High‐level somatic mosaicism of <i>AKT1</i> c.49G&gt;A mutation in skin scrapings from epidermal nevi enables non‐invasive molecular diagnosis in patients with Proteus syndrome

Wieland, Ilse; Tinschert, Sigrid; Zenker, Martin

doi:10.1002/ajmg.a.35764

Cited by 12 publications

(10 citation statements)

References 11 publications

(17 reference statements)

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“…Interestingly, the two samples with the highest levels of mutation in the keratinocytes (101EN1 and 78EN2) had the lowest mutation percentages in dermal cells or tissue. Detection of the mutant allele in the EN keratinocytes is consistent with the identification of the AKT1 p.Glu17Lys mutation in skin scrapings of PS epidermal nevi (Wieland et al 2013). …”

supporting

confidence: 80%

AKT1 Gene Mutation Levels Are Correlated with the Type of Dermatologic Lesions in Patients with Proteus Syndrome

Lindhurst

Wang

Bloomhardt

et al. 2014

Journal of Investigative Dermatology

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supporting

confidence: 80%

AKT1 Gene Mutation Levels Are Correlated with the Type of Dermatologic Lesions in Patients with Proteus Syndrome

Lindhurst

Wang

Bloomhardt

et al. 2014

Journal of Investigative Dermatology

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“…If other cell types are mutation positive, the resultant phenotype is cellular overgrowth, which can manifest as nodules, tumors and cysts or simply as increased tissue mass as was seen in the increased amount of omental fat. Previous studies on superficial skin scrapings from epidermal nevi, which are characterized by epidermal hyperplasia, demonstrated high levels of mutant allele in the keratinocytes [Wieland et al, ]. Our previous work showed that in epidermal nevi both the keratinocytes and fibroblasts are mutation positive, and in CCTN where there is massive deposition of extracellular matrix, only the fibroblasts harbor the PS mutation [Lindhurst et al, ].…”

Section: Discussionmentioning

confidence: 95%

Lack of mutation–histopathology correlation in a patient with Proteus syndrome

Doucet

Bloomhardt

Moroz

et al. 2016

American J of Med Genetics Pt A

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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 while 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.

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“…While traditional genetic analysis of mosaic patients can be equally difficult, sampling the affected tissue, rather than blood, using deep sequencing methods appears to have greater diagnostic accuracy. 11, 19, 22, 66, 67, 69, 70 For instance, studies suggest that up to 15% of patients with TSC may be mosaic; however, conventional sequencing methods may fail to detect low levels of the mutant allele in the blood. 11, 59–61, 71 Next generation sequencing techniques that analyze angiofibroma samples for genetic mutations are promising to close the diagnostic gap for patients with no mutation identified from blood samples.…”

Section: Diagnosis Of Mosaicismmentioning

confidence: 99%

“…11, 69 A similar approach has been utilized by harvesting epidermal nevi, vascular malformations or overgrown muscle samples to allow molecular diagnosis in patients with Proteus syndrome and PROS. 26, 30, 40, 67, 70, 72 Mutational analysis of resected dysplastic cerebellar tissue in Cowden syndrome has also been employed for mosaic diagnosis. 19 As all of the conditions discussed here present with at least some pathogenic skin findings, sequencing of DNA isolated from cutaneous tissue samples may be the least invasive, yet effective, way of arriving at molecular diagnosis for these patients.…”

Section: Diagnosis Of Mosaicismmentioning

confidence: 99%

Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway

Nathan

Keppler‐Noreuil

Biesecker

et al. 2017

Dermatologic Clinics

101

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Mosaicism is the presence of two or more genetically distinct cell lineages originating from a single zygote. The skin frequently marks mosaic conditions through migration patterns of a population of mutant cells during embryogenesis. Somatic mutations in genes of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway can result in segmental overgrowth, hamartomas, and malignant tumors, given the crucial role of this axis in cell growth. Mosaicism for activating mutations in AKT1 and PIK3CA is responsible for Proteus syndrome and PIK3CA-Related Overgrowth Spectrum, respectively. These frequently exemplify Happle’s patterns of cutaneous mosaicism. Postzygotic mutations in PTEN and TSC1/TSC2 result in mosaic forms of the PTEN Hamartoma Tumor Syndrome and tuberous sclerosis complex, which may present as disseminated or segmental disease. Distinct features observed in these mosaic conditions may be attributed to differences in embryological timing or tissue type harboring the mutant cells. Deep sequencing methods of affected tissue is often necessary to diagnosis these disorders. Oral mTORC1 inhibitors, such as sirolimus and everolimus, are useful for treating tuberous sclerosis complex, and drugs targeting mTORC1 or other points along this signaling pathway are in clinical trials to treat several of these disorders.

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High‐level somatic mosaicism of AKT1 c.49G>A mutation in skin scrapings from epidermal nevi enables non‐invasive molecular diagnosis in patients with Proteus syndrome

Cited by 12 publications

References 11 publications

AKT1 Gene Mutation Levels Are Correlated with the Type of Dermatologic Lesions in Patients with Proteus Syndrome

AKT1 Gene Mutation Levels Are Correlated with the Type of Dermatologic Lesions in Patients with Proteus Syndrome

Lack of mutation–histopathology correlation in a patient with Proteus syndrome

Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway

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