with BWS.

[Tumor predisposition syndromes and nephroblastoma : Early diagnosis with imaging]. / Tumorprädispositionssyndrome und Nephroblastom : Frühe Diagnose mit Bildgebung.

CLINICAL/METHODICAL ISSUE: The Beckwith-Wiedemann spectrum (BWSp) as well as the WT1-related syndromes, Denys-Drash syndrome (DDS) and WAGR spectrum (Wilms tumor, Aniridia, genitourinary anomalies and a range of developmental delays) are tumor predisposition syndromes (TPS) of Wilms tumor (WT). Patients with associated TPS are at higher risk of developing chronic kidney disease and bilateral and metachronous tumors as well as nephrogenic rests. STANDARD RADIOLOGICAL METHODS: Standard imaging diagnostics for WT include renal ultrasound and magnetic resonance imaging (MRI). In the current renal tumor studies Umbrella SIOP-RTSG 2016 and Randomet 2017, thoracic computed tomography (CT) is also recommended as standard. Positron emission tomography (PET)-CT and whole-body MRI, on the other hand, are not part of routine diagnostics. METHODOLOGICAL INNOVATIONS: In recent publications, renal ultrasound is recommended every 3 months until the age of 7 years in cases of clinical suspicion or molecularly proven TPS. PERFORMANCE: Patients with TPS and regular renal ultrasounds have smaller tumor volumes and lower tumor stages at WT diagnosis than patients without such a screening. This allows a reduction of therapy intensity and facilitates the performance of nephron sparing surgery, which is prognostically relevant especially in bilateral WT. ACHIEVEMENTS: Early diagnosis of WT in the context of TPS ensures the greatest possible preservation of healthy and functional renal tissue. Standardized screening by regular renal ultrasounds should therefore be firmly established in clinical practice. PRACTICAL RECOMMENDATIONS: The initial diagnosis of TPS is clinical and requires a skilled and attentive examiner in the presence of sometimes subtle clinical manifestations, especially in the case of BWSp. Clinical diagnosis should be followed by genetic testing, which should then be followed by sonographic screening.

Molecular networks of hepatoblastoma predisposition and oncogenesis in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann Syndrome (BWS) is the most common human overgrowth disorder caused by structural and epigenetic changes to chromosome 11p15. Patients with BWS are predisposed to developing hepatoblastoma (HB). To better understand the mechanism of HB oncogenesis in this cancer predisposition background, we performed the first multi-dimensional study of HB samples collected from patients diagnosed with BWS. This multi-omic investigation of seven BWS HB and five matched nontumor BWS liver samples from 7 unique patients included examination of whole exome sequences, messenger RNA/microRNA expression, and methylation levels to elucidate the genomic, transcriptomic, and epigenomic landscape of BWS-associated HB. We compared the transcriptional profiles of the BWS samples, both HB and nontumor, to that of control livers. Genes differentially expressed across BWS tissues were identified as BWS HB predisposition factors; this gene group included cell cycle regulators, chromatin organizers, and WNT, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT members. We also compared transcriptional changes associated with non-syndromic HB carrying BWS-like 11p15 alterations compared to those without, as well as to BWS HB. Through this analysis, we identified factors specific to 11p15-altered HB oncogenesis, termed the BWS oncogenesis network. We propose that 11p15 alterations drive HB oncogenesis by initially dysregulating cell-cycle regulators and chromatin organizers, including histone deacetylase 1 (HDAC1), ATP-dependent helicase X, and F-Box and WD repeat domain containing 7. Furthermore, we found oncogenic factors such as dickkopf WNT signaling pathway inhibitor 1 and 4, WNT16, forkhead box O3 (FOXO3), and MAPK10 are differentially expressed in 11p15-altered HB in both the BWS and non-syndromic backgrounds. These genes warrant further investigation as diagnostic or therapeutic targets.

Novel multilocus imprinting disturbances in a child with expressive language delay and intellectual disability.

Multilocus imprinting disturbances (MLID) have been associated with up to 12% of patients with Beckwith-Wiedemann syndrome, Silver-Russell syndrome, and pseudohypoparathyroidism type 1B (PHP1B). Single-gene defects affecting components of the subcortical maternal complex (SCMC) have been reported in cases with multilocus hypomethylation defects. We present a patient with speech and language impairment with mild Angelman syndrome (AS) features who demonstrates maternal hypomethylation at 15q11.2 (SNRPN) as well as 11p15.5 (KCNQ1OT1) imprinted loci, but normal methylation at 6q24.2 (PLAGL1), 7p12.1 (GRB10), 7q32.2 (MEST), 11p15.5 (H19), 14q32.2 (MEG3), 19q13.43 (PEG3), and 20q13.32 (GNAS and GNAS-AS1). The proband also has no copy number nor sequence variants within the AS imprinting center or in UBE3A. Maternal targeted next generation sequencing did not identify any pathogenic variants in ZPF57, NLRP2, NLRP5, NLRP7, KHDC3L, PADI6, TLE6, OOEP, UHRF1 or ZAR1. The presence of very delayed, yet functional speech, behavioral difficulties, EEG abnormalities but without clinical seizures, and normocephaly are consistent with the 15q11.2 hypomethylation defect observed in this patient. To our knowledge, this is the first report of MLID in a patient with mild, likely mosaic, Angelman syndrome.

Glioblastoma in Beckwith-Wiedemann syndrome: first case report and review of potential pathomechanisms.

Beckwith-Wiedemann syndrome (BWS) is a rare congenital overgrowth syndrome associated with certain childhood tumours. We present the case of a 36-year-old lady with BWS who developed a left frontoinsular secondary glioblastoma. This is the first case report in the literature of glioblastoma associated with BWS. We explore similarities in the molecular pathomechanisms of BWS and glioblastoma.