Proteus syndrome

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Classifications

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Discussions and Knowledge Gaps

2

Does the non-cell-autonomous (paracrine) spread of pAKT activation from AKT1 p.E17K clones into adjacent mutation-negative cells, observed in Akt1E17K mouse chimeras, also operate in human Proteus syndrome lesions, or is lesion formation in humans predominantly cell-autonomous?

HUMAN MODEL MISMATCH OPEN gap_proteus_non_cell_autonomous_mouse_fidelity

Attached to

pathophysiology#Non-cell-autonomous pAKT activation in adjacent cells

The non-cell-autonomous branch is supported chiefly by mouse-chimera data (DOI:10.1093/hmg/ddz116), where hyperplastic mammary epithelium contained mutation-negative cells with increased pAKT. Whether the same paracrine amplification drives human overgrowth lesions is unconfirmed; the well-established human causal chain is somatic AKT1 p.E17K driving cell-autonomous PI3K/AKT activation. The distinction matters for lesion-margin behavior and for how completely a clone-directed therapy would need to reach mutation-negative cells.

Proposed experiments

Single-cell pAKT versus AKT1 allele fraction across human Proteus lesion margins

exp_proteus_human_lesion_paracrine_pakt

Quantify pAKT and AKT1 variant allele fraction at single-cell resolution across human Proteus lesion margins to test whether mutation-negative cells show elevated pAKT.

Show evidence (1 reference)

DOI:10.1093/hmg/ddz116 SUPPORT Model Organism

"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."

The non-cell-autonomous claim derives from mouse-chimera data; human validation is the open question.

Do the endothelial hyperconnectivity and PDGFRβ+ mural-cell dysfunction seen in mosaic-AKT1 iPSC vascular organoids reproduce the mechanism of human Proteus syndrome vascular malformations, given that the supporting data are from a preprint organoid model?

HUMAN MODEL MISMATCH OPEN gap_proteus_vascular_organoid_preprint_fidelity

Attached to

pathophysiology#AKT overactivation induces excessive vasculogenesis pathophysiology#Mural cell dysfunction destabilizes vascular connections

The endothelial/mural vascular branch is supported by an iPSC-derived vascular-organoid study available only as a bioRxiv preprint (DOI:10.1101/2024.01.26.577324). Organoids recapitulate PS-like network hyperconnectivity and mural-cell abnormalities and respond to AKT inhibitors, but the model's fidelity to human Proteus vascular malformation biology is unconfirmed and the data are not yet peer-reviewed. It is a useful mechanistic hypothesis, not established human pathophysiology.

Proposed experiments

Mural-cell coverage and endothelial junction stability in human Proteus vascular malformations

exp_proteus_human_vascular_malformation_mural

Characterize PDGFRβ+ mural-cell coverage and endothelial junction stability in resected human Proteus vascular malformations and compare with the organoid phenotype.

Show evidence (1 reference)

DOI:10.1101/2024.01.26.577324 SUPPORT In Vitro

"Additionally, a notable increase in dysfunctional PDGFRβ + mural cells, impaired in matrix secretion, was observed in these AKT-overactivated organoids."

The mural-cell dysfunction claim derives from a preprint organoid model; human tissue validation is the open question.

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Pathophysiology

6

Somatic AKT1 p.E17K activation in mosaic cell clones

Proteus syndrome is caused by a post-zygotic activating AKT1 p.E17K variant present in a mosaic subset of cells.

Downstream

Elevated PI3K/AKT signaling in AKT1-mutant cells

Increased pAKT signaling in AKT1-mutant lesion cells

Show evidence (1 reference)

DOI:10.1038/srep17162 SUPPORT

"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."

This establishes mosaic, somatic AKT1 p.E17K activation in Proteus syndrome.

Elevated PI3K/AKT signaling in AKT1-mutant cells

AKT1 p.E17K drives increased PI3K/AKT pathway activity in mutation-positive cells, promoting downstream overgrowth signals.

phosphatidylinositol 3-kinase/protein kinase B signal transduction GO:0043491 ↑ INCREASED

Downstream

Non-cell-autonomous pAKT activation in adjacent cells

AKT overactivation induces excessive vasculogenesis

Overgrowth

Asymmetric growth

Cerebriform connective tissue nevus

Epidermal nevus

Pain

Scoliosis

Emphysema

Multiple pulmonary cysts

Lipoma

Limbal dermoid

Cataract

Nystagmus

Myopia

Optic disc drusen

Proptosis

Visual impairment

Neoplasm

Show evidence (1 reference)

DOI:10.1038/srep17162 SUPPORT

"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."

This directly links AKT1 activation to elevated AKT signaling in mutation-positive cells.

Increased pAKT signaling in AKT1-mutant lesion cells

Lesion cells harboring AKT1 p.E17K show increased pAKT signaling within hyperplastic regions.

protein phosphorylation GO:0006468 ↑ INCREASED

Show evidence (1 reference)

DOI:10.1093/hmg/ddz116 SUPPORT Model Organism

"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."

This demonstrates increased pAKT signaling in mutant clones within lesions.

Non-cell-autonomous pAKT activation in adjacent cells

AKT1-mutant clones can induce increased pAKT signaling in nearby mutation-negative cells, consistent with non-cell-autonomous lesion propagation. This branch rests chiefly on mouse-chimera model evidence and remains a mechanistic hypothesis whose fidelity to human disease is not yet established (see discussions).

cell-cell signaling GO:0007267 ↑ INCREASED

Show evidence (1 reference)

DOI:10.1093/hmg/ddz116 SUPPORT Model Organism

"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."

This provides evidence for non-cell-autonomous effects in lesion formation.

AKT overactivation induces excessive vasculogenesis

AKT1 activation increases vascular connectivity and promotes vasculogenesis with enhanced vascular sprouting. Support comes from an iPSC-derived vascular-organoid preprint, so this branch should be read as emerging/model-based rather than established in human tissue (see discussions).

endothelial cell CL:0000115

vasculogenesis GO:0001570 ↑ INCREASED angiogenesis GO:0001525 ↑ INCREASED

Downstream

Mural cell dysfunction destabilizes vascular connections

Venous malformation

Capillary malformation

Varicose veins

Show evidence (2 references)

DOI:10.1101/2024.01.26.577324 SUPPORT In Vitro

"Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections."

AKT overactivation increases vascular connectivity in organoid vasculature.

DOI:10.1101/2024.01.26.577324 SUPPORT In Vitro

"This could be due to the significant vasculogenesis induced by AKT overactivation."

The study explicitly links AKT overactivation to increased vasculogenesis.

Mural cell dysfunction destabilizes vascular connections

AKT-driven vascular malformations include dysfunctional PDGFRβ+ mural cells with impaired matrix secretion, contributing to unstable vessel connections. This is emerging/model-based support from an iPSC vascular-organoid preprint and is not yet confirmed in human tissue (see discussions).

pericyte CL:0000669

extracellular matrix organization GO:0030198 ↓ DECREASED

Downstream

Deep vein thrombosis

Pulmonary embolism

Show evidence (2 references)

DOI:10.1101/2024.01.26.577324 SUPPORT In Vitro

"Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections."

AKT overactivation is linked to unstable vascular connections.

DOI:10.1101/2024.01.26.577324 SUPPORT In Vitro

"Additionally, a notable increase in dysfunctional PDGFRβ + mural cells, impaired in matrix secretion, was observed in these AKT-overactivated organoids."

This supports mural cell dysfunction as part of the vascular phenotype.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

25

Blood 1

Deep vein thrombosis FREQUENT Deep venous thrombosis HP:0002625

Show evidence (2 references)

PMID:22876373 SUPPORT

"It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism."

GeneReviews documents a predisposition to deep vein thrombosis in Proteus syndrome.

PMID:33987133 SUPPORT

"Thus, Proteus syndrome patients are at risk of developing deep vein thrombosis and pulmonary embolism."

This case report confirms thrombotic risk in Proteus syndrome.

Cardiovascular 3

Venous malformation FREQUENT Venous malformation HP:0012721

Show evidence (2 references)

DOI:10.1093/hmg/ddz116 SUPPORT

"Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors."

This lists vascular malformations among common Proteus syndrome manifestations.

PMID:33987133 SUPPORT

"Many individuals develop cutaneous capillary malformation and prominent varicosities (large and complex vascular malformations)."

This documents vascular malformations with prominent varicosities in Proteus syndrome.

Varicose veins FREQUENT Varicose veins HP:0002619

Show evidence (1 reference)

PMID:33987133 SUPPORT

"Many individuals develop cutaneous capillary malformation and prominent varicosities (large and complex vascular malformations)."

Prominent varicosities are reported as part of Proteus syndrome vascular disease.

Pulmonary embolism FREQUENT Pulmonary embolism HP:0002204

Show evidence (2 references)

PMID:22876373 SUPPORT

"It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism."

GeneReviews identifies pulmonary embolism as a complication in Proteus syndrome.

PMID:33987133 SUPPORT

"Thus, Proteus syndrome patients are at risk of developing deep vein thrombosis and pulmonary embolism."

This case report reiterates risk of pulmonary embolism.

Eye 7

Limbal dermoid VERY_RARE Limbal dermoid HP:0001140

Show evidence (1 reference)

PMID:36113118 SUPPORT

"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."

This case report documents limbal dermoid in Proteus syndrome.

Cataract VERY_RARE Cataract HP:0000518

Show evidence (1 reference)

PMID:36113118 SUPPORT

"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."

The report lists unilateral cataract among ophthalmic anomalies.

Nystagmus VERY_RARE Nystagmus HP:0000639

Show evidence (1 reference)

PMID:36113118 SUPPORT

"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."

Bilateral nystagmus is reported in a Proteus syndrome patient.

Myopia VERY_RARE Myopia HP:0000545

Show evidence (1 reference)

PMID:36113118 SUPPORT

"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."

Severe myopia is included among the ophthalmic anomalies.

Optic disc drusen VERY_RARE Optic disc drusen HP:0012426

Show evidence (1 reference)

PMID:36113118 SUPPORT

"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."

Optic nerve head drusen are reported in a Proteus syndrome patient.

Proptosis VERY_RARE Proptosis HP:0000520

Show evidence (1 reference)

PMID:37975355 SUPPORT

"Her proptosis and vision impairment were relieved after Endoscope-Navigation system (ENS)-aided optic canal decompression."

This case report documents proptosis in Proteus syndrome.

Visual impairment VERY_RARE Visual impairment HP:0000505

Show evidence (1 reference)

PMID:37975355 SUPPORT

"Her proptosis and vision impairment were relieved after Endoscope-Navigation system (ENS)-aided optic canal decompression."

Vision impairment is reported among ocular manifestations.

Integument 2

Epidermal nevus FREQUENT Epidermal nevus HP:0010816

Show evidence (1 reference)

PMID:33987133 SUPPORT

"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."

This case report includes epidermal nevi among overgrowth manifestations.

Capillary malformation FREQUENT Capillary malformation HP:0025104

Show evidence (1 reference)

PMID:33987133 SUPPORT

"Many individuals develop cutaneous capillary malformation and prominent varicosities (large and complex vascular malformations)."

This documents cutaneous capillary malformations in Proteus syndrome.

Musculoskeletal 3

Cerebriform connective tissue nevus FREQUENT Cerebriform connective tissue nevus HP:6000009

Show evidence (2 references)

DOI:10.1101/mcs.a006134 SUPPORT

"The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi."

This reports cerebriform connective tissue nevi in Proteus syndrome.

PMID:34668833 SUPPORT

"The main histological findings are diffuse patchy overgrowth of skin and subcutaneous tissue, plantar cerebriform connective tissue nevus, and ossification defects."

The case report highlights cerebriform connective tissue nevi as a key histologic finding.

Scoliosis FREQUENT Scoliosis HP:0002650

Show evidence (1 reference)

DOI:10.1038/s41598-021-86029-0 SUPPORT

"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%)."

This provides cohort evidence for scoliosis due to bony overgrowth.

Lipoma OCCASIONAL Lipoma HP:0012032

Show evidence (1 reference)

PMID:37692275 SUPPORT

"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."

This review lists lipomas as part of Proteus syndrome presentations.

Respiratory 3

Emphysema OCCASIONAL Emphysema HP:0002097

Show evidence (1 reference)

DOI:10.1186/s13023-023-03013-9 SUPPORT

"Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention."

This documents emphysematous lung changes in Proteus syndrome.

Multiple pulmonary cysts OCCASIONAL Multiple pulmonary cysts HP:0005948

Show evidence (1 reference)

DOI:10.1186/s13023-023-03013-9 SUPPORT

"Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention."

This supports cystic lung changes in Proteus syndrome.

Band-like lung scarring FREQUENT Pulmonary fibrosis HP:0002206

Show evidence (1 reference)

DOI:10.1038/s41598-021-86029-0 SUPPORT Human Clinical

"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%)."

The imaging cohort reports band-like lung scarring in 56% of individuals.

Constitutional 1

Pain OCCASIONAL Pain HP:0012531

Show evidence (1 reference)

DOI:10.1101/mcs.a006134 SUPPORT

"The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi."

Pain is reported as a symptom improved with targeted therapy.

Growth 2

Overgrowth VERY_FREQUENT Overgrowth HP:0001548

Show evidence (4 references)

DOI:10.1093/hmg/ddz116 SUPPORT

"Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors."

This highlights skin and bony overgrowth as common manifestations.

DOI:10.1055/a-2300-7002 SUPPORT

"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."

This describes the characteristic disproportionate overgrowth in Proteus syndrome.

PMID:22876373 SUPPORT

"Proteus syndrome (PS) is characterized by progressive segmental or patchy overgrowth most commonly affecting the skeleton, skin, adipose, and central nervous systems."

GeneReviews describes the hallmark progressive segmental overgrowth in Proteus syndrome.

+ 1 more reference

Asymmetric growth VERY_FREQUENT Asymmetric growth HP:0100555

Show evidence (2 references)

DOI:10.1055/a-2300-7002 SUPPORT

"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."

This explicitly describes asymmetric overgrowth as a defining feature.

PMID:33987133 SUPPORT

"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."

This case report underscores asymmetric, disproportionate overgrowth.

Neoplasm 1

Neoplasm OCCASIONAL Neoplasm HP:0002664

Show evidence (3 references)

DOI:10.1136/jmg-2024-110173 SUPPORT

"AKT1-related Proteus syndrome is an ultra-rare mosaic overgrowth disorder with tumour predisposition."

This systematic review establishes tumor predisposition in Proteus syndrome.

PMID:22876373 SUPPORT

"It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism."

GeneReviews notes association with a range of tumors.

PMID:38074478 SUPPORT

"We report a 35-year-old patient with PS, who underwent successful surgical removal of a well-differentiated SNEC obstructing his nasal cavity"

This case report documents sinonasal neuroendocrine carcinoma in Proteus syndrome.

Other 2

Pulmonary venous dilation FREQUENT Abnormal pulmonary vein morphology HP:0030968

Show evidence (1 reference)

DOI:10.1038/s41598-021-86029-0 SUPPORT Human Clinical

"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%)."

The imaging cohort reports pulmonary venous dilation in 62% of individuals.

Intramyocardial fat FREQUENT Abnormal myocardium morphology HP:0001637

Show evidence (1 reference)

DOI:10.1038/s41598-021-86029-0 SUPPORT Human Clinical

"of 20 individuals who underwent cardiac MRI, 9/20 (45%) had intramyocardial fat, mostly involving the endocardial surface of the left ventricular septal wall"

Cardiac MRI identified intramyocardial fat in 45% of imaged individuals.

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Genetic Associations

1

AKT1 (Causative)

Gene: AKT1 hgnc:391

Show evidence (2 references)

DOI:10.1038/srep17162 SUPPORT

"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."

This identifies the causative somatic AKT1 variant.

DOI:10.1093/hmg/ddz116 SUPPORT

"Proteus syndrome is a mosaic, progressive overgrowth disorder caused by a somatic activating variant c.49G > A p.(E17K) in AKT1."

This independently confirms the AKT1 p.E17K mosaic variant as the cause.

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Medical Actions

4

Multidisciplinary supportive and orthopedic management

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Standard of care. Because no disease-modifying therapy is established, management is phenotype-directed and multidisciplinary: orthopedic procedures to delay or halt linear bone growth and correct skeletal deformities such as scoliosis, rehabilitation medicine with physical and occupational therapy, dermatologic management of skin lesions (including the cerebriform connective tissue nevi), and pulmonary care for bullous lung disease.

Show evidence (1 reference)

PMID:22876373 SUPPORT Human Clinical

"Management of overgrowth including orthopedic procedures to delay or halt linear bone growth; rehabilitation medicine care including physical and occupational therapy; correction of skeletal deformities such as scoliosis; dermatologic management of the skin manifestations, especially the..."

GeneReviews establishes the standard multidisciplinary, phenotype-directed management of Proteus syndrome.

Surgical intervention

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Standard phenotype-directed care. Surgical debulking or corrective procedures are used to manage focal overgrowth and deformity.

Show evidence (1 reference)

DOI:10.1055/a-2300-7002 SUPPORT Human Clinical

"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..."

This case report documents surgical intervention for overgrowth management.

Thromboembolism surveillance and prophylaxis

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Standard of care and a key surveillance priority. Deep vein thrombosis and pulmonary embolism are leading causes of morbidity and mortality in Proteus syndrome, so evaluation and treatment of thromboembolism (including perioperative prophylaxis) is essential, and procoagulant medications should be avoided.

Show evidence (1 reference)

PMID:22876373 SUPPORT Human Clinical

"Agents/circumstances to avoid: Medications that increase the risk of deep vein thrombosis or are procoagulant; medications that increase growth (e.g., androgenic steroids, growth hormone)."

GeneReviews specifies avoidance of procoagulant medications given the thromboembolic predisposition.

AKT inhibitor (miransertib/ARQ 092)

Action: Pharmacotherapy NCIT:C15986

Agent: miransertib NCIT:C99172

Investigational, pathway-directed therapy — not an established disease-modifying standard of care. The allosteric pan-AKT inhibitor miransertib suppresses AKT signaling and has target-engagement, single-case, and organoid support, and is under evaluation in clinical trials, but its disease-modifying benefit in Proteus syndrome is not yet established.

Show evidence (2 references)

DOI:10.1038/srep17162 SUPPORT In Vitro

"ARQ 092 reduced phosphorylation of AKT and downstream targets of AKT in a concentration-dependent manner in as little as two hours."

This shows AKT pathway suppression by ARQ 092 in Proteus syndrome cells (target engagement).

DOI:10.1101/mcs.a006134 SUPPORT Human Clinical

"The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi."

This single case report describes symptomatic benefit with miransertib (ARQ 092).

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Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Proteus syndrome:

Klippel-Trenaunay-Weber syndrome

Overlapping Features 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

Show evidence (1 reference)

PMID:25009745 SUPPORT

"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."

This review explicitly lists Klippel-Trenaunay-Weber syndrome alongside Proteus syndrome in differential evaluation of overgrowth syndromes.

Madelung's disease (multiple symmetric lipomatosis) Not Yet Curated MONDO:0007908

Overlapping Features 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

Show evidence (1 reference)

PMID:25009745 SUPPORT

"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."

This review includes Madelung's disease among Proteus syndrome differentials.

Neurofibromatosis type I MONDO:0018975

Overlapping Features 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

Show evidence (1 reference)

PMID:25009745 SUPPORT

"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."

This review includes neurofibromatosis type I among overgrowth syndromes that overlap with Proteus syndrome.

CLOVES syndrome MONDO:0013038

Overlapping Features 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

Show evidence (1 reference)

PMID:34668833 SUPPORT

"Discussion: CLOVES syndrome, neurofibromatosis 1 or PTEN hamartoma tumor syndrome are partially superimposable entities to Proteus syndrome and may generate diagnostic doubt."

This case report lists CLOVES among overlapping entities in differential diagnosis.

PTEN hamartoma tumor syndrome MONDO:0017623

Overlapping Features 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

Show evidence (3 references)

PMID:34668833 SUPPORT

"Discussion: CLOVES syndrome, neurofibromatosis 1 or PTEN hamartoma tumor syndrome are partially superimposable entities to Proteus syndrome and may generate diagnostic doubt."

This case report highlights PTEN hamartoma tumor syndrome as a differential.

PMID:20301661 SUPPORT

"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."

GeneReviews links PTEN hamartoma tumor syndrome to PTEN-related Proteus/Proteus-like presentations.

PMID:40058215 SUPPORT

"PTEN hamartomas cause a variety of conditions, including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome."

This case report reiterates PTEN-related Proteus syndromes within the PTEN hamartoma spectrum.

Bannayan-Riley-Ruvalcaba syndrome Not Yet Curated MONDO:0007924

Overlapping Features 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

Show evidence (1 reference)

PMID:20301661 SUPPORT

"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."

GeneReviews includes BRRS within the PTEN hamartoma tumor syndrome spectrum relevant to Proteus differentials.

🔬

Clinical Trials

6

NCT04316546 PHASE_II RECRUITING

Multi-cohort Phase 2 dose-escalation study of miransertib (MK-7075) in Proteus syndrome.

Show evidence (1 reference)

clinicaltrials:NCT04316546 SUPPORT

"To learn if miransertib is a safe and effective treatment for Proteus syndrome."

The trial objective confirms evaluation of miransertib for Proteus syndrome.

NCT02594215 PHASE_I COMPLETED

Dose-finding study of MK-7075 (miransertib) in children and adults with Proteus syndrome.

Show evidence (1 reference)

clinicaltrials:NCT02594215 SUPPORT

"To determine the safety, tolerability, and recommended dose of MK-7075 in people with PS."

The trial objective defines dose-finding and safety assessment in Proteus syndrome.

NCT03094832 PHASE_I TERMINATED

Phase 1/2 open-label study of oral miransertib (MK-7075) in PROS and Proteus syndrome (MOSAIC).

Show evidence (1 reference)

clinicaltrials:NCT03094832 SUPPORT

"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)."

The trial summary describes the Phase 1/2 MOSAIC study including Proteus syndrome.

NCT04980872 PHASE_II ACTIVE_NOT_RECRUITING

Extension study evaluating safety/tolerability of oral miransertib in PROS or Proteus syndrome.

Show evidence (1 reference)

clinicaltrials:NCT04980872 SUPPORT

"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)."

The study summary states the safety/tolerability focus for PROS or Proteus syndrome participants.

NCT03317366 NOT_APPLICABLE UNKNOWN

Expanded access for ARQ 092 (miransertib) in overgrowth diseases or vascular anomalies with PI3K/AKT alterations.

Show evidence (1 reference)

clinicaltrials:NCT03317366 SUPPORT

"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..."

The summary describes expanded access for PI3K/AKT-pathway overgrowth disorders including Proteus syndrome.

NCT00001403 NOT_APPLICABLE RECRUITING

Observational natural-history study (non-therapeutic) of Proteus syndrome and related congenital overgrowth disorders; it characterizes disease course and does not evaluate a treatment.

Show evidence (1 reference)

clinicaltrials:NCT00001403 SUPPORT

"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..."

The study description states a natural history focus on Proteus syndrome.

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name: Proteus syndrome
synonyms:
- Proteus syndrome, AKT1-related
creation_date: '2026-01-27T17:46:29Z'
updated_date: '2026-05-07T00:00:00Z'
description: >-
  Proteus syndrome is a rare mosaic overgrowth disorder caused by a postzygotic
  activating mutation in AKT1 (classically the c.49G>A, p.Glu17Lys variant) that
  constitutively activates the PI3K-AKT-mTOR growth-signaling pathway in a subset
  of cells. Because the mutation arises after conception, only mosaic tissues are
  affected, producing the characteristic asymmetric, progressive, and
  disproportionate overgrowth of bone, connective tissue, skin, and adipose
  tissue. Hallmark features include cerebriform connective tissue nevi,
  epidermal nevi, vascular malformations, lipomatous overgrowth, and a
  predisposition to thrombosis, with severity dictated by the distribution of the
  mutant cell clone.
category: Mendelian
parents: []
disease_term:
  preferred_term: Proteus syndrome
  term:
    id: MONDO:0008318
    label: Proteus syndrome
classifications:
  isds_skeletal_category:
  - classification_value: overgrowth_syndromes_with_skeletal_involvement
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 30 "Overgrowth (tall
      stature) syndromes with skeletal involvement"; listed as "Proteus syndrome".
prevalence:
- population: Reported cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  percentage: Rare
  notes: Approximately 250 cases documented in the literature over the past four decades.
  evidence:
  - reference: DOI:10.1186/s13023-023-03013-9
    reference_title: "Quantification of Proteus syndrome-associated lung disease"
    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
    reference_title: "Proteus Syndrome: Case Report and Updated Literature Review"
    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
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.1
  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
    reference_title: "Cardiothoracic imaging findings of Proteus syndrome"
    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
    reference_title: "Cardiothoracic imaging findings of Proteus syndrome"
    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.
- name: Premature mortality risk
  description: >-
    Kaplan-Meier survival analysis shows substantial premature mortality that is
    concentrated in the pediatric age range.
  unit: probability
  notes: >-
    25% probability of death by 22 years of age, with nearly all deaths occurring
    before age 22 — underscoring the need for pediatric surveillance of
    life-threatening complications such as thromboembolism.
  evidence:
  - reference: PMID:28661492
    reference_title: "Quantifying survival in patients with Proteus syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on this analysis, there was 25% probability of death by 22 years of age."
    explanation: Quantifies premature mortality risk in Proteus syndrome.
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
    reference_title: "Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome"
    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.
  downstream:
  - target: Elevated PI3K/AKT signaling in AKT1-mutant cells
    causal_link_type: DIRECT
  - target: Increased pAKT signaling in AKT1-mutant lesion cells
    causal_link_type: DIRECT
- 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
    reference_title: "Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome"
    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.
  downstream:
  - target: Non-cell-autonomous pAKT activation in adjacent cells
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: AKT overactivation induces excessive vasculogenesis
    causal_link_type: DIRECT
  - target: Overgrowth
    causal_link_type: DIRECT
  - target: Asymmetric growth
    causal_link_type: DIRECT
  - target: Cerebriform connective tissue nevus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Epidermal nevus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Emphysema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Multiple pulmonary cysts
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Lipoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Limbal dermoid
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cataract
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Nystagmus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Myopia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Optic disc drusen
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Proptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Visual impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Neoplasm
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- 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
    reference_title: "A mouse model of Proteus syndrome"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    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. This branch rests chiefly on mouse-chimera model evidence and
    remains a mechanistic hypothesis whose fidelity to human disease is not yet
    established (see discussions).
  biological_processes:
  - preferred_term: cell-cell signaling
    term:
      id: GO:0007267
      label: cell-cell signaling
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1093/hmg/ddz116
    reference_title: "A mouse model of Proteus syndrome"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    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. Support comes from an
    iPSC-derived vascular-organoid preprint, so this branch should be read as
    emerging/model-based rather than established in human tissue (see
    discussions).
  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
    reference_title: "Human vascular organoids with a mosaic <i>AKT1</i> mutation recapitulate Proteus syndrome"
    supports: SUPPORT
    evidence_source: IN_VITRO
    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
    reference_title: "Human vascular organoids with a mosaic <i>AKT1</i> mutation recapitulate Proteus syndrome"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This could be due to the significant vasculogenesis induced by AKT overactivation."
    explanation: The study explicitly links AKT overactivation to increased vasculogenesis.
  downstream:
  - target: Mural cell dysfunction destabilizes vascular connections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Venous malformation
    causal_link_type: DIRECT
  - target: Capillary malformation
    causal_link_type: DIRECT
  - target: Varicose veins
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- 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. This is emerging/model-based support from an iPSC vascular-organoid
    preprint and is not yet confirmed in human tissue (see discussions).
  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
    reference_title: "Human vascular organoids with a mosaic <i>AKT1</i> mutation recapitulate Proteus syndrome"
    supports: SUPPORT
    evidence_source: IN_VITRO
    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
    reference_title: "Human vascular organoids with a mosaic <i>AKT1</i> mutation recapitulate Proteus syndrome"
    supports: SUPPORT
    evidence_source: IN_VITRO
    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.
  downstream:
  - target: Deep vein thrombosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pulmonary embolism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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
    reference_title: "A mouse model of Proteus syndrome"
    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
    reference_title: "Proteus Syndrome: Case Report and Updated Literature Review"
    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
    reference_title: "Proteus Syndrome: Case Report and Updated Literature Review"
    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
    reference_title: "A mouse model of Proteus syndrome"
    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
    reference_title: "Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome"
    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
    reference_title: "Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome"
    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
    reference_title: "Cardiothoracic imaging findings of Proteus syndrome"
    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
    reference_title: "Quantification of Proteus syndrome-associated lung disease"
    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
    reference_title: "Quantification of Proteus syndrome-associated lung disease"
    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: Pulmonary venous dilation
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Dilation of the pulmonary veins is the second most common cardiothoracic
    imaging finding after scoliosis in Proteus syndrome.
  phenotype_term:
    preferred_term: Pulmonary venous dilation
    term:
      id: HP:0030968
      label: Abnormal pulmonary vein morphology
  evidence:
  - reference: DOI:10.1038/s41598-021-86029-0
    reference_title: "Cardiothoracic imaging findings of Proteus syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: The imaging cohort reports pulmonary venous dilation in 62% of individuals.
- name: Band-like lung scarring
  category: Respiratory
  frequency: FREQUENT
  description: >-
    Band-like areas of lung scarring are a common cardiothoracic imaging finding
    in Proteus syndrome.
  phenotype_term:
    preferred_term: Band-like lung scarring
    term:
      id: HP:0002206
      label: Pulmonary fibrosis
  evidence:
  - reference: DOI:10.1038/s41598-021-86029-0
    reference_title: "Cardiothoracic imaging findings of Proteus syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: The imaging cohort reports band-like lung scarring in 56% of individuals.
- name: Intramyocardial fat
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Intramyocardial fat, mostly involving the left ventricular septal wall, was
    seen on cardiac MRI in a large Proteus syndrome imaging cohort, generally
    without functional consequence.
  phenotype_term:
    preferred_term: Intramyocardial fat
    term:
      id: HP:0001637
      label: Abnormal myocardium morphology
  evidence:
  - reference: DOI:10.1038/s41598-021-86029-0
    reference_title: "Cardiothoracic imaging findings of Proteus syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of 20 individuals who underwent cardiac MRI, 9/20 (45%) had intramyocardial fat, mostly involving the endocardial surface of the left ventricular septal wall"
    explanation: Cardiac MRI identified intramyocardial fat in 45% of imaged individuals.
- name: Deep vein thrombosis
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    A striking thromboembolic predisposition; deep vein thrombosis (with
    pulmonary embolism) is a leading cause of premature mortality in Proteus
    syndrome and warrants active surveillance and perioperative prophylaxis.
  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
  description: >-
    Pulmonary embolism, often arising from deep vein thrombosis, is a major
    cause of morbidity and premature death in Proteus syndrome and is a priority
    for surveillance and thromboprophylaxis, especially perioperatively.
  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
    reference_title: "Tumour spectrum in <i>AKT1</i>-related Proteus syndrome: a systematic review of clinical reports and series"
    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
  gene_term:
    preferred_term: AKT1
    term:
      id: hgnc:391
      label: AKT1
  notes: Somatic activating mosaic variant (c.49G>A, p.Glu17Lys); HGNC:391
  evidence:
  - reference: DOI:10.1038/srep17162
    reference_title: "Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome"
    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
    reference_title: "A mouse model of Proteus syndrome"
    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: Multidisciplinary supportive and orthopedic management
  description: >-
    Standard of care. Because no disease-modifying therapy is established,
    management is phenotype-directed and multidisciplinary: orthopedic procedures
    to delay or halt linear bone growth and correct skeletal deformities such as
    scoliosis, rehabilitation medicine with physical and occupational therapy,
    dermatologic management of skin lesions (including the cerebriform connective
    tissue nevi), and pulmonary care for bullous lung disease.
  evidence:
  - reference: PMID:22876373
    reference_title: "Proteus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Management of overgrowth including orthopedic procedures to delay or halt
      linear bone growth; rehabilitation medicine care including physical and
      occupational therapy; correction of skeletal deformities such as scoliosis;
      dermatologic management of the skin manifestations, especially the
      cerebriform connective tissue nevi with pedorthic intervention as needed;
      surgery as needed for lipomatous overgrowth
    explanation: >-
      GeneReviews establishes the standard multidisciplinary, phenotype-directed
      management of Proteus syndrome.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Surgical intervention
  description: >-
    Standard phenotype-directed care. Surgical debulking or corrective procedures
    are used to manage focal overgrowth and deformity.
  evidence:
  - reference: DOI:10.1055/a-2300-7002
    reference_title: "Proteus Syndrome: Case Report and Updated Literature Review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Thromboembolism surveillance and prophylaxis
  description: >-
    Standard of care and a key surveillance priority. Deep vein thrombosis and
    pulmonary embolism are leading causes of morbidity and mortality in Proteus
    syndrome, so evaluation and treatment of thromboembolism (including
    perioperative prophylaxis) is essential, and procoagulant medications should
    be avoided.
  evidence:
  - reference: PMID:22876373
    reference_title: "Proteus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: Medications that increase the risk of deep
      vein thrombosis or are procoagulant; medications that increase growth
      (e.g., androgenic steroids, growth hormone).
    explanation: >-
      GeneReviews specifies avoidance of procoagulant medications given the
      thromboembolic predisposition.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: AKT inhibitor (miransertib/ARQ 092)
  description: >-
    Investigational, pathway-directed therapy — not an established
    disease-modifying standard of care. The allosteric pan-AKT inhibitor
    miransertib suppresses AKT signaling and has target-engagement, single-case,
    and organoid support, and is under evaluation in clinical trials, but its
    disease-modifying benefit in Proteus syndrome is not yet established.
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: DOI:10.1038/srep17162
    reference_title: "Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome"
    supports: SUPPORT
    evidence_source: IN_VITRO
    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 cells (target engagement).
  - reference: DOI:10.1101/mcs.a006134
    reference_title: "Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi."
    explanation: This single case report describes symptomatic benefit with miransertib (ARQ 092).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: miransertib
      term:
        id: NCIT:C99172
        label: Miransertib
diagnosis:
- name: Clinical diagnostic criteria
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: NCIT:C20989
      label: Physical Examination
  description: >-
    Proteus syndrome is a clinical diagnosis requiring all three general criteria
    — mosaic (patchy) distribution of lesions, sporadic occurrence, and a
    progressive course — plus a threshold clinical score from specific
    positive/negative criteria. Hallmark specific features include the
    cerebriform connective tissue nevus and disproportionate, progressive,
    segmental/asymmetric overgrowth of skeleton, skin, and adipose tissue with
    vascular malformations.
  results: >-
    Meeting all three general criteria plus the specific clinical-score threshold
    establishes the diagnosis; fewer points are required when a mosaic AKT1
    variant is confirmed.
  evidence:
  - reference: PMID:22876373
    reference_title: "Proteus Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of PS is established in a proband with all three general
      criteria (mosaic distribution of lesions, sporadic occurrence, progressive
      course) and a clinical score based on positive and negative criteria of at
      least ten points in an individual with a mosaic AKT1 pathogenic variant or
      at least 15 points in an individual without a mosaic AKT1 pathogenic variant
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews defines the general criteria and clinical-score diagnostic
      thresholds for Proteus syndrome.
- name: Mosaic AKT1 molecular testing on affected tissue
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Molecular confirmation targets the somatic AKT1 c.49G>A (p.Glu17Lys) variant.
    Because the variant is post-zygotic and mosaic, testing should prioritize DNA
    from clinically affected (lesional) tissue using a sensitive variant-detection
    method; peripheral blood is frequently negative, so a negative blood result
    does not exclude the diagnosis. A confirmed mosaic AKT1 variant lowers the
    clinical-score threshold required for diagnosis.
  results: >-
    Detection of a mosaic AKT1 p.Glu17Lys variant in affected tissue confirms the
    molecular diagnosis; its absence in blood does not exclude Proteus syndrome.
  evidence:
  - reference: DOI:10.1038/srep17162
    reference_title: "Repression of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: >-
      Establishes the mosaic somatic AKT1 p.Glu17Lys variant as the molecular
      target for confirmatory testing.
- name: Cardiothoracic and skeletal imaging
  diagnosis_term:
    preferred_term: computed tomography procedure
    term:
      id: NCIT:C17204
      label: Computed Tomography
  description: >-
    Imaging documents the extent of skeletal overgrowth and scoliosis and screens
    for the cardiopulmonary complications that drive morbidity and mortality —
    bullous/cystic and emphysematous lung disease and pulmonary venous dilation —
    and supports evaluation for deep vein thrombosis and pulmonary embolism.
  results: >-
    Scoliosis, pulmonary cystic/emphysematous disease, and vascular complications
    on imaging support the diagnosis and guide surveillance.
  evidence:
  - reference: DOI:10.1038/s41598-021-86029-0
    reference_title: "Cardiothoracic imaging findings of Proteus syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: >-
      Cohort cardiothoracic imaging documents the skeletal and pulmonary findings
      relevant to diagnosis and surveillance.
- name: Differential diagnosis
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: NCIT:C20989
      label: Physical Examination
  description: >-
    Diagnosis requires excluding overlapping overgrowth disorders, chiefly
    PIK3CA-related overgrowth spectrum (PROS)/CLOVES syndrome, Klippel-Trenaunay
    syndrome, PTEN hamartoma tumor syndrome and Proteus-like syndromes,
    neurofibromatosis type 1, and isolated vascular malformation disorders (see
    the differential_diagnoses entries for distinguishing features). The mosaic,
    progressive, segmental overgrowth pattern with a cerebriform connective tissue
    nevus is most specific for Proteus syndrome.
  results: >-
    Exclusion of PROS/CLOVES, Klippel-Trenaunay, PTEN hamartoma/Proteus-like
    syndromes, and NF1 supports a Proteus syndrome diagnosis.
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
    reference_title: "A Multi-Cohort Phase 2 Dose-Escalation Study of MK-7075 (Miransertib) in Proteus Syndrome"
    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
    reference_title: "Phase 1 Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome"
    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
    reference_title: "A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome"
    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
    reference_title: "A Multicenter, Open-label, Phase 2, Extension Trial to Study the Long-term Safety in Participants With PROS or Proteus Syndrome Who Are Currently Being Treated With Miransertib in Other Studies"
    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
    reference_title: "Expanded Access to Provide ARQ 092 for the Treatment of Overgrowth Diseases and/or Vascular Anomalies With Genetic Alterations of the PI3K/AKT Pathway"
    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: >-
    Observational natural-history study (non-therapeutic) of Proteus syndrome and
    related congenital overgrowth disorders; it characterizes disease course and
    does not evaluate a treatment.
  evidence:
  - reference: clinicaltrials:NCT00001403
    reference_title: "The Phenotype and Etiology of Proteus Syndrome"
    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: []
discussions:
- discussion_id: gap_proteus_non_cell_autonomous_mouse_fidelity
  prompt: >-
    Does the non-cell-autonomous (paracrine) spread of pAKT activation from AKT1
    p.E17K clones into adjacent mutation-negative cells, observed in Akt1E17K
    mouse chimeras, also operate in human Proteus syndrome lesions, or is lesion
    formation in humans predominantly cell-autonomous?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Non-cell-autonomous pAKT activation in adjacent cells
  rationale: >-
    The non-cell-autonomous branch is supported chiefly by mouse-chimera data
    (DOI:10.1093/hmg/ddz116), where hyperplastic mammary epithelium contained
    mutation-negative cells with increased pAKT. Whether the same paracrine
    amplification drives human overgrowth lesions is unconfirmed; the
    well-established human causal chain is somatic AKT1 p.E17K driving
    cell-autonomous PI3K/AKT activation. The distinction matters for
    lesion-margin behavior and for how completely a clone-directed therapy would
    need to reach mutation-negative cells.
  proposed_experiments:
  - experiment_id: exp_proteus_human_lesion_paracrine_pakt
    name: Single-cell pAKT versus AKT1 allele fraction across human Proteus lesion margins
    description: >-
      Quantify pAKT and AKT1 variant allele fraction at single-cell resolution
      across human Proteus lesion margins to test whether mutation-negative cells
      show elevated pAKT.
  evidence:
  - reference: DOI:10.1093/hmg/ddz116
    reference_title: "A mouse model of Proteus syndrome"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    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: >-
      The non-cell-autonomous claim derives from mouse-chimera data; human
      validation is the open question.
- discussion_id: gap_proteus_vascular_organoid_preprint_fidelity
  prompt: >-
    Do the endothelial hyperconnectivity and PDGFRβ+ mural-cell dysfunction seen
    in mosaic-AKT1 iPSC vascular organoids reproduce the mechanism of human
    Proteus syndrome vascular malformations, given that the supporting data are
    from a preprint organoid model?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#AKT overactivation induces excessive vasculogenesis
  - pathophysiology#Mural cell dysfunction destabilizes vascular connections
  rationale: >-
    The endothelial/mural vascular branch is supported by an iPSC-derived
    vascular-organoid study available only as a bioRxiv preprint
    (DOI:10.1101/2024.01.26.577324). Organoids recapitulate PS-like network
    hyperconnectivity and mural-cell abnormalities and respond to AKT inhibitors,
    but the model's fidelity to human Proteus vascular malformation biology is
    unconfirmed and the data are not yet peer-reviewed. It is a useful
    mechanistic hypothesis, not established human pathophysiology.
  proposed_experiments:
  - experiment_id: exp_proteus_human_vascular_malformation_mural
    name: Mural-cell coverage and endothelial junction stability in human Proteus vascular malformations
    description: >-
      Characterize PDGFRβ+ mural-cell coverage and endothelial junction stability
      in resected human Proteus vascular malformations and compare with the
      organoid phenotype.
  evidence:
  - reference: DOI:10.1101/2024.01.26.577324
    reference_title: "Human vascular organoids with a mosaic <i>AKT1</i> mutation recapitulate Proteus syndrome"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Additionally, a notable increase in dysfunctional PDGFRβ + mural cells, impaired in matrix secretion, was observed in these AKT-overactivated organoids."
    explanation: >-
      The mural-cell dysfunction claim derives from a preprint organoid model;
      human tissue validation is the open question.
references:
- reference: PMID:22876373
  title: "Proteus Syndrome."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301661
  title: "PTEN Hamartoma Tumor Syndrome."
  tags:
  - GeneReviews
  findings: []

📚

References & Deep Research

References

2

PMID:22876373

Proteus Syndrome.

No top-level findings curated for this source.

PMID:20301661

PTEN Hamartoma Tumor Syndrome.

No top-level findings curated for this source.

Deep Research

2

Disorder ▸

Disorder

Name: Proteus syndrome
Category: Mendelian
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 66

Key Pathophysiology Nodes

Somatic AKT1 p.E17K activation in mosaic cell clones
Elevated PI3K/AKT signaling in AKT1-mutant cells
Increased pAKT signaling in AKT1-mutant lesion cells
Non-cell-autonomous pAKT activation in adjacent cells
AKT overactivation induces excessive vasculogenesis
Mural cell dysfunction destabilizes vascular connections

Citation Inventory (for evidence mapping)

DOI:10.1038/s41598-021-86029-0
DOI:10.1038/srep17162
DOI:10.1055/a-2300-7002
DOI:10.1093/hmg/ddz116
DOI:10.1101/2024.01.26.577324
DOI:10.1101/mcs.a006134
DOI:10.1136/jmg-2024-110173
DOI:10.1186/s13023-023-03013-9

Falcon ▸

Pathophysiology description

Edison Scientific Literature 24 citations 2026-01-26T19:36:02.845990

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

(lindhurst2015repressionofakt pages 1-2): Marjorie J. Lindhurst, Miranda R. Yourick, Yi Yu, Ronald E. Savage, Dora Ferrari, and Leslie G. Biesecker. Repression of akt signaling by arq 092 in cells and tissues from patients with proteus syndrome. Scientific Reports, Dec 2015. URL: https://doi.org/10.1038/srep17162, doi:10.1038/srep17162. This article has 77 citations and is from a peer-reviewed journal.
(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.
(mirmomen2021cardiothoracicimagingfindings pages 1-2): S. Mojdeh Mirmomen, Andrew E. Arai, Evrim B. Turkbey, Andrew J. Bradley, Julie C. Sapp, Leslie G. Biesecker, and Arlene Sirajuddin. Cardiothoracic imaging findings of proteus syndrome. Scientific Reports, Mar 2021. URL: https://doi.org/10.1038/s41598-021-86029-0, doi:10.1038/s41598-021-86029-0. This article has 11 citations and is from a peer-reviewed journal.
(klimeczekchrapusta2024proteussyndromecase pages 2-5): Maria K Klimeczek-Chrapusta, Marek Kachnic, and Anna Chrapusta. Proteus syndrome: case report and updated literature review. Archives of Plastic Surgery, 51:423-431, Apr 2024. URL: https://doi.org/10.1055/a-2300-7002, doi:10.1055/a-2300-7002. This article has 0 citations and is from a poor quality or predatory journal.
(ours2021casereportfiveyear pages 1-2): Christopher A. Ours, Julie C. Sapp, Mia B. Hodges, Allison J. de Moya, and Leslie G. Biesecker. Case report: five-year experience of akt inhibition with miransertib (mk-7075) in an individual with proteus syndrome. Cold Spring Harbor Molecular Case Studies, 7:a006134, Oct 2021. URL: https://doi.org/10.1101/mcs.a006134, doi:10.1101/mcs.a006134. This article has 31 citations and is from a peer-reviewed journal.
(rostagni2025tumourspectrumin pages 8-9): Olivia M Rostagni, Charlotte LR Early, Mia B Hodges, Justice O Obasohan, Julie C Sapp, Alicia A Livinski, Leslie G Biesecker, and Christopher A Ours. Tumour spectrum in akt1-related proteus syndrome: a systematic review of clinical reports and series. Journal of Medical Genetics, 62:74-81, Dec 2025. URL: https://doi.org/10.1136/jmg-2024-110173, doi:10.1136/jmg-2024-110173. This article has 0 citations and is from a domain leading peer-reviewed journal.

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