The clinical consequences of hemizygosity across 2 MB of 10q23 are restricted to Cowden syndrome

Cowden syndrome is caused by germline mutations in PTEN and clinically characterized by hamartomas, macrocephaly, classic dermatologic stigmata, and an estimated 85 % lifetime risk of female breast cancer. A young woman with macrocephaly, tricholemmomas, AV malformations, and mammary papillomatosis was found to be hemizygous for PTEN in her germline DNA. Using MLPA, comparative genomic hybridization, and DNA sequencing, we identified a 2-Mb deletion in chromosome 10 spanning 344-kb centromeric and 1.7-Mb telomeric of PTEN. Her father who has a clinical history including macrocephaly, Hashimoto’s thyroiditis, colonic polyposis, acral keratoses, and goiter was also found to have the same deletion. In benign breast tissue from the hemizygous female, PTEN protein expression was significantly reduced in luminal and stromal cells but present in the myoepithelium. Compared with a typical papilloma of the breast which had intense cytoplasmic PTEN staining, the majority of the patient’s papilloma had significantly decreased PTEN expression while some cells had mislocalized perinuclear PTEN expression. In addition to PTEN, 22 other protein-coding genes were deleted including two predicted haploinsufficient genes and five additional genes that have previously been associated with hereditary predispositions to certain diseases. However, because all significant clinical features of the proband and her father are common to patients with genetic alterations in PTEN, the other 22 hemizygous protein-coding genes appear to be haplosufficient.