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Article ; Online: Phenotypic Features of Cystic Lung Disease in Proteus Syndrome: A Clinical Trial.

Keppler-Noreuil, Kim M / Burton-Akright, Jasmine / Kleiner, David E / Sapp, Julie C / Lindhurst, Marjorie J / Han, Chen G / Biesecker, Leslie G / Gochuico, Bernadette R

Annals of the American Thoracic Society

2022 Volume 19, Issue 11, Page(s) 1871–1880

Abstract: Rationale: ...

Abstract	Rationale:
MeSH term(s)	Humans ; Proteus Syndrome/diagnosis ; Proteus Syndrome/genetics ; Proteus Syndrome/surgery ; Retrospective Studies ; Lung Diseases/complications ; Phenotype ; Pulmonary Emphysema/etiology ; Cysts
Language	English
Publishing date	2022-06-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2717461-X
ISSN	2325-6621 ; 1943-5665 ; 2325-6621
ISSN (online)	2325-6621 ; 1943-5665
ISSN	2325-6621
DOI	10.1513/AnnalsATS.202111-1214OC
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Article ; Online: Allelic heterogeneity of Proteus syndrome.

Buser, Anna / Lindhurst, Marjorie J / Kondolf, Hannah C / Yourick, Miranda R / Keppler-Noreuil, Kim M / Sapp, Julie C / Biesecker, Leslie G

Cold Spring Harbor molecular case studies

2020 Volume 6, Issue 3

Abstract: Proteus syndrome is a mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively associated with the mosaic c.49G > A p.(Glu17Lys) pathogenic variant ... ...

Abstract	Proteus syndrome is a mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively associated with the mosaic c.49G > A p.(Glu17Lys) pathogenic variant in
MeSH term(s)	Alleles ; Allelic Imbalance ; Amino Acid Substitution ; Cervical Vertebrae/abnormalities ; Cervical Vertebrae/diagnostic imaging ; Genetic Association Studies ; Genetic Heterogeneity ; Genetic Predisposition to Disease ; Genetic Testing ; Humans ; Infant ; Magnetic Resonance Imaging ; Male ; Medical History Taking ; Mutation ; Phenotype ; Proteus Syndrome/diagnosis ; Proteus Syndrome/genetics ; Proto-Oncogene Proteins c-akt/genetics ; Radiography ; Symptom Assessment
Chemical Substances	AKT1 protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2020-06-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2835759-0
ISSN	2373-2873 ; 2373-2873
ISSN (online)	2373-2873
ISSN	2373-2873
DOI	10.1101/mcs.a005181
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Article ; Online: Ubiquitous expression of Akt1 p.(E17K) results in vascular defects and embryonic lethality in mice.

Lindhurst, Marjorie J / Li, Wenling / Laughner, Nathaniel / Shwetar, Jasmine J / Kondolf, Hannah C / Ma, Xuefei / Mukouyama, Yoh-Suke / Biesecker, Leslie G

Human molecular genetics

2020 Volume 29, Issue 20, Page(s) 3350–3360

Abstract: Proteus syndrome is a progressive overgrowth disorder with vascular malformations caused by mosaic expression of the AKT1 c.49G > A, p.(E17K) activating variant which was predicted to cause lethality if expressed ubiquitously. To test that hypothesis, we ...

Abstract	Proteus syndrome is a progressive overgrowth disorder with vascular malformations caused by mosaic expression of the AKT1 c.49G > A, p.(E17K) activating variant which was predicted to cause lethality if expressed ubiquitously. To test that hypothesis, we used the ACTB-Cre gene to activate a conditional Akt1 p.(E17K) allele in the mouse. No offspring that was heterozygous for both Cre and the conditional allele (βA-Akt1WT/flx) was viable. Fewer than expected numbers of βA-Akt1WT/flx embryos were seen beginning at E11.5, but a few survived until E17.5. The phenotype ranged from mild to severe, but generally βA-Akt1WT/flx embryos had fewer visible blood vessels and more hemorrhages than their wild-type littermates, which was suggestive of a vascular abnormality. Examination of E13.5 limb skin showed a primitive capillary network with increased branching complexity and abnormal patterning compared with wild-type skin. By E15.5, wild-type skin had undergone angiogenesis and formed a hierarchical network of remodeled vessels, whereas in βA-Akt1WT/flx embryos, the capillary network failed to remodel. Mural cell coverage of the blood vessels was also reduced in βA-Akt1WT/flx skin compared with that of wild type. Restricting expression of Akt1E17K to endothelial, cardiac or smooth muscle cells resulted in viable offspring and remodeled vasculature and did not recapitulate the βA-Akt1WT/flx phenotype. We conclude that ubiquitous expression of Akt1E17K suppresses remodeling and inhibits the formation of a normal skin vasculature. We postulate that this failure prevents proper circulation necessary to support the growing embryo and that it is the result of interactions of multiple cell types with increased AKT signaling.
MeSH term(s)	Animals ; Embryo Loss/etiology ; Embryo Loss/metabolism ; Embryo Loss/pathology ; Embryo, Mammalian/metabolism ; Embryo, Mammalian/pathology ; Female ; Mice ; Mice, Transgenic ; Neovascularization, Pathologic/etiology ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/pathology ; Peripheral Vascular Diseases/etiology ; Peripheral Vascular Diseases/metabolism ; Peripheral Vascular Diseases/pathology ; Proteus Syndrome/etiology ; Proteus Syndrome/metabolism ; Proteus Syndrome/pathology ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction
Chemical Substances	Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2020-10-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddaa216
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Article ; Online: Molecular heterogeneity of the cerebriform connective tissue nevus in mosaic overgrowth syndromes.

Keppler-Noreuil, Kim M / Burton-Akright, Jasmine / Lindhurst, Marjorie J / Shwetar, Jasmine / Sapp, Julie C / Darling, Thomas / Biesecker, Leslie G

Cold Spring Harbor molecular case studies

2019 Volume 5, Issue 4

Abstract: The clinical diagnostic criteria for Proteus syndrome were defined before the discovery of ... ...

Abstract	The clinical diagnostic criteria for Proteus syndrome were defined before the discovery of the
MeSH term(s)	Adult ; Class I Phosphatidylinositol 3-Kinases/genetics ; Class I Phosphatidylinositol 3-Kinases/metabolism ; Female ; Genetic Testing ; Humans ; Male ; Nevus/diagnosis ; Nevus/genetics ; Proteus Syndrome/diagnosis ; Proteus Syndrome/genetics ; Proto-Oncogene Proteins c-akt ; Skin Neoplasms/genetics
Chemical Substances	Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PIK3CA protein, human (EC 2.7.1.137) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2019-08-01
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2835759-0
ISSN	2373-2873 ; 2373-2873
ISSN (online)	2373-2873
ISSN	2373-2873
DOI	10.1101/mcs.a004036
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Article ; Online: Somatic AKT1 mutations cause meningiomas colocalizing with a characteristic pattern of cranial hyperostosis.

Keppler-Noreuil, Kim M / Baker, Eva H / Sapp, Julie C / Lindhurst, Marjorie J / Biesecker, Leslie G

American journal of medical genetics. Part A

2016 Volume 170, Issue 10, Page(s) 2605–2610

Abstract: Somatic genetic mutations in meningiomas are associated with histologic subtypes, anatomical location, and grade. Concomitant hyperostosis occurs with some meningiomas and the pathogenesis is not well understood. Cranial hyperostosis and meningiomas are ... ...

Abstract	Somatic genetic mutations in meningiomas are associated with histologic subtypes, anatomical location, and grade. Concomitant hyperostosis occurs with some meningiomas and the pathogenesis is not well understood. Cranial hyperostosis and meningiomas are common in patients with Proteus syndrome, which is caused by a somatic activating mutation in AKT1 c.49G>A. This same mutation has also been found in 6-9% of sporadic non-syndromic meningiomas. Sixty-one patients with Proteus syndrome meeting clinical diagnostic criteria were evaluated at the NIH from 1997 to 2014. Of these 61, 52 had a somatic activating mutation (c.49G>A, p.Glu17Lys) in AKT1 confirmed from affected tissue samples. Photographs, physical examination and/or autopsy, X-rays, CT, and/or MRI scan of the head were reviewed in 29/52 patients. Of the 29 patients, the most common intracranial tumor was meningioma, all co-localizing with cranial hyperostosis, and diagnosed at younger ages than typical for isolated, non-syndromic meningiomas. These patients had progressive cranial overgrowth that consisted primarily of diploic space expansion, and was characterized by unilateral, parasagittal, and frontal bone involvement. We hypothesize that sporadic meningothelial and transitional subtype meningiomas are a forme fruste or microform of Proteus syndrome, and activation of the AKT/PI3K pathway drives hyperostosis in both non-syndromic, and Proteus-related meningiomas. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.
MeSH term(s)	Adolescent ; Adult ; Aged ; Autopsy ; Child ; Child, Preschool ; Facies ; Female ; Humans ; Hyperostosis/complications ; Hyperostosis/diagnosis ; Magnetic Resonance Imaging ; Male ; Meningeal Neoplasms/complications ; Meningeal Neoplasms/diagnosis ; Meningeal Neoplasms/genetics ; Meningioma/complications ; Meningioma/diagnosis ; Meningioma/genetics ; Middle Aged ; Mutation ; Phenotype ; Proto-Oncogene Proteins c-akt/genetics ; Skull/pathology ; Tomography, X-Ray Computed ; Young Adult
Chemical Substances	AKT1 protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2016-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1493479-6
ISSN	1552-4833 ; 1552-4825
ISSN (online)	1552-4833
ISSN	1552-4825
DOI	10.1002/ajmg.a.37737
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Article ; Online: Lack of mutation-histopathology correlation in a patient with Proteus syndrome.

Doucet, Meggie E / Bloomhardt, Hadley M / Moroz, Krzysztof / Lindhurst, Marjorie J / Biesecker, Leslie G

American journal of medical genetics. Part A

2016 Volume 170, Issue 6, Page(s) 1422–1432

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Alleles ; Autopsy ; Biopsy ; Fatal Outcome ; Female ; Genetic Association Studies ; Humans ; Magnetic Resonance Imaging ; Mutation ; Proteus Syndrome/diagnostic imaging ; Proteus Syndrome/genetics ; Proteus Syndrome/pathology ; Proto-Oncogene Proteins c-akt/genetics ; Tomography, X-Ray Computed ; Young Adult
Chemical Substances	AKT1 protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2016-04-26
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1493479-6
ISSN	1552-4833 ; 1552-4825
ISSN (online)	1552-4833
ISSN	1552-4825
DOI	10.1002/ajmg.a.37612
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Article ; Online: Erratum: Orofacial overgrowth with peripheral nerve enlargement and perineuriomatous pseudo-onion bulb proliferations is part of the

Koutlas, Ioannis G / Anbinder, Ana-Lia / Alshagroud, Rana / Rodrigues Cavalcante, Ana Sueli / Al Kindi, Mohammed / Crenshaw, Molly M / Sapp, Julie C / Kondolf, Hannah / Lindhurst, Marjorie J / Dudley, Jeffrey N / Johnston, Jennifer J / Ryan, Elyse / Rafferty, Keith / Ganguly, Arupa / Biesecker, Leslie G

HGG advances

2021 Volume 3, Issue 1, Page(s) 100062

Abstract: This corrects the article DOI: 10.1016/j.xhgg.2020.100009.]. ...

Abstract	[This corrects the article DOI: 10.1016/j.xhgg.2020.100009.].
Language	English
Publishing date	2021-10-26
Publishing country	United States
Document type	Published Erratum
ISSN	2666-2477
ISSN (online)	2666-2477
DOI	10.1016/j.xhgg.2021.100062
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Article ; Online: Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome.

Lindhurst, Marjorie J / Yourick, Miranda R / Yu, Yi / Savage, Ronald E / Ferrari, Dora / Biesecker, Leslie G

Scientific reports

2015 Volume 5, Page(s) 17162

Abstract: A somatic activating mutation in AKT1, c.49G>A, pGlu17Lys, that results in elevated AKT signaling in mutation-positive cells, is responsible for the mosaic overgrowth condition, Proteus syndrome. ARQ 092 is an allosteric pan-AKT inhibitor under ... ...

Abstract	A somatic activating mutation in AKT1, c.49G>A, pGlu17Lys, that results in elevated AKT signaling in mutation-positive cells, is responsible for the mosaic overgrowth condition, Proteus syndrome. ARQ 092 is an allosteric pan-AKT inhibitor under development for treatment in cancer. We tested the efficacy of this drug for suppressing AKT signaling in cells and tissues from patients with Proteus syndrome. ARQ 092 reduced phosphorylation of AKT and downstream targets of AKT in a concentration-dependent manner in as little as two hours. While AKT signaling was suppressed with ARQ 092 treatment, cells retained their ability to respond to growth factor stimulation by increasing pAKT levels proportionally to untreated cells. At concentrations sufficient to decrease AKT signaling, little reduction in cell viability was seen. These results indicate that ARQ 092 can suppress AKT signaling and warrants further development as a therapeutic option for patients with Proteus syndrome.
MeSH term(s)	Aminopyridines/pharmacology ; Becaplermin ; Cell Survival/drug effects ; Cells, Cultured ; Humans ; Imidazoles/pharmacology ; Mutation ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Proteus Syndrome/genetics ; Proteus Syndrome/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-sis/pharmacology ; Signal Transduction/drug effects
Chemical Substances	Aminopyridines ; Imidazoles ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-sis ; Becaplermin (1B56C968OA) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Miransertib (T1DQI1B52Y)
Language	English
Publishing date	2015-12-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep17162
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Article ; Online: Pathogenetic insights from quantification of the cerebriform connective tissue nevus in Proteus syndrome.

Nathan, Neera R / Patel, Rachna / Crenshaw, Molly M / Lindhurst, Marjorie J / Olsen, Cara / Biesecker, Leslie G / Keppler-Noreuil, Kim M / Darling, Thomas N

Journal of the American Academy of Dermatology

2017 Volume 78, Issue 4, Page(s) 725–732

Abstract: Background: The plantar cerebriform connective tissue nevus (CCTN) is the most common and problematic cutaneous manifestation of Proteus syndrome.: Objective: To gain insights into CCTN pathogenesis and natural history.: Methods: The size and ... ...

Abstract	Background: The plantar cerebriform connective tissue nevus (CCTN) is the most common and problematic cutaneous manifestation of Proteus syndrome. Objective: To gain insights into CCTN pathogenesis and natural history. Methods: The size and location of plantar CCTN was measured on 152 images from 22 individuals with Proteus syndrome by 2 independent, blinded reviewers. Average measures of plantar CCTN were transformed into a linear mixed model to estimate proportionate change in size with age. Results: Median patient age was 6.9 years at study onset. The intraclass correlation coefficient between 2 blinded reviewers was 0.946 for CCTN single measures. The CCTN relative area increased with age in children (n = 18, P < .0001) by 5.6% per year. Confluent papules and nodules extending beyond the boundaries of CCTNs were gradually replaced by typical CCTN over time. The location of CCTN in different individuals overlapped near the ball of the foot. A positive relationship between CCTN growth rate and AKT1 mutant allele frequency was observed (0.62, P = .10, n = 8). Limitations: This was a retrospective review using photographs. Conclusion: CCTN growth is affected by age and extent of the CCTN precursor lesion. Monitoring of CCTN size might prove useful for evaluating drug response in the treatment of Proteus syndrome.
MeSH term(s)	Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Foot Diseases/etiology ; Foot Diseases/pathology ; Humans ; Infant ; Male ; Middle Aged ; Nevus/etiology ; Nevus/pathology ; Proteus Syndrome/complications ; Retrospective Studies ; Skin Neoplasms/etiology ; Skin Neoplasms/pathology ; Young Adult
Language	English
Publishing date	2017-10-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	603641-7
ISSN	1097-6787 ; 0190-9622
ISSN (online)	1097-6787
ISSN	0190-9622
DOI	10.1016/j.jaad.2017.10.018
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Zs.A 1540: Show issues

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Article ; Online: Orofacial overgrowth with peripheral nerve enlargement and perineuriomatous pseudo-onion bulb proliferations is part of the

HGG advances

2020 Volume 1, Issue 1, Page(s) 100009

Abstract: Individuals with orofacial asymmetry due to mucosal overgrowths, ipsilateral bone and dental aberrations with perineurial hyperplasia and/or perineuriomatous pseudo-onion bulb proliferations, comprise a recognizable clinical entity. In this article, we ... ...

Abstract	Individuals with orofacial asymmetry due to mucosal overgrowths, ipsilateral bone and dental aberrations with perineurial hyperplasia and/or perineuriomatous pseudo-onion bulb proliferations, comprise a recognizable clinical entity. In this article, we describe three individuals with this clinical entity and mosaic
Language	English
Publishing date	2020-08-14
Publishing country	United States
Document type	Journal Article
ISSN	2666-2477
ISSN (online)	2666-2477
DOI	10.1016/j.xhgg.2020.100009
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