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SignatureChip® Detection Rates for PTEN Hamartoma Tumor Syndrome and Allelic Disorders

PTEN Hamartoma Tumor Syndrome is a syndrome that incorporates several disorders with phenotypic overlap caused by mutations in PTEN, including Bannayan-Riley Ruvalcaba syndrome, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome. While these disorders have specific distinguishing characteristics, they have features in common and recommended management is virtually identical for all.

2-11% of cases of Bannayan-Riley-Ruvalcaba syndrome (BRRS) are caused by deletions of the PTEN gene, the majority of which are detectable by array CGH technology. Approximately 60% have identifiable PTEN point mutations. Subjects with this condition often have autistic features, macrocephaly, hamartomatous intestinal polyps, lipomas and penile freckling.

~1% of Cowden syndrome (CS) are caused by deletions of the PTEN gene, the majority of which are detectable by array CGH technology. Approximately 80% have identifiable PTEN point mutations that are not detectable by array CGH. Subjects with this condition may have cancers of the breast, uterus, thyroid, and urogenital tract as well as macrocephaly, Lhermitte-Duclos disease (macrocephaly, seizures, and intellectual disability associated with dysplastic gangliocytoma of the cerebellum), specific skin lesions (e.g., trichelemmomas, lipomas), hamartomatous polyps, fibrocystic breasts, and urogenital system malformations and tumors. Autistic-like tendencies have also been reported in some patients.

No large deletions have been reported in cases of Proteus syndrome or Proteus-like syndrome. However, this disorder has phenotypic overlap with BRRS and CS and is considered part of the PTEN Hamartoma Tumor Syndrome Spectrum. Detection rates for point mutations are not reported consistently, implying a possible second locus for these syndromes. These are disorders of mosaic, progressive overgrowth, including connective tissue nevi, macrocephaly, ovarian and parotid tumors, atypical adipose tissue growth, and vascular malformations.

While Macrocephaly/autism syndrome is not considered part of the PTEN Hamartoma Tumor Syndrome, it is allelic to these tumor syndromes and has the overlapping phenotype of both macrocephaly and autistic-like features. Approximately 4% of patients with a head circumference >2 standard deviations above the mean and autism spectrum disorder have point mutations in PTEN, that are not detectable by array CGH.