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Proteus syndrome

Mendelian MONDO:0008318
0
Mappings
0
Definitions
0
Inheritance
6
Pathophysiology
0
Histopathology
22
Phenotypes
1
Genes
2
Treatments
0
Subtypes
6
Differentials
0
Datasets
6
Trials
⚙

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.
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 link ↑ INCREASED
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 link ↑ INCREASED
Show evidence (1 reference)
DOI:10.1093/hmg/ddz116 SUPPORT
"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.
cell-cell signaling link ↑ INCREASED
Show evidence (1 reference)
DOI:10.1093/hmg/ddz116 SUPPORT
"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.
endothelial cell link
vasculogenesis link ↑ INCREASED angiogenesis link ↑ INCREASED
Show evidence (2 references)
DOI:10.1101/2024.01.26.577324 SUPPORT
"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
"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.
pericyte link
extracellular matrix organization link ↓ DECREASED
Show evidence (2 references)
DOI:10.1101/2024.01.26.577324 SUPPORT
"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
"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.
●

Phenotypes

22
Blood(1) Cardiovascular(3) Eye(7) Integument(2) Musculoskeletal(3) Respiratory(2) Constitutional(1) Growth(2) Neoplasm(1)
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 2
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.
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.
🧬

Genetic Associations

1
AKT1 (Causative)
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.
💊

Treatments

2
AKT inhibitor (miransertib/ARQ 092) MAXO:0000058
Allosteric pan-AKT inhibitor used to suppress AKT signaling and evaluated clinically for symptom and overgrowth control in Proteus syndrome.
Show evidence (2 references)
DOI:10.1038/srep17162 SUPPORT
"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 samples.
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 case report describes clinical benefit with miransertib (ARQ 092).
Surgical intervention MAXO:0000004
Surgical debulking or corrective procedures used to manage focal overgrowth and deformity.
Show evidence (1 reference)
DOI:10.1055/a-2300-7002 SUPPORT
"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.
🔀

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 Not Yet Curated 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 Not Yet Curated 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
Natural history study of Proteus syndrome and related congenital overgrowth disorders.
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.
{ }

Source YAML

click to show 
name: Proteus syndrome
creation_date: '2026-01-27T17:46:29Z'
updated_date: '2026-01-28T17:04:03Z'
category: Mendelian
parents: []
disease_term:
  preferred_term: Proteus syndrome
  term:
    id: MONDO:0008318
    label: Proteus syndrome
prevalence:
- population: Reported cases
  percentage: Rare
  notes: Approximately 250 cases documented in the literature over the past four decades.
  evidence:
  - reference: DOI:10.1186/s13023-023-03013-9
    supports: SUPPORT
    snippet: "Proteus syndrome is an ultra-rare mosaic overgrowth disorder."
    explanation: This statement characterizes Proteus syndrome as ultra-rare.
  - reference: DOI:10.1055/a-2300-7002
    supports: SUPPORT
    snippet: "Proteus syndrome (PS) is an exceptionally uncommon genetic disorder that has been documented in only approximately 250 cases in the literature spanning the past four decades."
    explanation: This provides a literature-based estimate of reported case counts.
- population: Live births
  percentage: 0.0001
  notes: Estimated prevalence is less than 1 per 1,000,000 live births.
  evidence:
  - reference: PMID:33987133
    supports: SUPPORT
    snippet: "It has an estimated prevalence of less than 1/1,000,000 live births."
    explanation: This case report provides a population prevalence estimate for Proteus syndrome.
epidemiology:
- name: Sex distribution in imaging cohort
  description: Male predominance reported in a cardiothoracic imaging cohort.
  unit: cases
  notes: In a cohort of 38 imaged individuals, 23 were men.
  evidence:
  - reference: DOI:10.1038/s41598-021-86029-0
    supports: SUPPORT
    snippet: "Of 53 individuals with a confirmed diagnosis of Proteus syndrome at our institution from 10/2001 to 10/2019, 38 individuals (men, n = 23; average age = 24 years) underwent cardiothoracic imaging"
    explanation: This cohort reports a male-predominant sex distribution among imaged individuals.
- name: Sex distribution in longitudinal cohort
  description: Male predominance reported in a 64-patient natural history cohort.
  unit: cases
  notes: 36 males and 28 females in the cohort.
  evidence:
  - reference: PMID:28661492
    supports: SUPPORT
    snippet: "There were 64 patients with Proteus syndrome identified in this study, 28 (43.8%) were female and 36 were male (56.3%)."
    explanation: The longitudinal cohort reports a modest male predominance.
- name: Age in imaging cohort
  description: Average age reported for the cardiothoracic imaging cohort.
  mean_range: 24 years
  unit: years
  evidence:
  - reference: DOI:10.1038/s41598-021-86029-0
    supports: SUPPORT
    snippet: "Of 53 individuals with a confirmed diagnosis of Proteus syndrome at our institution from 10/2001 to 10/2019, 38 individuals (men, n = 23; average age = 24 years) underwent cardiothoracic imaging"
    explanation: The imaging cohort reports an average age of 24 years.
- name: Age at diagnosis
  description: Median age at diagnosis in a natural history cohort.
  mean_range: 19 months
  unit: months
  evidence:
  - reference: PMID:28661492
    supports: SUPPORT
    snippet: "The median age of diagnosis was 19 months."
    explanation: The cohort analysis reports a median diagnosis age of 19 months.
pathophysiology:
- name: Somatic AKT1 p.E17K activation in mosaic cell clones
  description: >
    Proteus syndrome is caused by a post-zygotic activating AKT1 p.E17K
    variant present in a mosaic subset of cells.
  evidence:
  - reference: DOI:10.1038/srep17162
    supports: SUPPORT
    snippet: "A somatic activating mutation in AKT1, c.49G>A, pGlu17Lys, that results in elevated AKT signaling in mutation-positive cells, is responsible for the mosaic overgrowth condition, Proteus syndrome."
    explanation: This establishes mosaic, somatic AKT1 p.E17K activation in Proteus syndrome.
- name: Elevated PI3K/AKT signaling in AKT1-mutant cells
  description: >
    AKT1 p.E17K drives increased PI3K/AKT pathway activity in mutation-positive
    cells, promoting downstream overgrowth signals.
  biological_processes:
  - preferred_term: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1038/srep17162
    supports: SUPPORT
    snippet: "A somatic activating mutation in AKT1, c.49G>A, pGlu17Lys, that results in elevated AKT signaling in mutation-positive cells, is responsible for the mosaic overgrowth condition, Proteus syndrome."
    explanation: This directly links AKT1 activation to elevated AKT signaling in mutation-positive cells.
- name: Increased pAKT signaling in AKT1-mutant lesion cells
  description: >
    Lesion cells harboring AKT1 p.E17K show increased pAKT signaling within
    hyperplastic regions.
  biological_processes:
  - preferred_term: protein phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1093/hmg/ddz116
    supports: SUPPORT
    snippet: "Identification of variant-positive cells by green fluorescent protein (GFP) staining in chimeric Proteus syndrome mice showed that in some lesions, hyperplastic cells were predominantly GFP/Akt1E17K-positive and showed increased pAKT signal compared to GFP-negative cells."
    explanation: This demonstrates increased pAKT signaling in mutant clones within lesions.
- name: Non-cell-autonomous pAKT activation in adjacent cells
  description: >
    AKT1-mutant clones can induce increased pAKT signaling in nearby
    mutation-negative cells, consistent with non-cell-autonomous lesion
    propagation.
  biological_processes:
  - preferred_term: cell-cell signaling
    term:
      id: GO:0007267
      label: cell-cell signaling
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1093/hmg/ddz116
    supports: SUPPORT
    snippet: "However, hyperplastic mammary epithelium was a mixture of GFP/Akt1E17K-positive and negative cells with some GFP/Akt1E17K-negative cells also having increased pAKT signal suggesting that the variant-positive cells can induce lesion formation in a non-cell autonomous manner."
    explanation: This provides evidence for non-cell-autonomous effects in lesion formation.
- name: AKT overactivation induces excessive vasculogenesis
  description: >
    AKT1 activation increases vascular connectivity and promotes
    vasculogenesis with enhanced vascular sprouting.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: vasculogenesis
    term:
      id: GO:0001570
      label: vasculogenesis
    modifier: INCREASED
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1101/2024.01.26.577324
    supports: SUPPORT
    snippet: "Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections."
    explanation: AKT overactivation increases vascular connectivity in organoid vasculature.
  - reference: DOI:10.1101/2024.01.26.577324
    supports: SUPPORT
    snippet: "This could be due to the significant vasculogenesis induced by AKT overactivation."
    explanation: The study explicitly links AKT overactivation to increased vasculogenesis.
- name: Mural cell dysfunction destabilizes vascular connections
  description: >
    AKT-driven vascular malformations include dysfunctional PDGFRβ+ mural
    cells with impaired matrix secretion, contributing to unstable vessel
    connections.
  cell_types:
  - preferred_term: pericyte
    term:
      id: CL:0000669
      label: pericyte
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DECREASED
  evidence:
  - reference: DOI:10.1101/2024.01.26.577324
    supports: SUPPORT
    snippet: "Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections."
    explanation: AKT overactivation is linked to unstable vascular connections.
  - reference: DOI:10.1101/2024.01.26.577324
    supports: SUPPORT
    snippet: "Additionally, a notable increase in dysfunctional PDGFRβ + mural cells, impaired in matrix secretion, was observed in these AKT-overactivated organoids."
    explanation: This supports mural cell dysfunction as part of the vascular phenotype.
phenotypes:
- name: Overgrowth
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Overgrowth
    term:
      id: HP:0001548
      label: Overgrowth
  evidence:
  - reference: DOI:10.1093/hmg/ddz116
    supports: SUPPORT
    snippet: "Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors."
    explanation: This highlights skin and bony overgrowth as common manifestations.
  - reference: DOI:10.1055/a-2300-7002
    supports: SUPPORT
    snippet: "It is characterized by a disproportionate, asymmetric overgrowth of all types of tissues, provoked by a somatic activating mutation in serine/threonine protein kinase 1."
    explanation: This describes the characteristic disproportionate overgrowth in Proteus syndrome.
  - reference: PMID:22876373
    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
    supports: SUPPORT
    snippet: "Proteus syndrome is an extremely rare disorder that manifests as an asymmetric, disproportionate overgrowth of any connective tissue, such as bone, fat or epidermal nevi, in a mosaic or patchy pattern."
    explanation: This case report emphasizes disproportionate connective tissue overgrowth.
- name: Asymmetric growth
  category: Growth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Asymmetric growth
    term:
      id: HP:0100555
      label: Asymmetric growth
  evidence:
  - reference: DOI:10.1055/a-2300-7002
    supports: SUPPORT
    snippet: "It is characterized by a disproportionate, asymmetric overgrowth of all types of tissues, provoked by a somatic activating mutation in serine/threonine protein kinase 1."
    explanation: This explicitly describes asymmetric overgrowth as a defining feature.
  - reference: PMID:33987133
    supports: SUPPORT
    snippet: "Proteus syndrome is an extremely rare disorder that manifests as an asymmetric, disproportionate overgrowth of any connective tissue, such as bone, fat or epidermal nevi, in a mosaic or patchy pattern."
    explanation: This case report underscores asymmetric, disproportionate overgrowth.
- name: Venous malformation
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Venous malformation
    term:
      id: HP:0012721
      label: Venous malformation
  evidence:
  - reference: DOI:10.1093/hmg/ddz116
    supports: SUPPORT
    snippet: "Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors."
    explanation: This lists vascular malformations among common Proteus syndrome manifestations.
  - reference: PMID:33987133
    supports: SUPPORT
    snippet: "Many individuals develop cutaneous capillary malformation and prominent varicosities (large and complex vascular malformations)."
    explanation: This documents vascular malformations with prominent varicosities in Proteus syndrome.
- name: Cerebriform connective tissue nevus
  category: Dermatologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cerebriform connective tissue nevus
    term:
      id: HP:6000009
      label: Cerebriform connective tissue nevus
  evidence:
  - reference: DOI:10.1101/mcs.a006134
    supports: SUPPORT
    snippet: "The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi."
    explanation: This reports cerebriform connective tissue nevi in Proteus syndrome.
  - reference: PMID:34668833
    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
    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
    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
    supports: SUPPORT
    snippet: "Many individuals develop cutaneous capillary malformation and prominent varicosities (large and complex vascular malformations)."
    explanation: Prominent varicosities are reported as part of Proteus syndrome vascular disease.
- name: Pain
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pain
    term:
      id: HP:0012531
      label: Pain
  evidence:
  - reference: DOI:10.1101/mcs.a006134
    supports: SUPPORT
    snippet: "The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi."
    explanation: Pain is reported as a symptom improved with targeted therapy.
- name: Scoliosis
  category: Musculoskeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: DOI:10.1038/s41598-021-86029-0
    supports: SUPPORT
    snippet: "The cardiothoracic findings of Proteus syndrome were diverse, but several were much more common and included: scoliosis from bony overgrowth (94%), pulmonary venous dilation (62%), band-like areas of lung scarring (56%), and hyperlucent lung parenchyma (50%)."
    explanation: This provides cohort evidence for scoliosis due to bony overgrowth.
- name: Emphysema
  category: Respiratory
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Emphysema
    term:
      id: HP:0002097
      label: Emphysema
  evidence:
  - reference: DOI:10.1186/s13023-023-03013-9
    supports: SUPPORT
    snippet: "Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention."
    explanation: This documents emphysematous lung changes in Proteus syndrome.
- name: Multiple pulmonary cysts
  category: Respiratory
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Multiple pulmonary cysts
    term:
      id: HP:0005948
      label: Multiple pulmonary cysts
  evidence:
  - reference: DOI:10.1186/s13023-023-03013-9
    supports: SUPPORT
    snippet: "Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention."
    explanation: This supports cystic lung changes in Proteus syndrome.
- name: Deep vein thrombosis
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Deep venous thrombosis
    term:
      id: HP:0002625
      label: Deep venous thrombosis
  evidence:
  - reference: PMID:22876373
    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
    supports: SUPPORT
    snippet: "Thus, Proteus syndrome patients are at risk of developing deep vein thrombosis and pulmonary embolism."
    explanation: This case report confirms thrombotic risk in Proteus syndrome.
- name: Pulmonary embolism
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pulmonary embolism
    term:
      id: HP:0002204
      label: Pulmonary embolism
  evidence:
  - reference: PMID:22876373
    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
    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
    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
    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
    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
    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
    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
    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
    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
    supports: SUPPORT
    snippet: "Her proptosis and vision impairment were relieved after Endoscope-Navigation system (ENS)-aided optic canal decompression."
    explanation: Vision impairment is reported among ocular manifestations.
- name: Neoplasm
  category: Oncologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Neoplasm
    term:
      id: HP:0002664
      label: Neoplasm
  evidence:
  - reference: DOI:10.1136/jmg-2024-110173
    supports: SUPPORT
    snippet: "AKT1-related Proteus syndrome is an ultra-rare mosaic overgrowth disorder with tumour predisposition."
    explanation: This systematic review establishes tumor predisposition in Proteus syndrome.
  - reference: PMID:22876373
    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
    supports: SUPPORT
    snippet: "We report a 35-year-old patient with PS, who underwent successful surgical removal of a well-differentiated SNEC obstructing his nasal cavity"
    explanation: This case report documents sinonasal neuroendocrine carcinoma in Proteus syndrome.
biochemical: []
genetic:
- name: AKT1
  association: Causative
  notes: Somatic activating mosaic variant (c.49G>A, p.Glu17Lys); HGNC:391
  evidence:
  - reference: DOI:10.1038/srep17162
    supports: SUPPORT
    snippet: "A somatic activating mutation in AKT1, c.49G>A, pGlu17Lys, that results in elevated AKT signaling in mutation-positive cells, is responsible for the mosaic overgrowth condition, Proteus syndrome."
    explanation: This identifies the causative somatic AKT1 variant.
  - reference: DOI:10.1093/hmg/ddz116
    supports: SUPPORT
    snippet: "Proteus syndrome is a mosaic, progressive overgrowth disorder caused by a somatic activating variant c.49G > A p.(E17K) in AKT1."
    explanation: This independently confirms the AKT1 p.E17K mosaic variant as the cause.
environmental: []
treatments:
- name: AKT inhibitor (miransertib/ARQ 092)
  description: >-
    Allosteric pan-AKT inhibitor used to suppress AKT signaling and evaluated
    clinically for symptom and overgrowth control in Proteus syndrome.
  evidence:
  - reference: DOI:10.1038/srep17162
    supports: SUPPORT
    snippet: "ARQ 092 reduced phosphorylation of AKT and downstream targets of AKT in a concentration-dependent manner in as little as two hours."
    explanation: This shows AKT pathway suppression by ARQ 092 in Proteus syndrome samples.
  - reference: DOI:10.1101/mcs.a006134
    supports: SUPPORT
    snippet: "The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi."
    explanation: This case report describes clinical benefit with miransertib (ARQ 092).
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: miransertib
        term:
          id: NCIT:C99172
          label: Miransertib
- name: Surgical intervention
  description: Surgical debulking or corrective procedures used to manage focal overgrowth and deformity.
  evidence:
  - reference: DOI:10.1055/a-2300-7002
    supports: SUPPORT
    snippet: "We report a case of PS in a two-year-old female patient with the following clinical features: unilateral overgrowth of connective tissue in the right buttock and right foot, where multiple surgeries were performed to achieve a desirable aesthetic outcome and ensure psychological comfort of the young patient."
    explanation: This case report documents surgical intervention for overgrowth management.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
differential_diagnoses:
- name: Klippel-Trenaunay-Weber syndrome
  description: >
    Overgrowth with vascular malformations can resemble Proteus syndrome and
    requires clinical and radiologic differentiation.
  distinguishing_features:
  - Capillary/venous malformations with limb hypertrophy and port-wine stains
  - Typically lacks cerebriform connective tissue nevi
  evidence:
  - reference: PMID:25009745
    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
    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
    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
    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
    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
    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
    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
    supports: SUPPORT
    snippet: "The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome."
    explanation: GeneReviews includes BRRS within the PTEN hamartoma tumor syndrome spectrum relevant to Proteus differentials.
clinical_trials:
- name: NCT04316546
  phase: PHASE_II
  status: RECRUITING
  description: Multi-cohort Phase 2 dose-escalation study of miransertib (MK-7075) in Proteus syndrome.
  evidence:
  - reference: clinicaltrials:NCT04316546
    supports: SUPPORT
    snippet: "To learn if miransertib is a safe and effective treatment for Proteus syndrome."
    explanation: The trial objective confirms evaluation of miransertib for Proteus syndrome.
- name: NCT02594215
  phase: PHASE_I
  status: COMPLETED
  description: Dose-finding study of MK-7075 (miransertib) in children and adults with Proteus syndrome.
  evidence:
  - reference: clinicaltrials:NCT02594215
    supports: SUPPORT
    snippet: "To determine the safety, tolerability, and recommended dose of MK-7075 in people with PS."
    explanation: The trial objective defines dose-finding and safety assessment in Proteus syndrome.
- name: NCT03094832
  phase: PHASE_I
  status: TERMINATED
  description: Phase 1/2 open-label study of oral miransertib (MK-7075) in PROS and Proteus syndrome (MOSAIC).
  evidence:
  - reference: clinicaltrials:NCT03094832
    supports: SUPPORT
    snippet: "This is an open label, Phase 1/2 study of oral miransertib (MK-7075) administered to participants at least 2 years of age with phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA)-related Overgrowth Spectrum (PROS) and Proteus Syndrome (PS) (MOSAIC)."
    explanation: The trial summary describes the Phase 1/2 MOSAIC study including Proteus syndrome.
- name: NCT04980872
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: Extension study evaluating safety/tolerability of oral miransertib in PROS or Proteus syndrome.
  evidence:
  - reference: clinicaltrials:NCT04980872
    supports: SUPPORT
    snippet: "This is a study of the safety and tolerability of oral miransertib (MK-7075) administered to participants at least 2 years of age with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS) or Proteus Syndrome (PS)."
    explanation: The study summary states the safety/tolerability focus for PROS or Proteus syndrome participants.
- name: NCT03317366
  phase: NOT_APPLICABLE
  status: UNKNOWN
  description: Expanded access for ARQ 092 (miransertib) in overgrowth diseases or vascular anomalies with PI3K/AKT alterations.
  evidence:
  - reference: clinicaltrials:NCT03317366
    supports: SUPPORT
    snippet: "ARQ 092 is being investigated for patients with overgrowth diseases and/or vascular anomalies with genetic alterations of the PI3K/AKT pathway and may be available for patients who are ineligible for an ongoing ARQ 092 clinical trial or have other considerations that prevent access to ARQ 092 through an existing clinical trial."
    explanation: The summary describes expanded access for PI3K/AKT-pathway overgrowth disorders including Proteus syndrome.
- name: NCT00001403
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: Natural history study of Proteus syndrome and related congenital overgrowth disorders.
  evidence:
  - reference: clinicaltrials:NCT00001403
    supports: SUPPORT
    snippet: "This study will examine rare congenital disorders that involve malformations and abnormal growth. It will focus on patients with Proteus syndrome, whose physical features are characterized by overgrowth, benign tumors of fatty tissue or blood vessels, asymmetric arms or legs, and large feet with very thick soles."
    explanation: The study description states a natural history focus on Proteus syndrome.
datasets: []