Morphometric measurements of intraoral anatomy in children with Beckwith-Wiedemann syndrome: a novel approach.

BACKGROUND: An easy-to-use tool to objectively measure intraoral anatomy with meaningful clinical correlations may improve care for patients with Beckwith-Wiedemann syndrome (BWS), who commonly have symptomatic macroglossia. METHODS: Children aged 2-17 years with BWS were enrolled between 12/2021 and 01/2024. Digital intraoral photographs with a laser ruler were taken, and morphometric measurements were made using ImageJ software. Relationships between morphometrics and outcomes including BWS clinical score, percentage mosaicism, and incidence of tongue reduction surgery were examined using t-tests and multivariate linear models. RESULTS: Pharyngeal morphometric measurements were obtained in 49 patients with BWS. Mouth area, width, and height differed significantly across BWS molecular subtypes. Right-to-left tongue width and mouth width were larger in those with loss of methylation at imprinting control region 2 (IC2 LOM) than other BWS variants. Patients with paternal uniparental isodisomy of chromosome 11p15 (pUPD11) had narrower mouths than others. Those with tongue reduction surgery had more tongue ridging than those without surgery. There were correlations between mouth area and BWS clinical score, tongue width and BWS clinical score, and tongue length and percentage mosaicism. CONCLUSION: Intraoral morphometric measurements are associated with phenotypic burden in BWS. Tongue morphology varies across the BWS spectrum, with IC2 LOM having wider tongues and mouths, and pUPD11 having narrower mouths. Tongue ridging is more common in those selected for surgery. Intraoral morphometric measurements may be safely obtained at low costs across centers caring for children with BWS or others at risk of upper airway obstruction.

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.

The Utility of Early Tongue Reduction Surgery for Macroglossia in Beckwith-Wiedemann Syndrome.

BACKGROUND: Macroglossia, a cardinal feature of the (epi)genetic disorder Beckwith-Wiedemann syndrome, is associated with obstructive sleep apnea, speech and/or feeding difficulties, and dental or jaw malalignment. These sequelae may be treated and/or prevented with tongue reduction surgery; the authors sought to determine whether certain Beckwith-Wiedemann syndrome patients may benefit from early surgical intervention before age 12 months. METHODS: The authors conducted a retrospective review of patients with Beckwith-Wiedemann syndrome who underwent tongue reduction from 2014 to 2019. The authors assessed primary outcomes of change in obstructive sleep apnea by polysomnography, respiratory support required, and feeding route before and after tongue reduction, and reviewed postoperative complications and the need for repeated tongue reduction. RESULTS: Of the 36 patients included, the median age at tongue reduction was 9.5 months (interquartile range, 3.8 to 22.8 months). For those with severe obstructive sleep apnea, there was a significant reduction in the obstructive apnea hypopnea index from 30.9 ± 21.8 per hour to 10.0 ± 18.3 per hour (p =0.019) and improvement in nadir oxyhemoglobin saturation from 72 ± 10 percent to 83 ± 6 percent (p =0.008). Although there was no significant change in overall supplemental feeding tube or respiratory support, there were specific patients who experienced clinically meaningful improvement. Of note, these positive outcomes applied equally to those who underwent surgery at a younger age (<12 months). To date, only one patient required a repeated tongue reduction. CONCLUSION: Based on improved polysomnographic findings and rarity of surgical complications or repeated surgery, the authors' data support the safety and efficacy of this early intervention when clinical indications are present and an experienced multidisciplinary team is available for consultation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome.

Glypicans are a family of heparan sulfate proteoglycans that are linked to the cell surface through a glycosyl-phosphatidylinositol anchor. One member of this family, glypican-3 (Gpc3), is mutated in patients with the Simpson-Golabi-Behmel syndrome (SGBS). These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms. The clinical features of SGBS are very similar to the more extensively studied Beckwith-Wiedemann syndrome (BWS). Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II. However, there is still no biochemical evidence indicating that GPC3 plays such a role.Here, we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development. A proportion of the mutant mice also display mandibular hypoplasia and an imperforate vagina. In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element. The degree of developmental overgrowth of the GPC3-deficient mice is similar to that of mice deficient in IGF receptor type 2 (IGF2R), a well characterized negative regulator of IGF-II. Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates.

Beckwith-Wiedemann syndrome with asymmetric mosaic of paternal disomy causing hemihyperplasia.

Beckwith-Wiedemann syndrome (BWS) is a congenital disorder with 3 main features-overgrowth in infancy, macroglossia, and abdominal wall defects. Here, we report on a 5-month old girl with hemihyperplasia and macroglossia caused by paternal uniparental disomy (pUPD) asymmetric mosaic on chromosome 11p15.5. She could not retract her tongue into her mouth and the midline of the tongue was shifted to the left. Glossectomy was performed at age 1 year. A specimen of the tongue showed normal skeletal muscle, but the muscle fibers were closely spaced, and there were fewer stroma components in the tissue from the right side of the tongue than that from the left side. With respect to pUPD of chromosome 11p15.5, microsatellite marker analysis of the tongue tissue specimen revealed a higher mosaic rate in the tissue from the right side of the tongue (average 48.3%) than that from the left side (average 16.9%). Methylation analysis of Kv differentially methylated region (DMR) 1 (KvDMR1) and H19DMR revealed hypomethylation of KvDMR1 and hypermethylation of H19DMR in the tissue on the right side of the tongue (hyperplastic side). In this case, the difference in mosaic rate of pUPD in the 11p15.5 region was hypothesized to influence the expression level of insulin-like growth factor 2. This result may be helpful to clinicians, especially surgeons, when planning plastic surgery for hemihyperplasia.

Isolated facial hemihyperplasia: manifestation of Beckwith-Wiedemann syndrome.

Facial asymmetry is a common finding in infants and can be the result of a number of distinctive conditions such as hemifacial microsomia, overgrowth syndromes, a soft tissue tumor, and a vascular malformation. However, overgrowth syndromes such as Beckwith-Wiedemann syndrome (BWS) typically manifest more extensive involvement; it rarely presents as isolated facial overgrowth.Here, we present a 7-year-old boy who presented with facial asymmetry. He was found to have isolated facial hemihyperplasia, involving his right cheek and teeth. No abnormalities were seen in the rest of his examination. The diagnosis of BWS was considered and was confirmed by detection of a methylation abnormality in H19 (DMR1). This case demonstrates that BWS should be considered, even with isolated facial involvement. This is important, as affected patients are predisposed to certain malignancies, especially in the first 5 to 8 years of life. Therefore, specialized surveillance is recommended as the part of management.

Genetic craniofacial aberrations.

Many craniofacial and dental anomalies have a genetic background. Much research related to the molecular pathology of genetic conditions is being carried out, and new information related to mapping of disease genes, gene identification, and mutations in these genes is accumulating with incredible speed. It is important to be well informed of the molecular background of the conditions that we treat at anomaly clinics. This article reviews the most recent molecular findings related to Turner syndrome, Beckwith-Wiedemann syndrome, Marfan syndrome, Treacher Collins syndrome, cleidocranial dysplasia, and cleft lip and palate.

A less-invasive approach with orthodontic treatment in Beckwith-Wiedemann patients.

The Beckwith-Wiedemann syndrome (BWS) is a rare genetic disorder, linked to an alteration on the short arm of chromosome 11 that comprises multiple congenital anomalies. Macroglossia is the predominant finding, with subsequent protrusion of dentoalveolar structures, which results in a protruding mandible, anterior open bite, abnormally obtuse gonial angle and increased mandibular length. A less-invasive treatment with orthopaedic appliances in a patient with early tongue reduction is presented. This work summarizes the oral signs linked to macroglossia, and highlights the influence of macroglossia on mandibular growth structures. In our opinion, glossotomy could be carried out in the paediatric patient as a preventive measure in that it curbs the tongue's influence on skeletal growth and dramatically reduces the duration and extensiveness of subsequent treatment.