Lack of mutation-histopathology correlation in a patient with Proteus syndrome.
Proteus syndrome (PS) is characterized by progressive, disproportionate, segmental overgrowth, and tumor susceptibility caused by a somatic mosaic AKT1 activating mutation. Each individual has unique manifestations making this disorder extremely heterogeneous. We correlated three variables in 38 tissue samples from a patient who died with PS: the gross affection status, the microscopic affection status, and the mutation level. The AKT1 mutation was measured using a PCR-based RFLP assay. Thirteen samples were grossly normal; six had detectable mutation (2-29%) although four of these six were histopathologically normal. Of the seven grossly normal samples that had no mutation, only four were histologically normal. The mutation level in the grossly abnormal samples was 3-35% and all but the right and left kidneys, skull, and left knee bone, with mutation levels of 19%, 15%, 26%, and 17%, respectively, had abnormal histopathology. The highest mutation level was in a toe bone sample whereas the lowest levels were in the soft tissue surrounding that toe, and an omental fat nodule. We also show here that PS overgrowth can be caused by cellular proliferation or by extracellular matrix expansion. Additionally, papillary thyroid carcinoma was identified, a tumor not previously associated with PS. We conclude that gross pathology and histopathology correlate poorly with mutation levels in PS, that overgrowth can be mediated by cellular proliferation or extracellular matrix expansion, and that papillary thyroid carcinoma is part of the tumor susceptibility of PS. New methods need to be developed to facilitate genotype-phenotype correlation in mosaic disorders. © 2016 Wiley Periodicals, Inc.
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Meggie E
ME
Doucet
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.
Hadley M
HM
Bloomhardt
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Krzysztof
K
Moroz
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.
Marjorie J
MJ
Lindhurst
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.
Leslie G
LG
Biesecker
D000483:Alleles; D001344:Autopsy; D001706:Biopsy; D017809:Fatal Outcome; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D009154:Mutation; D016715:Proteus Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D014057:Tomography, X-Ray Computed; D055815:Young Adult
C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
AKT1 mutations; Proteus syndrome; histopathology; somatic mutation