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De novo germline PTEN mutation in a man with Lhermitte-Duclos disease which arose on the paternal chromosome and was transmitted to his child with polydactyly and Wormian bones
  1. M B Delatycki1,2,
  2. A Danks3,
  3. A Churchyard4,
  4. X-P Zhou5,
  5. C Eng5
  1. 1Bruce Lefroy Centre for Genetic Health Research, Royal Children’s Hospital, Parkville, Victoria, 3052, Australia
  2. 2Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, 3052, Australia
  3. 3Department of Neurosurgery, Southern Health, Monash Medical Centre, Clayton, Victoria, 3168, Australia
  4. 4Department of Neurology, Southern Health, Monash Medical Centre, Clayton, Victoria, 3168, Australia
  5. 5Human Cancer Genetics Program, and the Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA
  1. Correspondence to:
 Dr M B Delatycki, Bruce Lefroy Centre for Genetic Health Research, Royal Children’s Hospital, Flemington Road Parkville, 3052 Victoria, Australia; 

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Cowden syndrome (CS), also known as multiple hamartoma-neoplasia syndrome, is an autosomal dominant disease with numerous possible clinical manifestations.1 Commonly present are skin changes including acral keratoses and facial trichilemmomas, as well as oral papillomas and scrotal tongue. There is an increased risk of malignancies including breast, thyroid, and endometrial cancers. Hamartomas may affect multiple systems including the skin, gastrointestinal tract, central nervous system, breast, and thyroid.1

CS is the result of germline mutations in the PTEN (phosphatase and tensin homologue deleted on chromosome 10) gene on chromosome subband 10q23.2 Germline PTEN mutations have been described in a family with CS with one member with Lhermitte-Duclos disease (LDD),2,3 Bannayan-Riley-Ruvalcaba syndrome (in the past variously called Bannayan-Zonana, Riley-Smith, or Ruvalcaba-Myhre-Smith syndrome)4 as well as some cases of Proteus syndrome.5–7 These diseases resulting from germline PTEN mutations are grouped as the PTEN hamartoma-tumour syndrome (PHTS).8 Lhermitte-Duclos disease is characterised by dysplastic gangliocytoma of the cerebellum, usually presenting with signs of cerebellar dysfunction, cranial nerve palsies, and raised intracranial pressure.9,10 Bannayan-Riley-Ruvalcaba syndrome is characterised by macrocephaly, lipomatosis, and pigmented macules of the glans penis.8 Proteus syndrome, by contrast, is characterised by hemihypertrophy, macrocephaly, connective tissue naevi, and lipomatosis.5

Here we present a case of a male proband with LDD found to have a de novo PTEN mutation, whose son, with the same mutation, had macrocephaly, developmental delay, preaxial polydactyly, and wormian bones. This case raises the question of whether the last two features in the son relate to the PTEN mutation or are a coincidental occurrence. Of relevance, we show that the proband’s de novo germline PTEN mutation arose on the paternal chromosome.


PTEN mutation analysis

Genomic DNA was extracted from peripheral blood leucocytes from the proband, his son, and the proband’s parents …

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