Mutation analysis of the tumor suppressor PTEN and the glypican 3 (GPC3) gene in patients diagnosed with Proteus syndrome

  title={Mutation analysis of the tumor suppressor PTEN and the glypican 3 (GPC3) gene in patients diagnosed with Proteus syndrome},
  author={Isabelle Thiffault and Charles E. Schwartz and Vazken M. Der Kaloustian and William D. Foulkes},
  journal={American Journal of Medical Genetics Part A},
Proteus syndrome is a complex hamartomatous disorder characterized by asymmetrical gigantism, epidermal nevi, vascular malformations, hamartomas, lipomas, and hyperostosis. Since the syndrome was first described, many hypotheses have been proposed to explain its occurrence. The most plausible is Happle's somatic mosaic hypothesis, but no somatic mutations in candidate genes have been reported to be clearly involved in Proteus syndrome. However, germ‐line PTEN mutations have been reported in… 
A mosaic activating mutation in AKT1 associated with the Proteus syndrome.
The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder.
PTEN hamartoma tumor syndromes
Improved understanding of the biology of PTEN and the PI3K/Akt/mTOR pathway means inhibitors of this pathway are being developed as anticancer agents and could have applications for patients with PHTS, for whom no medical options currently exist.
Proteus syndrome with syringohydromyelia and arachnoid cyst
The authors make a good review of the main clinical and genetic aspects of Proteus syndrome and classify its classification, along with Cowden and Bannayan–Zonana syndromes, as part of the spectrum of PTEN hamartoma–tumor syndrome (PHTS).
Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity
Data provide a new demonstration of the Happle hypothesis to explain some segmental exacerbation of autosomal-dominant disorders and show that a bi-allelic inactivation of PTEN can lead to developmental anomalies instead of malignant transformation, raising the question of the limitations of the tumor suppressive function in this gene.
Cowden syndrome and Bannayan–Riley–Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers
Careful phenotyping gives further support for the suggestion that BRRS and CS are actually one condition, presenting variably at different ages, as in other tumour-suppressor disorders such as neurofibromatosis type 1.
PTEN Hamartoma Tumor Syndrome (PHTS)-GeneReviews-NCBI Bookshelf
Because the most serious consequences of PHTS relate to the increased risk of breast, thyroid, endometrial, and renal cancers, the most important aspect of management of an individual with a PTEN mutation is increased cancer surveillance.
PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature
The limited understanding of the natural history of childhood‐onset PHTS as a cancer predisposition syndrome is acknowledged and a summary of important management considerations is presented.
Cerebral cavernous malformations do not fall in the spectrum of PIK3CA-related overgrowth
This paper reviews and attempts to conceptualise the relationships and differences among clinical presentations, genotypic and phenotypic correlations and possible coexistence of PIK3CA and CCM mutations/phenotypes in CCM lesions and presents a model reflecting the hypothetical understanding of CCM pathogenesis based on a systematic review and conceptualisation of data obtained from other studies.
Overgrowth syndromes:from classical to new.
The aim of this review is to give a comprehensive overview of the clinical, molecular genetic and pathophysiological aspects of each of the classic and new overgrowth syndromes.


Germline mutation of the tumour suppressor PTEN in Proteus syndrome
Clinical overlap exists between PS and another hamartoma syndrome, Bannayan-Riley-Ruvalcaba syndrome, in which up to 60% of affected subjects are known to carry a germline mutation of the tumour suppressor gene PTEN .6 BRR also shows partial clinical overlap with Cowden syndrome.
Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes
PTEN mutations are uncommon in Proteus syndrome
One of the mandatory diagnostic criteria for Proteus syndrome is a mosaic distribution of lesions and sporadic occurrence, entirely consistent with Happle's hypothesis.
Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis.
PTEN may be involved in Proteus-like syndrome with its implications for cancer development in the future and postulate that the second hit, R130X, occurred early in embryonic development and may even represent germline mosaicism.
Proteus syndrome: Misdiagnosis with PTEN mutations
The high frequency of misdiagnosis of Proteus syndrome by clinicians less familiar with the disorder is demonstrated and reported PTEN mutations, using the unhelpful and confounding clinical term ‘‘Proteuslike syndrome’’ are analyzed.
Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.
The PTEN/MMAC1 gene, encoding a putative protein tyrosine or dual-specificity phosphatase, is confirmed as the gene for Cowden disease by a refined localization of the gene to the interval between D 10S1761 and D10S541, which contains the PTEN-MMAC 1 gene and by mutation analysis in eight unrelated familial and 11 sporadic patients with Cowden Disease.
Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome
Mutational analysis of PTEN in CD kindreds has identified germline mutations that are predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain of this gene, and implies that PTEN may play a role in organizing the relationship of different cell types within an organ during development.
Simpson-Golabi-Behmel syndrome: genotype/phenotype analysis of 18 affected males from 7 unrelated families.
The lack of correlation between the phenotype of 18 affected males from these 7 families and the location and size of the GPC3 gene mutations suggest that SGBS is caused by a nonfunctional G PC3 protein.
Identification of a PTEN mutation in a family with Cowden syndrome and Bannayan-Zonana syndrome.
A single kindred with individuals manifesting both CS and BZS phenotypes within the same family in which a novel mutation in PTEN is identified by DNA sequencing, suggesting that these two syndromes represent different phenotypic expressions of one disease.
PTEN: One Gene, Many Syndromes
  • C. Eng
  • Biology, Medicine
    Human mutation
  • 2003
Genotype–phenotype association analyses have revealed that the presence of germline PTEN mutations is associated with breast tumor development, and that mutations occurring within and 5′ of the phosphatase motif were associated with multi‐organ involvement.