A Recessive Form of Extreme Macrocephaly

A Recessive Form of Extreme Macrocephaly and Mild Intellectual Disability Complements the Spectrum of PTEN Hamartoma Tumour Syndrome

Eur J Hum Genet. 2016 Jun;24(6):889-94. doi: 10.1038/ejhg.2015.209. Epub 2015 Oct 7.


PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious.


  • Tobias Schwerd
  • et al.