Table 4.

Disorders to Consider in the Differential Diagnosis of EZH2-Related Overgrowth

Gene / Genetic MechanismDisorderMOIClinical Features of Disorder
Overlapping w/EZH2-Related OvergrowthDistinguishing from EZH2-Related Overgrowth
Key differential diagnoses
NSD1 1 Sotos syndrome AD 2
  • Pre- & postnatal overgrowth
  • Variable ID
  • Similar (but distinctive) facial appearance
  • Advanced bone age
  • Scoliosis
  • Joint hypermobility
  • Prominent chin, malar flushing in children
  • Most easily distinguishable from EZH2-related overgrowth at ages 1-3 yrs
EED Cohen-Gibson syndrome (EED-related overgrowth)AD
  • Overgrowth
  • Macrocephaly
  • Hypertelorism, round face, "stuck on" chin
  • Advanced bone age
  • Scoliosis
  • Umbilical hernia
  • Joint hypermobility
  • ID is usually more prominent (variable in EZH2-related overgrowth).
  • Camptodactyly/clinodactyly tends to affect fingers only (not toes).
  • Cryptorchidism
  • No tumors have been reported.
  • Cervical spine anomalies
  • Congenital heart defects
  • There are too few cases of Cohen-Gibson syndrome to clarify which clinical features might distinguish them from EZH2-related overgrowth.
SUZ12 Imagawa-Matsumoto syndrome (SUZ12-related overgrowth syndrome) (OMIM 618786)AD
  • Overgrowth
  • Macrocephaly
  • Hypertelorism
  • Variable ID
  • Scoliosis
  • Joint hypermobility
  • Hypertrichosis
  • Normal skin texture
  • No tumors have been reported.
  • There are too few cases of Imagawa-Matsumoto syndrome to clarify which clinical features might distinguish them from EZH2-related overgrowth.
Other disorders of interest
Abnormal regulation of gene transcription in 2 imprinted domains at 11p15.5 4 Beckwith-Wiedemann syndrome AD 3
  • ↑ birth weight
  • Tall stature (not as frequent in BWS as other conditions in the differential diagnosis)
  • Umbilical hernia
  • Macroglossia
  • Earlobe creases/pits
  • Omphalocele
  • Visceromegaly
  • Usually normal intellect
  • Neonatal hypoglycemia
  • Polyhydramnios
  • Predisposition to embryonal tumors, esp Wilms tumor
DNMT3A Tatton-Brown-Rahman syndrome (DNMT3A-related overgrowth syndrome)AD
  • Tall stature
  • Variable ID
  • Autism spectrum disorder
  • Scoliosis
  • Joint hypermobility
  • Facial appearance (round, heavy; w/horizontal eyebrows & narrow palpebral fissures) most recognizable in early teen / adult yrs.
  • ↑ weight
  • Neuropsychiatric issues
FBN1 FBN1-related Marfan syndrome AD
  • Tall stature
  • Scoliosis
  • Joint hypermobility
  • Cognitive abilities are usually normal.
  • Ocular findings (myopia & lens dislocation)
  • Cardiovascular findings (dilatation of aorta; mitral & tricuspid valve prolapse)
  • Pectus abnormalities are common.
FBN2 Congenital contractural arachnodactyly (Beals syndrome)AD
  • Tall stature
  • Scoliosis
  • Camptodactyly
  • Cognitive abilities are usually normal.
  • Cardiovascular findings (dilatation of aorta; mitral & tricuspid valve prolapse)
  • Crumpled appearance to top of ear
  • Pectus abnormalities are common.
GPC3
GPC4 4		 Simpson-Golabi-Behmel syndrome type 1 XL
  • ↑ birth weight
  • Tall stature
  • Variable ID
  • Characteristic facial appearance
  • Supernumerary nipples
  • Polydactyly
  • Diastasis recti 5
NFIX Malan syndrome (OMIM 614753)AD
  • Sotos syndrome-like condition
  • Tall stature
  • Variable ID 6
  • Ophthalmologic abnormalities are common.
  • Growth frequently normalizes in teenagers & young adults.

AD = autosomal dominant; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

Pathogenic variants in NSD1 (the cause of Sotos syndrome) were once reported to cause Weaver syndrome [Douglas et al 2003]. However, this association has been refuted [Tatton-Brown et al 2005].

2.

More than 95% of individuals have a de novo pathogenic variant.

3.

Beckwith-Wiedemann syndrome (BWS) (without multilocus imprinting disturbances) is associated with abnormal expression of imprinted genes in the BWS critical region. Abnormal expression of imprinted genes can be caused by an epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5, a copy number variant of chromosome 11p15.5, or a heterozygous maternally inherited CDKN1C pathogenic variant. Reliable recurrence risk assessment requires identification of the genetic mechanism in the proband that underlies the abnormal expression of imprinted genes in the BWS critical region. While most families have a recurrence risk of less than 1%, certain underlying genetic mechanisms involve a recurrence risk as high as 50%.

4.

Simpson-Golabi-Behmel syndrome type 1 is caused by a hemizygous pathogenic variant in GPC3, an intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a large multiexon duplication of GPC4.

5.
6.

From: EZH2-Related Overgrowth

Cover of GeneReviews®
GeneReviews® [Internet].
Adam MP, Feldman J, Mirzaa GM, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2024.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.