Conditions with similar clinical presentations that must be differentiated from Proteus syndrome:
Pathophysiology description Proteus syndrome is an ultra-rare, progressive, mosaic overgrowth disorder caused by a somatic, activating AKT1 c.49G>A (p.E17K) variant that dysregulates PI3K→AKT→mTOR signaling and drives regionally confined overgrowth across multiple tissues. The E17K substitution increases AKT affinity for membrane phosphoinositides and disrupts autoinhibition, producing constitutive pAKT and downstream signaling in mutation-positive clones, with both cell-autonomous and non–cell-autonomous effects evident in vivo and ex vivo (lateral spread of pathway activation into nearby wild-type cells) (https://doi.org/10.1038/srep17162, 2015-12-11; https://doi.org/10.1093/hmg/ddz116, 2019-09-01) (lindhurst2015repressionofakt pages 1-2, lindhurst2019amousemodel pages 1-2, lindhurst2019amousemodel pages 14-15).
Endothelial and mural cell dysfunction is central to vascular malformations in Proteus syndrome. Human iPSC-derived vascular organoids engineered with mosaic AKT1 E17K recapitulate PS-like network hyperconnectivity with unstable vascular contacts, mural cell (PDGFRβ+) abnormalities, and increased vasculogenesis that can be pharmacologically normalized by AKT inhibitors, supporting a direct endothelial–mural etiology of the vascular phenotype (preprint; https://doi.org/10.1101/2024.01.26.577324, 2024-01-27) (he2024humanvascularorganoids pages 14-17). Clinically, thoracic imaging shows frequent pulmonary venous dilation, scarring, hyperlucent parenchyma, and intramyocardial fat, underscoring multi-tissue involvement and highlighting cardiopulmonary vulnerability (https://doi.org/10.1038/s41598-021-86029-0, 2021-03-22) (mirmomen2021cardiothoracicimagingfindings pages 1-2). Progressive cystic/emphysematous lung disease can be quantified and is more rapidly progressive in children (https://doi.org/10.1186/s13023-023-03013-9, 2024-02-15) (mirmomen2021cardiothoracicimagingfindings pages 1-2).
Core pathophysiology - Primary mechanisms: Somatic mosaicism for AKT1 p.E17K drives constitutive AKT activity via enhanced PI(3,4,5)P3/PI(4,5)P2 binding and release of PH–kinase autoinhibition, with activation by PDK1 (T308) and mTORC2 (S473). Downstream, this promotes growth, proliferation, survival, anabolic metabolism, and extracellular matrix (ECM) remodeling, producing overgrowth, cysts, and ectasia (https://doi.org/10.1038/srep17162, 2015-12-11; https://doi.org/10.1093/hmg/ddz116, 2019-09-01) (lindhurst2015repressionofakt pages 1-2, lindhurst2019amousemodel pages 1-2, lindhurst2019amousemodel pages 14-15). - Dysregulated pathways: PI3K/AKT/mTOR signaling in endothelial, mural, mesenchymal (fibroblast), osteogenic, and adipocytic lineages; paracrine signaling drives non–cell-autonomous pAKT elevation in adjacent wild-type cells within lesions (https://doi.org/10.1093/hmg/ddz116, 2019-09-01) (lindhurst2019amousemodel pages 1-2, lindhurst2019amousemodel pages 14-15). - Affected cellular processes: Enhanced vasculogenesis/angiogenic sprouting, impaired vessel stability (mural cell dysfunction), increased proliferation and matrix deposition in skin/dermis (cerebriform connective tissue nevi), hyperplasia in bone and adipose, and cyst formation in lung and biliary epithelium (https://doi.org/10.1101/2024.01.26.577324, 2024-01-27; https://doi.org/10.1093/hmg/ddz116, 2019-09-01) (he2024humanvascularorganoids pages 14-17, lindhurst2019amousemodel pages 1-2).
Key molecular players, cells, anatomy, and phenotypes | Category | Entity (ontology ID) | Role in Proteus syndrome pathophysiology | Supporting sources | |---|---|---|---| | Gene/Protein | AKT1 (HGNC:391) | Somatic activating mutation c.49G>A (p.E17K) → constitutive AKT activation driving mosaic overgrowth | (lindhurst2015repressionofakt pages 1-2, lindhurst2019amousemodel pages 1-2) | | Gene/Protein | PDK1 / PDPK1 (HGNC:8769) | Phosphorylates AKT at T308; required for AKT activation downstream of PI3K | (lindhurst2015repressionofakt pages 1-2) | | Gene/Protein | mTOR (MTOR; HGNC:3942) | Downstream nutrient/growth regulator; mediates anabolic responses to AKT signaling | (lindhurst2015repressionofakt pages 1-2, klimeczekchrapusta2024proteussyndromecase pages 2-5) | | Complex | mTORC2 (RICTOR; HGNC:28611) | Phosphorylates AKT at S473, sustaining AKT activity | (lindhurst2015repressionofakt pages 1-2) | | Gene/Protein | PI3K (PIK3CA; HGNC:8975) | Upstream lipid kinase generating PIP3; PIK3CA mutations produce overlapping overgrowth/VM phenotypes | (klimeczekchrapusta2024proteussyndromecase pages 2-5, lindhurst2015repressionofakt pages 1-2) | | Gene/Protein | PTEN (HGNC:9588) | Negative regulator of PI3K-AKT signaling; loss produces AKT pathway activation and overlapping features | (klimeczekchrapusta2024proteussyndromecase pages 2-5, lindhurst2015repressionofakt pages 1-2) | | Cell type | Endothelial cell (CL:0000115) | Key component of vascular malformations; shows altered signaling/structure in AKT1-mutant lesions | (he2024humanvascularorganoids pages 14-17, lindhurst2019amousemodel pages 1-2, mirmomen2021cardiothoracicimagingfindings pages 1-2) | | Cell type | Pericyte / mural cell (CL:0000669) | Mural cell dysfunction and PDGFRβ+ mural cell abnormalities contribute to unstable vasculature in mosaic AKT1 models | (he2024humanvascularorganoids pages 14-17, lindhurst2019amousemodel pages 1-2) | | Cell type | Fibroblast (CL:0000057) | Drives connective tissue overgrowth (e.g., cerebriform connective tissue nevus) via increased AKT signaling | (lindhurst2015repressionofakt pages 1-2, ours2021casereportfiveyear pages 1-2) | | Cell type | Osteoblast (CL:0000062) | Mediates asymmetric bony overgrowth and scoliosis through AKT-driven hyperplasia | (lindhurst2019amousemodel pages 1-2, mirmomen2021cardiothoracicimagingfindings pages 1-2) | | Cell type | Adipocyte (CL:0000136) | Lipomatous/fatty overgrowth and dysregulated adipose tissue in affected regions | (lindhurst2019amousemodel pages 1-2, ours2021casereportfiveyear pages 1-2) | | Anatomy | Lung (UBERON:0002048) | Site of cystic/emphysematous changes and progressive pulmonary disease in PS | (mirmomen2021cardiothoracicimagingfindings pages 1-2, lindhurst2019amousemodel pages 1-2) | | Anatomy | Skin / dermis (UBERON:0002097) | Location of cerebriform connective tissue nevi and epidermal/dermal overgrowth | (lindhurst2015repressionofakt pages 1-2, ours2021casereportfiveyear pages 1-2) | | Anatomy | Bone (UBERON:0001474) | Skeletal overgrowth, deformities, and asymmetric limb enlargement | (mirmomen2021cardiothoracicimagingfindings pages 1-2, lindhurst2019amousemodel pages 1-2) | | Anatomy | Vascular system (UBERON:0004535) | Vascular malformations (venous/lymphatic/other) are a central clinical and pathophysiologic feature | (klimeczekchrapusta2024proteussyndromecase pages 2-5, mirmomen2021cardiothoracicimagingfindings pages 1-2, he2024humanvascularorganoids pages 14-17) | | Phenotype | Cerebriform connective tissue nevus (HP:0032365) | Hallmark localized connective tissue overgrowth reflecting fibroblast/EC matrix expansion | (ours2021casereportfiveyear pages 1-2, lindhurst2015repressionofakt pages 1-2) | | Phenotype | Vascular malformation (HP:0004930) | Frequent manifestation driven by AKT/PI3K pathway dysregulation in endothelial and mural cells | (lindhurst2019amousemodel pages 1-2, mirmomen2021cardiothoracicimagingfindings pages 1-2, he2024humanvascularorganoids pages 14-17) | | Phenotype | Asymmetric limb overgrowth (HP:0009828) | Classic progressive, mosaic overgrowth of bone/soft tissue due to focal AKT1-mutant clones | (lindhurst2019amousemodel pages 1-2, mirmomen2021cardiothoracicimagingfindings pages 1-2) | | Phenotype | Pulmonary emphysema / cystic change (HP:0002090) | Progressive cystic lung disease associated with morbidity and radiographic progression | (mirmomen2021cardiothoracicimagingfindings pages 1-2, lindhurst2019amousemodel pages 1-2) | | Complication | Deep venous thrombosis (HP:0002625) | Major morbidity likely multifactorial (vascular malformations, stasis, altered endothelial factors) | (lindhurst2015repressionofakt pages 1-2, mirmomen2021cardiothoracicimagingfindings pages 1-2) | | Complication | Pulmonary embolism (HP:0002204) | Leading cause of premature mortality in PS; linked to DVT and vascular anomalies | (lindhurst2015repressionofakt pages 1-2, mirmomen2021cardiothoracicimagingfindings pages 1-2) |
Table: Compact table mapping genes, cells, tissues, phenotypes, and complications in Proteus syndrome with concise roles and supporting evidence (pqac IDs). This aids rapid cross-referencing of molecular players to pathophysiology and literature sources.
Biological processes (for GO annotation) - PI3K/AKT signaling; AKT phosphorylation by PDK1 and mTORC2; mTOR signaling; regulation of cell growth and proliferation; angiogenesis and vasculogenesis; endothelial cell migration; pericyte development; extracellular matrix organization; response to phosphoinositides; apoptotic signaling suppression. Mechanistic grounding from patient-derived cells/tissues showing elevated pAKT and downstream target phosphorylation, and reversal by AKT inhibition (https://doi.org/10.1038/srep17162, 2015-12-11) (lindhurst2015repressionofakt pages 1-2), corroborated by organoid data (https://doi.org/10.1101/2024.01.26.577324, 2024-01-27) (he2024humanvascularorganoids pages 14-17) and by in vivo mosaic models showing paracrine activation (https://doi.org/10.1093/hmg/ddz116, 2019-09-01) (lindhurst2019amousemodel pages 1-2, lindhurst2019amousemodel pages 14-15).
Cellular components - Plasma membrane (AKT PH-domain engagement with PIP2/PIP3), cytosol, and mTORC1/2-associated compartments; endothelial junctions and basement membrane; perivascular space (mural cells); dermal ECM; alveolar and biliary epithelia in cystic lesions. Supported by patient-cell signaling assays and tissue immunostaining for pAKT in mutant and neighboring wild-type cells, and by organoid localization in endothelial–mural networks (https://doi.org/10.1038/srep17162, 2015-12-11; https://doi.org/10.1093/hmg/ddz116, 2019-09-01; https://doi.org/10.1101/2024.01.26.577324, 2024-01-27) (lindhurst2015repressionofakt pages 1-2, lindhurst2019amousemodel pages 1-2, lindhurst2019amousemodel pages 14-15, he2024humanvascularorganoids pages 14-17).
Disease progression - Trigger: Post-zygotic AKT1 p.E17K in an early progenitor generates mosaic clones. - Early tissue-level events: Localized AKT hyperactivation induces hyperplasia/expansion and vascular maldevelopment (endothelial hyperconnectivity, unstable mural support), with ECM remodeling and cyst formation in susceptible epithelia (lung, biliary) (https://doi.org/10.1101/2024.01.26.577324, 2024-01-27; https://doi.org/10.1093/hmg/ddz116, 2019-09-01) (he2024humanvascularorganoids pages 14-17, lindhurst2019amousemodel pages 1-2). - Clinical emergence: Postnatal, progressive, asymmetric overgrowth; hallmark cerebriform connective tissue nevi; evolving vascular malformations; thoracic/lung changes detectable on imaging (https://doi.org/10.1038/s41598-021-86029-0, 2021-03-22) (mirmomen2021cardiothoracicimagingfindings pages 1-2). - Complications: Elevated risk of deep venous thrombosis and pulmonary embolism (PE), pneumonia and respiratory failure; tumor predisposition (notably meningiomas and gonadal epithelial tumors) (https://doi.org/10.1038/s41598-021-86029-0, 2021-03-22; https://doi.org/10.1136/jmg-2024-110173, 2025-12-01) (mirmomen2021cardiothoracicimagingfindings pages 1-2, rostagni2025tumourspectrumin pages 8-9). - Pace: Lung cystic disease is progressive and faster in children than adults, informing surveillance and interventional trial endpoints (https://doi.org/10.1186/s13023-023-03013-9, 2024-02-15) (mirmomen2021cardiothoracicimagingfindings pages 1-2).
Phenotypic manifestations (HP terms) - Asymmetric limb and skeletal overgrowth; scoliosis; vascular malformations (venous/lymphatic); cerebriform connective tissue nevi; fatty overgrowth/lipomatosis; cystic/emphysematous lung disease; intramyocardial fat. Imaging prevalence includes scoliosis 94%, pulmonary venous dilation 62%, scarring 56%, hyperlucency 50%, intramyocardial fat 45% (https://doi.org/10.1038/s41598-021-86029-0, 2021-03-22) (mirmomen2021cardiothoracicimagingfindings pages 1-2). Increased thromboembolism risk is a key morbidity; tumors are mostly benign and occur predominantly in genitourinary and CNS sites (https://doi.org/10.1136/jmg-2024-110173, 2025-12-01) (rostagni2025tumourspectrumin pages 8-9).
Current applications and real-world implementations - AKT inhibition (miransertib/MK-7075/ARQ-092): In patient-derived cells/tissues, ARQ-092 rapidly suppresses pAKT and downstream signaling without reducing viability, supporting target engagement (https://doi.org/10.1038/srep17162, 2015-12-11) (lindhurst2015repressionofakt pages 1-2). Clinical case experience demonstrates long-term tolerability with symptomatic benefit (reduced pain) and slowed progression of cerebriform nevi and overgrowth over 5 years in an individual with PS (https://doi.org/10.1101/mcs.a006134, 2021-10-01) (ours2021casereportfiveyear pages 1-2). A systematic review notes an ongoing Phase 2 AKT inhibitor trial in PS (NCT04316546) (https://doi.org/10.1136/jmg-2024-110173, 2025-12-01) (rostagni2025tumourspectrumin pages 8-9). Vascular organoids modeling mosaic AKT1 E17K demonstrate reversal of vascular malformations by AKT inhibitors (Miransertib, Capivasertib, Ipatasertib), functionally linking target inhibition to network normalization (preprint; https://doi.org/10.1101/2024.01.26.577324, 2024-01-27) (he2024humanvascularorganoids pages 14-17). - mTOR pathway modulation: Contemporary reviews and case syntheses include sirolimus use in PS as pathway-directed therapy, though effects may be partial and surgical management remains critical for skeletal deformities (https://doi.org/10.1055/a-2300-7002, 2024-04-01) (klimeczekchrapusta2024proteussyndromecase pages 2-5).
Expert opinions and guidance - Contemporary imaging and clinical syntheses emphasize the multisystem burden, cardiopulmonary surveillance (including PE risk), and the role of molecular diagnosis (AKT1 testing) in confirming PS (https://doi.org/10.1038/s41598-021-86029-0, 2021-03-22) (mirmomen2021cardiothoracicimagingfindings pages 1-2). Review of tumor spectrum recommends awareness of genitourinary and CNS lesions, highlights predominance of benign tumors, and notes limited data on adult-onset malignancy—underscoring the need for longitudinal care and research (https://doi.org/10.1136/jmg-2024-110173, 2025-12-01) (rostagni2025tumourspectrumin pages 8-9). Mouse modeling and organoid studies provide mechanistic expert insight into non–cell-autonomous signaling and endothelial–mural dysfunction, guiding therapeutic targets and trial endpoints (https://doi.org/10.1093/hmg/ddz116, 2019-09-01; https://doi.org/10.1101/2024.01.26.577324, 2024-01-27) (lindhurst2019amousemodel pages 1-2, lindhurst2019amousemodel pages 14-15, he2024humanvascularorganoids pages 14-17).
Relevant statistics and data - Prevalence and demographics: Approximately 1 per 1,000,000 births; male predominance ≈2:1 in one institutional cohort (https://doi.org/10.1038/s41598-021-86029-0, 2021-03-22) (mirmomen2021cardiothoracicimagingfindings pages 1-2). - Survival: Literature synthesis estimates survival to age 22 around 82% (95% CI 74–91%), consistent with prior cohort observations of substantial pediatric mortality (https://doi.org/10.1136/jmg-2024-110173, 2025-12-01) (rostagni2025tumourspectrumin pages 8-9). - Cardiothoracic imaging prevalence: scoliosis 94%, pulmonary venous dilation 62%, band-like scarring 56%, hyperlucent lung 50%, intramyocardial fat 45% (https://doi.org/10.1038/s41598-021-86029-0, 2021-03-22) (mirmomen2021cardiothoracicimagingfindings pages 1-2). - Lung disease progression: Cystic Lung Score progression faster in children vs adults, correlating with symptoms and PFT decline (https://doi.org/10.1186/s13023-023-03013-9, 2024-02-15) (mirmomen2021cardiothoracicimagingfindings pages 1-2).
Gene/protein annotations with ontology terms (examples) - AKT1 (HGNC:391): PI3K/AKT signaling; positive regulation of cell growth; regulation of apoptosis; membrane recruitment via PIP3; kinase activity (supported by patient-cell pharmacology and mouse/paracrine data) (https://doi.org/10.1038/srep17162, 2015-12-11; https://doi.org/1093/hmg/ddz116, 2019-09-01) (lindhurst2015repressionofakt pages 1-2, lindhurst2019amousemodel pages 1-2). - PDPK1/PDK1 (HGNC:8769): AKT T308 phosphorylation; AGC kinase activation (lindhurst2015repressionofakt pages 1-2). - MTOR (HGNC:3942) and RICTOR (HGNC:28611): mTORC1/2 signaling; AKT S473 phosphorylation; anabolic growth responses (lindhurst2015repressionofakt pages 1-2). - PIK3CA (HGNC:8975) and PTEN (HGNC:9588): Upstream positive/negative regulators; overlapping overgrowth phenotypes in PI3K-pathway disorders (klimeczekchrapusta2024proteussyndromecase pages 2-5, lindhurst2015repressionofakt pages 1-2).
Phenotype associations (HP terms; examples) - HP:0032365 cerebriform connective tissue nevus; HP:0004930 vascular malformation; HP:0009828 asymmetric limb overgrowth; HP:0002090 pulmonary emphysema/cystic changes; HP:0002625 deep venous thrombosis; HP:0002204 pulmonary embolism (supported by clinical imaging and case series) (mirmomen2021cardiothoracicimagingfindings pages 1-2, ours2021casereportfiveyear pages 1-2, klimeczekchrapusta2024proteussyndromecase pages 2-5).
Cell type involvement (CL terms; examples) - CL:0000115 endothelial cell; CL:0000669 pericyte/mural cell; CL:0000057 fibroblast; CL:0000062 osteoblast; CL:0000136 adipocyte (mechanistic and histologic evidence in models and clinical tissues) (he2024humanvascularorganoids pages 14-17, lindhurst2019amousemodel pages 1-2, lindhurst2015repressionofakt pages 1-2, mirmomen2021cardiothoracicimagingfindings pages 1-2).
Anatomical locations (UBERON terms; examples) - UBERON:0004535 vasculature; UBERON:0002097 skin/dermis; UBERON:0001474 bone; UBERON:0002048 lung; UBERON:0002082 heart (imaging and pathology support) (mirmomen2021cardiothoracicimagingfindings pages 1-2, lindhurst2019amousemodel pages 1-2, ours2021casereportfiveyear pages 1-2).
Chemical entities (CHEBI names; examples) - Miransertib (ARQ‑092/MK‑7075; AKT inhibitor); Capivasertib (AKT inhibitor); Ipatasertib (AKT inhibitor); Sirolimus (mTOR inhibitor). Preclinical reversal of vascular phenotypes and clinical case benefits reported for AKT inhibition; sirolimus use reported with partial benefit (https://doi.org/10.1101/2024.01.26.577324, 2024-01-27; https://doi.org/10.1101/mcs.a006134, 2021-10-01; https://doi.org/10.1055/a-2300-7002, 2024-04-01) (he2024humanvascularorganoids pages 14-17, ours2021casereportfiveyear pages 1-2, klimeczekchrapusta2024proteussyndromecase pages 2-5).
Evidence items with PMIDs/DOIs/URLs - Lindhurst MJ et al. Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome. Scientific Reports. 2015-12-11. DOI: 10.1038/srep17162. URL: https://doi.org/10.1038/srep17162 (lindhurst2015repressionofakt pages 1-2). - Lindhurst MJ et al. A mouse model of Proteus syndrome. Human Molecular Genetics. 2019-09-01. DOI: 10.1093/hmg/ddz116. URL: https://doi.org/10.1093/hmg/ddz116 (lindhurst2019amousemodel pages 1-2, lindhurst2019amousemodel pages 14-15). - Mirmomen SM et al. Cardiothoracic imaging findings of Proteus syndrome. Scientific Reports. 2021-03-22. DOI: 10.1038/s41598-021-86029-0. URL: https://doi.org/10.1038/s41598-021-86029-0 (mirmomen2021cardiothoracicimagingfindings pages 1-2). - Ours CA et al. Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome. Cold Spring Harbor Molecular Case Studies. 2021-10-01. DOI: 10.1101/mcs.a006134. URL: https://doi.org/10.1101/mcs.a006134 (ours2021casereportfiveyear pages 1-2). - He S et al. Human vascular organoids with a mosaic AKT1 mutation recapitulate Proteus syndrome. bioRxiv. 2024-01-27. DOI: 10.1101/2024.01.26.577324. URL: https://doi.org/10.1101/2024.01.26.577324 (he2024humanvascularorganoids pages 14-17). - Klimeczek-Chrapusta MK et al. Proteus Syndrome: Case Report and Updated Literature Review. Archives of Plastic Surgery. 2024-04-01. DOI: 10.1055/a-2300-7002. URL: https://doi.org/10.1055/a-2300-7002 (klimeczekchrapusta2024proteussyndromecase pages 2-5). - Rostagni OM et al. Tumour spectrum in AKT1-related Proteus syndrome: a systematic review. Journal of Medical Genetics. 2025-12-01. DOI: 10.1136/jmg-2024-110173. URL: https://doi.org/10.1136/jmg-2024-110173 (rostagni2025tumourspectrumin pages 8-9).
Direct quotes supporting key statements - “A somatic activating mutation in AKT1, c.49G>A, pGlu17Lys… is responsible for the mosaic overgrowth condition, Proteus syndrome.” (https://doi.org/10.1038/srep17162, 2015-12-11) (lindhurst2015repressionofakt pages 1-2). - “Variant-positive cells can induce lesion formation in a non-cell autonomous manner.” (https://doi.org/10.1093/hmg/ddz116, 2019-09-01) (lindhurst2019amousemodel pages 14-15). - Thoracic phenotype prevalence: “scoliosis…94%, pulmonary venous dilation 62%, band-like areas of lung scarring 56%, hyperlucent lung parenchyma 50%… intramyocardial fat…45%.” (https://doi.org/10.1038/s41598-021-86029-0, 2021-03-22) (mirmomen2021cardiothoracicimagingfindings pages 1-2). - Organoid reversal with AKT inhibitors: “The application of AKT inhibitors (ARQ092, AZD5363, or GDC0068) reversed the vascular malformations” (https://doi.org/10.1101/2024.01.26.577324, 2024-01-27) (he2024humanvascularorganoids pages 14-17).
Notes and limitations - Some data on survival and tumor incidence derive from systematic review of case reports/series and may be influenced by ascertainment; nonetheless, they guide surveillance priorities (https://doi.org/10.1136/jmg-2024-110173, 2025-12-01) (rostagni2025tumourspectrumin pages 8-9).
Summary AKT1 p.E17K somatic mosaicism is the causal driver of Proteus syndrome, producing sustained PI3K→AKT→mTOR activation across endothelial, mural, mesenchymal, and epithelial compartments. Non–cell-autonomous propagation of pathway activation amplifies lesion formation. Vascular malformations and connective tissue overgrowth are core features, and cystic/emphysematous lung disease is progressive. AKT inhibition (miransertib) shows target engagement and encouraging case-level benefits; organoid models provide a translational platform linking AKT blockade to vascular normalization and supporting ongoing clinical trials (lindhurst2015repressionofakt pages 1-2, lindhurst2019amousemodel pages 1-2, lindhurst2019amousemodel pages 14-15, mirmomen2021cardiothoracicimagingfindings pages 1-2, he2024humanvascularorganoids pages 14-17, ours2021casereportfiveyear pages 1-2, rostagni2025tumourspectrumin pages 8-9, klimeczekchrapusta2024proteussyndromecase pages 2-5).
References
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(lindhurst2019amousemodel pages 1-2): Marjorie J Lindhurst, Lauren R Brinster, Hannah C Kondolf, Jasmine J Shwetar, Miranda R Yourick, Henoke Shiferaw, Kim M Keppler-Noreuil, Gene Elliot, Cecilia Rivas, Lisa Garrett, Julio Gomez-Rodriguez, Neil J Sebire, Stephen M Hewitt, Pamela L Schwartzberg, and Leslie G Biesecker. A mouse model of proteus syndrome. Human molecular genetics, 28:2920-2936, Sep 2019. URL: https://doi.org/10.1093/hmg/ddz116, doi:10.1093/hmg/ddz116. This article has 15 citations and is from a domain leading peer-reviewed journal.
(lindhurst2019amousemodel pages 14-15): Marjorie J Lindhurst, Lauren R Brinster, Hannah C Kondolf, Jasmine J Shwetar, Miranda R Yourick, Henoke Shiferaw, Kim M Keppler-Noreuil, Gene Elliot, Cecilia Rivas, Lisa Garrett, Julio Gomez-Rodriguez, Neil J Sebire, Stephen M Hewitt, Pamela L Schwartzberg, and Leslie G Biesecker. A mouse model of proteus syndrome. Human molecular genetics, 28:2920-2936, Sep 2019. URL: https://doi.org/10.1093/hmg/ddz116, doi:10.1093/hmg/ddz116. This article has 15 citations and is from a domain leading peer-reviewed journal.
(he2024humanvascularorganoids pages 14-17): Siyu He, Yuefei Zhu, Shradha Chauhan, Daniel Naveed Tavakol, Jong Ha Lee, Rayna Batya-Leia Berris, Cong Xu, Jounghyun H. Lee, Caleb Lee, Sarah Cai, Shannon McElroy, Gordana Vunjak-Novakovic, Raju Tomer, Elham Azizi, Bin Xu, Yeh-Hsing Lao, and Kam W. Leong. Human vascular organoids with a mosaic akt1 mutation recapitulate proteus syndrome. bioRxiv, Jan 2024. URL: https://doi.org/10.1101/2024.01.26.577324, doi:10.1101/2024.01.26.577324. This article has 3 citations and is from a poor quality or predatory journal.
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name: Proteus syndrome
creation_date: '2026-01-27T17:46:29Z'
updated_date: '2026-01-28T17:04:03Z'
category: Mendelian
parents: []
disease_term:
preferred_term: Proteus syndrome
term:
id: MONDO:0008318
label: Proteus syndrome
prevalence:
- population: Reported cases
percentage: Rare
notes: Approximately 250 cases documented in the literature over the past four decades.
evidence:
- reference: DOI:10.1186/s13023-023-03013-9
supports: SUPPORT
snippet: "Proteus syndrome is an ultra-rare mosaic overgrowth disorder."
explanation: This statement characterizes Proteus syndrome as ultra-rare.
- reference: DOI:10.1055/a-2300-7002
supports: SUPPORT
snippet: "Proteus syndrome (PS) is an exceptionally uncommon genetic disorder that has been documented in only approximately 250 cases in the literature spanning the past four decades."
explanation: This provides a literature-based estimate of reported case counts.
- population: Live births
percentage: 0.0001
notes: Estimated prevalence is less than 1 per 1,000,000 live births.
evidence:
- reference: PMID:33987133
reference_title: "Proteus Syndrome: A Rare Case in An Adult Ward."
supports: SUPPORT
snippet: "It has an estimated prevalence of less than 1/1,000,000 live births."
explanation: This case report provides a population prevalence estimate for Proteus syndrome.
epidemiology:
- name: Sex distribution in imaging cohort
description: Male predominance reported in a cardiothoracic imaging cohort.
unit: cases
notes: In a cohort of 38 imaged individuals, 23 were men.
evidence:
- reference: DOI:10.1038/s41598-021-86029-0
supports: SUPPORT
snippet: "Of 53 individuals with a confirmed diagnosis of Proteus syndrome at our institution from 10/2001 to 10/2019, 38 individuals (men, n = 23; average age = 24 years) underwent cardiothoracic imaging"
explanation: This cohort reports a male-predominant sex distribution among imaged individuals.
- name: Sex distribution in longitudinal cohort
description: Male predominance reported in a 64-patient natural history cohort.
unit: cases
notes: 36 males and 28 females in the cohort.
evidence:
- reference: PMID:28661492
reference_title: "Quantifying survival in patients with Proteus syndrome."
supports: SUPPORT
snippet: "There were 64 patients with Proteus syndrome identified in this study, 28 (43.8%) were female and 36 were male (56.3%)."
explanation: The longitudinal cohort reports a modest male predominance.
- name: Age in imaging cohort
description: Average age reported for the cardiothoracic imaging cohort.
mean_range: 24 years
unit: years
evidence:
- reference: DOI:10.1038/s41598-021-86029-0
supports: SUPPORT
snippet: "Of 53 individuals with a confirmed diagnosis of Proteus syndrome at our institution from 10/2001 to 10/2019, 38 individuals (men, n = 23; average age = 24 years) underwent cardiothoracic imaging"
explanation: The imaging cohort reports an average age of 24 years.
- name: Age at diagnosis
description: Median age at diagnosis in a natural history cohort.
mean_range: 19 months
unit: months
evidence:
- reference: PMID:28661492
reference_title: "Quantifying survival in patients with Proteus syndrome."
supports: SUPPORT
snippet: "The median age of diagnosis was 19 months."
explanation: The cohort analysis reports a median diagnosis age of 19 months.
pathophysiology:
- name: Somatic AKT1 p.E17K activation in mosaic cell clones
description: >
Proteus syndrome is caused by a post-zygotic activating AKT1 p.E17K
variant present in a mosaic subset of cells.
evidence:
- reference: DOI:10.1038/srep17162
supports: SUPPORT
snippet: "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."
explanation: This establishes mosaic, somatic AKT1 p.E17K activation in Proteus syndrome.
- name: Elevated PI3K/AKT signaling in AKT1-mutant cells
description: >
AKT1 p.E17K drives increased PI3K/AKT pathway activity in mutation-positive
cells, promoting downstream overgrowth signals.
biological_processes:
- preferred_term: phosphatidylinositol 3-kinase/protein kinase B signal transduction
term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
modifier: INCREASED
evidence:
- reference: DOI:10.1038/srep17162
supports: SUPPORT
snippet: "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."
explanation: This directly links AKT1 activation to elevated AKT signaling in mutation-positive cells.
- name: Increased pAKT signaling in AKT1-mutant lesion cells
description: >
Lesion cells harboring AKT1 p.E17K show increased pAKT signaling within
hyperplastic regions.
biological_processes:
- preferred_term: protein phosphorylation
term:
id: GO:0006468
label: protein phosphorylation
modifier: INCREASED
evidence:
- reference: DOI:10.1093/hmg/ddz116
supports: SUPPORT
snippet: "Identification of variant-positive cells by green fluorescent protein (GFP) staining in chimeric Proteus syndrome mice showed that in some lesions, hyperplastic cells were predominantly GFP/Akt1E17K-positive and showed increased pAKT signal compared to GFP-negative cells."
explanation: This demonstrates increased pAKT signaling in mutant clones within lesions.
- name: Non-cell-autonomous pAKT activation in adjacent cells
description: >
AKT1-mutant clones can induce increased pAKT signaling in nearby
mutation-negative cells, consistent with non-cell-autonomous lesion
propagation.
biological_processes:
- preferred_term: cell-cell signaling
term:
id: GO:0007267
label: cell-cell signaling
modifier: INCREASED
evidence:
- reference: DOI:10.1093/hmg/ddz116
supports: SUPPORT
snippet: "However, hyperplastic mammary epithelium was a mixture of GFP/Akt1E17K-positive and negative cells with some GFP/Akt1E17K-negative cells also having increased pAKT signal suggesting that the variant-positive cells can induce lesion formation in a non-cell autonomous manner."
explanation: This provides evidence for non-cell-autonomous effects in lesion formation.
- name: AKT overactivation induces excessive vasculogenesis
description: >
AKT1 activation increases vascular connectivity and promotes
vasculogenesis with enhanced vascular sprouting.
cell_types:
- preferred_term: endothelial cell
term:
id: CL:0000115
label: endothelial cell
biological_processes:
- preferred_term: vasculogenesis
term:
id: GO:0001570
label: vasculogenesis
modifier: INCREASED
- preferred_term: angiogenesis
term:
id: GO:0001525
label: angiogenesis
modifier: INCREASED
evidence:
- reference: DOI:10.1101/2024.01.26.577324
supports: SUPPORT
snippet: "Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections."
explanation: AKT overactivation increases vascular connectivity in organoid vasculature.
- reference: DOI:10.1101/2024.01.26.577324
supports: SUPPORT
snippet: "This could be due to the significant vasculogenesis induced by AKT overactivation."
explanation: The study explicitly links AKT overactivation to increased vasculogenesis.
- name: Mural cell dysfunction destabilizes vascular connections
description: >
AKT-driven vascular malformations include dysfunctional PDGFRβ+ mural
cells with impaired matrix secretion, contributing to unstable vessel
connections.
cell_types:
- preferred_term: pericyte
term:
id: CL:0000669
label: pericyte
biological_processes:
- preferred_term: extracellular matrix organization
term:
id: GO:0030198
label: extracellular matrix organization
modifier: DECREASED
evidence:
- reference: DOI:10.1101/2024.01.26.577324
supports: SUPPORT
snippet: "Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections."
explanation: AKT overactivation is linked to unstable vascular connections.
- reference: DOI:10.1101/2024.01.26.577324
supports: SUPPORT
snippet: "Additionally, a notable increase in dysfunctional PDGFRβ + mural cells, impaired in matrix secretion, was observed in these AKT-overactivated organoids."
explanation: This supports mural cell dysfunction as part of the vascular phenotype.
phenotypes:
- name: Overgrowth
category: Musculoskeletal
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Overgrowth
term:
id: HP:0001548
label: Overgrowth
evidence:
- reference: DOI:10.1093/hmg/ddz116
supports: SUPPORT
snippet: "Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors."
explanation: This highlights skin and bony overgrowth as common manifestations.
- reference: DOI:10.1055/a-2300-7002
supports: SUPPORT
snippet: "It is characterized by a disproportionate, asymmetric overgrowth of all types of tissues, provoked by a somatic activating mutation in serine/threonine protein kinase 1."
explanation: This describes the characteristic disproportionate overgrowth in Proteus syndrome.
- reference: PMID:22876373
reference_title: "Proteus Syndrome."
supports: SUPPORT
snippet: "Proteus syndrome (PS) is characterized by progressive segmental or patchy overgrowth most commonly affecting the skeleton, skin, adipose, and central nervous systems."
explanation: GeneReviews describes the hallmark progressive segmental overgrowth in Proteus syndrome.
- reference: PMID:33987133
reference_title: "Proteus Syndrome: A Rare Case in An Adult Ward."
supports: SUPPORT
snippet: "Proteus syndrome is an extremely rare disorder that manifests as an asymmetric, disproportionate overgrowth of any connective tissue, such as bone, fat or epidermal nevi, in a mosaic or patchy pattern."
explanation: This case report emphasizes disproportionate connective tissue overgrowth.
- name: Asymmetric growth
category: Growth
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Asymmetric growth
term:
id: HP:0100555
label: Asymmetric growth
evidence:
- reference: DOI:10.1055/a-2300-7002
supports: SUPPORT
snippet: "It is characterized by a disproportionate, asymmetric overgrowth of all types of tissues, provoked by a somatic activating mutation in serine/threonine protein kinase 1."
explanation: This explicitly describes asymmetric overgrowth as a defining feature.
- reference: PMID:33987133
reference_title: "Proteus Syndrome: A Rare Case in An Adult Ward."
supports: SUPPORT
snippet: "Proteus syndrome is an extremely rare disorder that manifests as an asymmetric, disproportionate overgrowth of any connective tissue, such as bone, fat or epidermal nevi, in a mosaic or patchy pattern."
explanation: This case report underscores asymmetric, disproportionate overgrowth.
- name: Venous malformation
category: Cardiovascular
frequency: FREQUENT
phenotype_term:
preferred_term: Venous malformation
term:
id: HP:0012721
label: Venous malformation
evidence:
- reference: DOI:10.1093/hmg/ddz116
supports: SUPPORT
snippet: "Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors."
explanation: This lists vascular malformations among common Proteus syndrome manifestations.
- reference: PMID:33987133
reference_title: "Proteus Syndrome: A Rare Case in An Adult Ward."
supports: SUPPORT
snippet: "Many individuals develop cutaneous capillary malformation and prominent varicosities (large and complex vascular malformations)."
explanation: This documents vascular malformations with prominent varicosities in Proteus syndrome.
- name: Cerebriform connective tissue nevus
category: Dermatologic
frequency: FREQUENT
phenotype_term:
preferred_term: Cerebriform connective tissue nevus
term:
id: HP:6000009
label: Cerebriform connective tissue nevus
evidence:
- reference: DOI:10.1101/mcs.a006134
supports: SUPPORT
snippet: "The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi."
explanation: This reports cerebriform connective tissue nevi in Proteus syndrome.
- reference: PMID:34668833
reference_title: "Proteus Syndrome: Case Report with Anatomopathological Correlation."
supports: SUPPORT
snippet: "The main histological findings are diffuse patchy overgrowth of skin and subcutaneous tissue, plantar cerebriform connective tissue nevus, and ossification defects."
explanation: The case report highlights cerebriform connective tissue nevi as a key histologic finding.
- name: Epidermal nevus
category: Dermatologic
frequency: FREQUENT
phenotype_term:
preferred_term: Epidermal nevus
term:
id: HP:0010816
label: Epidermal nevus
evidence:
- reference: PMID:33987133
reference_title: "Proteus Syndrome: A Rare Case in An Adult Ward."
supports: SUPPORT
snippet: "Proteus syndrome is an extremely rare disorder that manifests as an asymmetric, disproportionate overgrowth of any connective tissue, such as bone, fat or epidermal nevi, in a mosaic or patchy pattern."
explanation: This case report includes epidermal nevi among overgrowth manifestations.
- name: Capillary malformation
category: Cardiovascular
frequency: FREQUENT
phenotype_term:
preferred_term: Capillary malformation
term:
id: HP:0025104
label: Capillary malformation
evidence:
- reference: PMID:33987133
reference_title: "Proteus Syndrome: A Rare Case in An Adult Ward."
supports: SUPPORT
snippet: "Many individuals develop cutaneous capillary malformation and prominent varicosities (large and complex vascular malformations)."
explanation: This documents cutaneous capillary malformations in Proteus syndrome.
- name: Varicose veins
category: Cardiovascular
frequency: FREQUENT
phenotype_term:
preferred_term: Varicose veins
term:
id: HP:0002619
label: Varicose veins
evidence:
- reference: PMID:33987133
reference_title: "Proteus Syndrome: A Rare Case in An Adult Ward."
supports: SUPPORT
snippet: "Many individuals develop cutaneous capillary malformation and prominent varicosities (large and complex vascular malformations)."
explanation: Prominent varicosities are reported as part of Proteus syndrome vascular disease.
- name: Pain
category: Neurologic
frequency: OCCASIONAL
phenotype_term:
preferred_term: Pain
term:
id: HP:0012531
label: Pain
evidence:
- reference: DOI:10.1101/mcs.a006134
supports: SUPPORT
snippet: "The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi."
explanation: Pain is reported as a symptom improved with targeted therapy.
- name: Scoliosis
category: Musculoskeletal
frequency: FREQUENT
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: DOI:10.1038/s41598-021-86029-0
supports: SUPPORT
snippet: "The cardiothoracic findings of Proteus syndrome were diverse, but several were much more common and included: scoliosis from bony overgrowth (94%), pulmonary venous dilation (62%), band-like areas of lung scarring (56%), and hyperlucent lung parenchyma (50%)."
explanation: This provides cohort evidence for scoliosis due to bony overgrowth.
- name: Emphysema
category: Respiratory
frequency: OCCASIONAL
phenotype_term:
preferred_term: Emphysema
term:
id: HP:0002097
label: Emphysema
evidence:
- reference: DOI:10.1186/s13023-023-03013-9
supports: SUPPORT
snippet: "Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention."
explanation: This documents emphysematous lung changes in Proteus syndrome.
- name: Multiple pulmonary cysts
category: Respiratory
frequency: OCCASIONAL
phenotype_term:
preferred_term: Multiple pulmonary cysts
term:
id: HP:0005948
label: Multiple pulmonary cysts
evidence:
- reference: DOI:10.1186/s13023-023-03013-9
supports: SUPPORT
snippet: "Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention."
explanation: This supports cystic lung changes in Proteus syndrome.
- name: Deep vein thrombosis
category: Cardiovascular
frequency: FREQUENT
phenotype_term:
preferred_term: Deep venous thrombosis
term:
id: HP:0002625
label: Deep venous thrombosis
evidence:
- reference: PMID:22876373
reference_title: "Proteus Syndrome."
supports: SUPPORT
snippet: "It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism."
explanation: GeneReviews documents a predisposition to deep vein thrombosis in Proteus syndrome.
- reference: PMID:33987133
reference_title: "Proteus Syndrome: A Rare Case in An Adult Ward."
supports: SUPPORT
snippet: "Thus, Proteus syndrome patients are at risk of developing deep vein thrombosis and pulmonary embolism."
explanation: This case report confirms thrombotic risk in Proteus syndrome.
- name: Pulmonary embolism
category: Cardiovascular
frequency: FREQUENT
phenotype_term:
preferred_term: Pulmonary embolism
term:
id: HP:0002204
label: Pulmonary embolism
evidence:
- reference: PMID:22876373
reference_title: "Proteus Syndrome."
supports: SUPPORT
snippet: "It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism."
explanation: GeneReviews identifies pulmonary embolism as a complication in Proteus syndrome.
- reference: PMID:33987133
reference_title: "Proteus Syndrome: A Rare Case in An Adult Ward."
supports: SUPPORT
snippet: "Thus, Proteus syndrome patients are at risk of developing deep vein thrombosis and pulmonary embolism."
explanation: This case report reiterates risk of pulmonary embolism.
- name: Lipoma
category: Dermatologic
frequency: OCCASIONAL
phenotype_term:
preferred_term: Lipoma
term:
id: HP:0012032
label: Lipoma
evidence:
- reference: PMID:37692275
reference_title: "Lipomas: genetic basis of common skin lesions and their occurrence in rare diseases."
supports: SUPPORT
snippet: "Lipomas can run in families (familial multiple lipomatosis) or be a part of genetic syndromes such as PTEN hamartoma tumor syndrome, Proteus syndrome, and Pai syndrome."
explanation: This review lists lipomas as part of Proteus syndrome presentations.
- name: Limbal dermoid
category: Ophthalmologic
frequency: VERY_RARE
phenotype_term:
preferred_term: Limbal dermoid
term:
id: HP:0001140
label: Limbal dermoid
evidence:
- reference: PMID:36113118
reference_title: "Multimodal ocular imaging in Proteus syndrome."
supports: SUPPORT
snippet: "Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen."
explanation: This case report documents limbal dermoid in Proteus syndrome.
- name: Cataract
category: Ophthalmologic
frequency: VERY_RARE
phenotype_term:
preferred_term: Cataract
term:
id: HP:0000518
label: Cataract
evidence:
- reference: PMID:36113118
reference_title: "Multimodal ocular imaging in Proteus syndrome."
supports: SUPPORT
snippet: "Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen."
explanation: The report lists unilateral cataract among ophthalmic anomalies.
- name: Nystagmus
category: Ophthalmologic
frequency: VERY_RARE
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
evidence:
- reference: PMID:36113118
reference_title: "Multimodal ocular imaging in Proteus syndrome."
supports: SUPPORT
snippet: "Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen."
explanation: Bilateral nystagmus is reported in a Proteus syndrome patient.
- name: Myopia
category: Ophthalmologic
frequency: VERY_RARE
phenotype_term:
preferred_term: Myopia
term:
id: HP:0000545
label: Myopia
evidence:
- reference: PMID:36113118
reference_title: "Multimodal ocular imaging in Proteus syndrome."
supports: SUPPORT
snippet: "Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen."
explanation: Severe myopia is included among the ophthalmic anomalies.
- name: Optic disc drusen
category: Ophthalmologic
frequency: VERY_RARE
phenotype_term:
preferred_term: Optic disc drusen
term:
id: HP:0012426
label: Optic disc drusen
evidence:
- reference: PMID:36113118
reference_title: "Multimodal ocular imaging in Proteus syndrome."
supports: SUPPORT
snippet: "Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen."
explanation: Optic nerve head drusen are reported in a Proteus syndrome patient.
- name: Proptosis
category: Ophthalmologic
frequency: VERY_RARE
phenotype_term:
preferred_term: Proptosis
term:
id: HP:0000520
label: Proptosis
evidence:
- reference: PMID:37975355
reference_title: "Ophthalmic manifestations and treatments of proteus syndrome: a case report and systematic review."
supports: SUPPORT
snippet: "Her proptosis and vision impairment were relieved after Endoscope-Navigation system (ENS)-aided optic canal decompression."
explanation: This case report documents proptosis in Proteus syndrome.
- name: Visual impairment
category: Ophthalmologic
frequency: VERY_RARE
phenotype_term:
preferred_term: Visual impairment
term:
id: HP:0000505
label: Visual impairment
evidence:
- reference: PMID:37975355
reference_title: "Ophthalmic manifestations and treatments of proteus syndrome: a case report and systematic review."
supports: SUPPORT
snippet: "Her proptosis and vision impairment were relieved after Endoscope-Navigation system (ENS)-aided optic canal decompression."
explanation: Vision impairment is reported among ocular manifestations.
- name: Neoplasm
category: Oncologic
frequency: OCCASIONAL
phenotype_term:
preferred_term: Neoplasm
term:
id: HP:0002664
label: Neoplasm
evidence:
- reference: DOI:10.1136/jmg-2024-110173
supports: SUPPORT
snippet: "AKT1-related Proteus syndrome is an ultra-rare mosaic overgrowth disorder with tumour predisposition."
explanation: This systematic review establishes tumor predisposition in Proteus syndrome.
- reference: PMID:22876373
reference_title: "Proteus Syndrome."
supports: SUPPORT
snippet: "It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism."
explanation: GeneReviews notes association with a range of tumors.
- reference: PMID:38074478
reference_title: "Sinonasal Neuroendocrine Carcinoma in Adult Proteus Syndrome."
supports: SUPPORT
snippet: "We report a 35-year-old patient with PS, who underwent successful surgical removal of a well-differentiated SNEC obstructing his nasal cavity"
explanation: This case report documents sinonasal neuroendocrine carcinoma in Proteus syndrome.
biochemical: []
genetic:
- name: AKT1
association: Causative
notes: Somatic activating mosaic variant (c.49G>A, p.Glu17Lys); HGNC:391
evidence:
- reference: DOI:10.1038/srep17162
supports: SUPPORT
snippet: "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."
explanation: This identifies the causative somatic AKT1 variant.
- reference: DOI:10.1093/hmg/ddz116
supports: SUPPORT
snippet: "Proteus syndrome is a mosaic, progressive overgrowth disorder caused by a somatic activating variant c.49G > A p.(E17K) in AKT1."
explanation: This independently confirms the AKT1 p.E17K mosaic variant as the cause.
environmental: []
treatments:
- name: AKT inhibitor (miransertib/ARQ 092)
description: >-
Allosteric pan-AKT inhibitor used to suppress AKT signaling and evaluated
clinically for symptom and overgrowth control in Proteus syndrome.
evidence:
- reference: DOI:10.1038/srep17162
supports: SUPPORT
snippet: "ARQ 092 reduced phosphorylation of AKT and downstream targets of AKT in a concentration-dependent manner in as little as two hours."
explanation: This shows AKT pathway suppression by ARQ 092 in Proteus syndrome samples.
- reference: DOI:10.1101/mcs.a006134
supports: SUPPORT
snippet: "The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi."
explanation: This case report describes clinical benefit with miransertib (ARQ 092).
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
qualifiers:
- predicate:
preferred_term: therapeutic agent
term:
id: NCIT:C2259
label: Therapeutic Agent
value:
preferred_term: miransertib
term:
id: NCIT:C99172
label: Miransertib
- name: Surgical intervention
description: Surgical debulking or corrective procedures used to manage focal overgrowth and deformity.
evidence:
- reference: DOI:10.1055/a-2300-7002
supports: SUPPORT
snippet: "We report a case of PS in a two-year-old female patient with the following clinical features: unilateral overgrowth of connective tissue in the right buttock and right foot, where multiple surgeries were performed to achieve a desirable aesthetic outcome and ensure psychological comfort of the young patient."
explanation: This case report documents surgical intervention for overgrowth management.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
differential_diagnoses:
- name: Klippel-Trenaunay-Weber syndrome
description: >
Overgrowth with vascular malformations can resemble Proteus syndrome and
requires clinical and radiologic differentiation.
distinguishing_features:
- Capillary/venous malformations with limb hypertrophy and port-wine stains
- Typically lacks cerebriform connective tissue nevi
evidence:
- reference: PMID:25009745
reference_title: "Differential diagnoses of overgrowth syndromes: the most important clinical and radiological disease manifestations."
supports: SUPPORT
snippet: "In the current review, four overgrowth syndromes were characterized (Proteus syndrome, Klippel-Trenaunay-Weber syndrome, Madelung's disease, and neurofibromatosis type I) and illustrated using cases from our institution."
explanation: This review explicitly lists Klippel-Trenaunay-Weber syndrome alongside Proteus syndrome in differential evaluation of overgrowth syndromes.
- name: Madelung's disease (multiple symmetric lipomatosis)
disease_term:
preferred_term: multiple symmetric lipomatosis
term:
id: MONDO:0007908
label: multiple symmetric lipomatosis
description: >
Symmetric lipomatous overgrowth can resemble Proteus syndrome and should
be differentiated based on distribution and accompanying malformations.
distinguishing_features:
- Symmetric lipomatous masses rather than mosaic, segmental overgrowth
- Absence of cerebriform connective tissue nevi
evidence:
- reference: PMID:25009745
reference_title: "Differential diagnoses of overgrowth syndromes: the most important clinical and radiological disease manifestations."
supports: SUPPORT
snippet: "In the current review, four overgrowth syndromes were characterized (Proteus syndrome, Klippel-Trenaunay-Weber syndrome, Madelung's disease, and neurofibromatosis type I) and illustrated using cases from our institution."
explanation: This review includes Madelung's disease among Proteus syndrome differentials.
- name: Neurofibromatosis type I
disease_term:
preferred_term: neurofibromatosis type 1
term:
id: MONDO:0018975
label: neurofibromatosis type 1
description: >
Neurocutaneous overgrowth and benign tumors can overlap with Proteus
syndrome, but NF1 has distinct diagnostic features.
distinguishing_features:
- Cafe-au-lait macules and neurofibromas
- Lisch nodules and NF1 pathogenic variants
evidence:
- reference: PMID:25009745
reference_title: "Differential diagnoses of overgrowth syndromes: the most important clinical and radiological disease manifestations."
supports: SUPPORT
snippet: "In the current review, four overgrowth syndromes were characterized (Proteus syndrome, Klippel-Trenaunay-Weber syndrome, Madelung's disease, and neurofibromatosis type I) and illustrated using cases from our institution."
explanation: This review includes neurofibromatosis type I among overgrowth syndromes that overlap with Proteus syndrome.
- name: CLOVES syndrome
disease_term:
preferred_term: CLOVES syndrome
term:
id: MONDO:0013038
label: CLOVES syndrome
description: >
Segmental overgrowth with complex vascular and soft tissue malformations
can overlap with Proteus syndrome presentations.
distinguishing_features:
- Typically congenital, with lipomatous truncal overgrowth and vascular malformations
- PIK3CA-related overgrowth rather than AKT1 mosaic variant
evidence:
- reference: PMID:34668833
reference_title: "Proteus Syndrome: Case Report with Anatomopathological Correlation."
supports: SUPPORT
snippet: "Discussion: CLOVES syndrome, neurofibromatosis 1 or PTEN hamartoma tumor syndrome are partially superimposable entities to Proteus syndrome and may generate diagnostic doubt."
explanation: This case report lists CLOVES among overlapping entities in differential diagnosis.
- name: PTEN hamartoma tumor syndrome
disease_term:
preferred_term: PTEN hamartoma tumor syndrome
term:
id: MONDO:0017623
label: PTEN hamartoma tumor syndrome
description: >
PTEN-related overgrowth and hamartomatous features can mimic Proteus
syndrome, requiring molecular differentiation.
distinguishing_features:
- Germline PTEN variants with systemic hamartomas and cancer predisposition
- Macrocephaly and mucocutaneous findings typical of PHTS
evidence:
- reference: PMID:34668833
reference_title: "Proteus Syndrome: Case Report with Anatomopathological Correlation."
supports: SUPPORT
snippet: "Discussion: CLOVES syndrome, neurofibromatosis 1 or PTEN hamartoma tumor syndrome are partially superimposable entities to Proteus syndrome and may generate diagnostic doubt."
explanation: This case report highlights PTEN hamartoma tumor syndrome as a differential.
- reference: PMID:20301661
reference_title: "PTEN Hamartoma Tumor Syndrome."
supports: SUPPORT
snippet: "The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome."
explanation: GeneReviews links PTEN hamartoma tumor syndrome to PTEN-related Proteus/Proteus-like presentations.
- reference: PMID:40058215
reference_title: "A diagnostic challenge: A rare case of PTEN hamartoma of soft tissue of the mental region."
supports: SUPPORT
snippet: "PTEN hamartomas cause a variety of conditions, including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome."
explanation: This case report reiterates PTEN-related Proteus syndromes within the PTEN hamartoma spectrum.
- name: Bannayan-Riley-Ruvalcaba syndrome
disease_term:
preferred_term: Bannayan-Riley-Ruvalcaba syndrome
term:
id: MONDO:0007924
label: Bannayan-Riley-Ruvalcaba syndrome
description: >
PTEN-related overgrowth syndrome that can overlap with Proteus-like
features and should be distinguished by germline PTEN findings and classic
mucocutaneous/hamartomatous manifestations.
distinguishing_features:
- Macrocephaly with hamartomatous polyposis and lipomas
- Germline PTEN variants with systemic findings
evidence:
- reference: PMID:20301661
reference_title: "PTEN Hamartoma Tumor Syndrome."
supports: SUPPORT
snippet: "The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome."
explanation: GeneReviews includes BRRS within the PTEN hamartoma tumor syndrome spectrum relevant to Proteus differentials.
clinical_trials:
- name: NCT04316546
phase: PHASE_II
status: RECRUITING
description: Multi-cohort Phase 2 dose-escalation study of miransertib (MK-7075) in Proteus syndrome.
evidence:
- reference: clinicaltrials:NCT04316546
supports: SUPPORT
snippet: "To learn if miransertib is a safe and effective treatment for Proteus syndrome."
explanation: The trial objective confirms evaluation of miransertib for Proteus syndrome.
- name: NCT02594215
phase: PHASE_I
status: COMPLETED
description: Dose-finding study of MK-7075 (miransertib) in children and adults with Proteus syndrome.
evidence:
- reference: clinicaltrials:NCT02594215
supports: SUPPORT
snippet: "To determine the safety, tolerability, and recommended dose of MK-7075 in people with PS."
explanation: The trial objective defines dose-finding and safety assessment in Proteus syndrome.
- name: NCT03094832
phase: PHASE_I
status: TERMINATED
description: Phase 1/2 open-label study of oral miransertib (MK-7075) in PROS and Proteus syndrome (MOSAIC).
evidence:
- reference: clinicaltrials:NCT03094832
supports: SUPPORT
snippet: "This is an open label, Phase 1/2 study of oral miransertib (MK-7075) administered to participants at least 2 years of age with phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA)-related Overgrowth Spectrum (PROS) and Proteus Syndrome (PS) (MOSAIC)."
explanation: The trial summary describes the Phase 1/2 MOSAIC study including Proteus syndrome.
- name: NCT04980872
phase: PHASE_II
status: ACTIVE_NOT_RECRUITING
description: Extension study evaluating safety/tolerability of oral miransertib in PROS or Proteus syndrome.
evidence:
- reference: clinicaltrials:NCT04980872
supports: SUPPORT
snippet: "This is a study of the safety and tolerability of oral miransertib (MK-7075) administered to participants at least 2 years of age with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS) or Proteus Syndrome (PS)."
explanation: The study summary states the safety/tolerability focus for PROS or Proteus syndrome participants.
- name: NCT03317366
phase: NOT_APPLICABLE
status: UNKNOWN
description: Expanded access for ARQ 092 (miransertib) in overgrowth diseases or vascular anomalies with PI3K/AKT alterations.
evidence:
- reference: clinicaltrials:NCT03317366
supports: SUPPORT
snippet: "ARQ 092 is being investigated for patients with overgrowth diseases and/or vascular anomalies with genetic alterations of the PI3K/AKT pathway and may be available for patients who are ineligible for an ongoing ARQ 092 clinical trial or have other considerations that prevent access to ARQ 092 through an existing clinical trial."
explanation: The summary describes expanded access for PI3K/AKT-pathway overgrowth disorders including Proteus syndrome.
- name: NCT00001403
phase: NOT_APPLICABLE
status: RECRUITING
description: Natural history study of Proteus syndrome and related congenital overgrowth disorders.
evidence:
- reference: clinicaltrials:NCT00001403
supports: SUPPORT
snippet: "This study will examine rare congenital disorders that involve malformations and abnormal growth. It will focus on patients with Proteus syndrome, whose physical features are characterized by overgrowth, benign tumors of fatty tissue or blood vessels, asymmetric arms or legs, and large feet with very thick soles."
explanation: The study description states a natural history focus on Proteus syndrome.
datasets: []