Wide Fontanels, Delayed Speech Development and Hoarse Voice as Useful Signs in the Diagnosis of KBG Syndrome: A Clinical Description of 23 Cases with Pathogenic Variants Involving the ANKRD11 Gene or Submicroscopic Chromosomal Rearrangements of 16q24.3

Genes (Basel). 2021 Aug 17;12(8):1257. doi: 10.3390/genes12081257.


KBG syndrome is a neurodevelopmental autosomal dominant disorder characterized by short stature, macrodontia, developmental delay, behavioral problems, speech delay and delayed closing of fontanels. Most patients with KBG syndrome are found to have a mutation in the ANKRD11 gene or a chromosomal rearrangement involving this gene. We hereby present clinical evaluations of 23 patients aged 4 months to 26 years manifesting clinical features of KBG syndrome. Mutation analysis in the patients was performed using panel or exome sequencing and array CGH. Besides possessing dysmorphic features typical of the KBG syndrome, nearly all patients had psychomotor hyperactivity (86%), 81% had delayed speech, 61% had poor weight gain, 56% had delayed closure of fontanel and 56% had a hoarse voice. Macrodontia and a height range of -1 SDs to -2 SDs were noted in about half of the patients; only two patients presented with short stature below -3 SDs. The fact that wide, delayed closing fontanels were observed in more than half of our patients with KBG syndrome confirms the role of the ANKRD11 gene in skull formation and suture fusion. This clinical feature could be key to the diagnosis of KBG syndrome, especially in young children. Hoarse voice is a previously undescribed phenotype of KBG syndrome and could further reinforce clinical diagnosis.

Keywords: 16q24.3; ANKRD11 gene; KBG syndrome; dysmorphic syndrome; hoarse voice; psychomotor hyperactivity; short stature; speech delay; wide, delayed closing fontanels.

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / diagnostic imaging
  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / physiopathology
  • Adolescent
  • Adult
  • Bone Diseases, Developmental / diagnosis
  • Bone Diseases, Developmental / diagnostic imaging
  • Bone Diseases, Developmental / genetics*
  • Bone Diseases, Developmental / physiopathology
  • Child
  • Child, Preschool
  • Chromosome Aberrations
  • Chromosomes, Human, Pair 16 / genetics
  • Comparative Genomic Hybridization
  • Dwarfism / genetics
  • Dwarfism / physiopathology
  • Exome Sequencing
  • Facies
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Intellectual Disability / diagnosis
  • Intellectual Disability / diagnostic imaging
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Male
  • Mutation / genetics
  • Phenotype
  • Repressor Proteins / genetics*
  • Tooth Abnormalities / diagnosis
  • Tooth Abnormalities / diagnostic imaging
  • Tooth Abnormalities / genetics*
  • Tooth Abnormalities / physiopathology
  • Young Adult


  • ANKRD11 protein, human
  • Repressor Proteins

Supplementary concepts

  • KBG syndrome