Table 2.

Disorders to Consider in the Differential Diagnosis of Kleefstra Syndrome

DisorderGene / Genetic
Mechanism		MOIAdditional Overlapping Clinical Features
Down syndromeTrisomy 21Virtually all de novoSimilar facial characteristics, incl:
  • Brachycephaly
  • Protruding tongue
  • Hypotonia
  • Hypertelorism
  • Midface retrusion
Smith-Magenis syndrome Deletion or mutation of RAI1 on chromosome 17p11.2 1Virtually all de novo
  • Lethargy
  • Sleep disturbance
  • Midface retrusion
Pitt-Hopkins syndrome Haploinsufficiency of TCF4Most de novo
  • Speech is significantly delayed & most persons are nonverbal w/receptive language often stronger than expressive language.
  • Seizures
  • Sleep disturbance
Angelman syndrome Disruption of maternally imprinted UBE3ASee footnote 2.
  • Receptive language better than expressive language skills
  • Sleep disturbances w/multiple awakenings
  • Midface retrusion w/prognathism
  • See footnote 3 for distinguishing clinical features.
KMT2C-associated syndrome 4 KMT2C AD
  • Currently under study to determine overlap
  • ASD & ID
MBD5 haploinsufficiency See footnote 5.AD; typically de novo
  • ASD & ID
  • Seizures
  • Developmental regression

AD = autosomal dominant; ASD = autism spectrum disorder; ID = intellectual disability; MOI = mode of inheritance

1.

Approximately 95% of individuals with Smith-Magenis syndrome have the disorder as a result of an interstitial 17p11.2 deletion, which may have been previously excluded by chromosomal microarray testing.

2.

The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function.

3.

Facial features that differentiate Kleefstra syndrome from Angelman syndrome include synophrys and everted vermilion of the lower lip. Some mildly affected individuals with Kleefstra syndrome have a ≥100-word vocabulary & speak in sentences, which would be very unusual in an individual with Angelman syndrome.

4.
5.

The diagnosis of MBD5 haploinsufficiency is established in a proband with one of the following: deletion of 2q23.1 that encompasses all or part of MBD5 (~90% of affected individuals); intragenic deletion involving one or more exons of MBD5 (~5%); a heterozygous pathogenic sequence variant in MBD5 (~5%); or, rarely, an apparently balanced complex chromosome rearrangement of the 2q23.1 region involving MBD5.

From: Kleefstra Syndrome

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.