Table 5.

Overgrowth Disorders to Consider in the Differential Diagnosis of Beckwith-Wiedemann Syndrome

Gene(s) / Genetic MechanismDisorderMOIFeatures of DiffDx Disorder
Overlapping w/BWSDistinguishing from BWS
Multilocus imprinting disturbancesMultilocus imprinting disorderSee footnote 1.Variable (e.g., overgrowth, macroglossia, ear findings, nevus simplex, neonatal hypoglycemia)Discordance between (epi)genotype & phenotypic findings (i.e., clinical features of BWS & Angelman syndrome); assoc w/features of TNDM, SRS, & BWS.
Mosaic or chimeric genome-wide paternal uniparental isodisomyMosaic or chimeric genome-wide paternal uniparental isodisomySporadicSee Genetically Related Disorders.See Genetically Related Disorders.
GPC3
GPC4 		Simpson-Golabi-Behmel syndrome type 1 XLMacrosomia, visceromegaly, macroglossia, kidney anomalies, ↑ risk for embryonal tumorsVariable DD, facial features (coarse features, downslanted palpebral fissures, widely spaced eyes, macrostomia, midline groove in vermilion of lower lip), cleft lip, structural & conduction cardiac abnormalities, skeletal abnormalities incl polydactyly
DIS3L2 Perlman syndrome (OMIM 267000)ARMacrosomia, high incidence of Wilms tumorFacial features (micrognathia, low-set ears, depressed nasal bridge, inverted V shape to vermilion of upper lip), high neonatal mortality, significant ID (common)
EZH2 Weaver syndrome (See EZH2-Related Overgrowth.)AD 2Macrosomia, umbilical herniaLearning disability / ID, camptodactyly, ↑ risk of neuroblastoma
NSD1 Sotos syndrome AD 2MacrosomiaFacial features (dolichocephaly, frontal bossing, downslanted palpebral fissures, pointed chin), sparse hair in frontoparietal distribution, ID, macrocephaly
DNMT3A Tatton-Brown-Rahman syndrome AD 2Macrosomia, cardiac anomaliesMacrocephaly, obesity, ID, ASD, behavioral/psychiatric issues, distinctive facies w/prominent central incisors, joint hypermobility, scoliosis, seizures, ↑ risk of myeloid leukemia
HRAS Costello syndrome AD 2Can be similar to BWS in neonatal period (when affected infants present w/macrosomia).Cardiac abnormalities (incl structural defects, hypertrophic cardiomyopathy, or arrhythmias), failure to thrive, DD, coarse facial features

AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; BWS = Beckwith-Wiedemann syndrome; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; SRS = Silver-Russell syndrome; TNDM = transient neonatal diabetes mellitus; XL = X-linked

1.

Multilocus imprinting disorder can be associated with pathogenic variants in maternal effect genes (e.g., NLRP2, NLRP5, NLRP7, PADI6) [Eggermann et al 2022; Pignata et al 2022].

2.

Most probands have the disorder as the result of a de novo pathogenic variant.

From: Beckwith-Wiedemann Syndrome

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