High-yield overview
Mosaic AKT1 Overgrowth with Cerebriform Naevi
26 of 29Patients carried the mosaic AKT1 p.Glu17Lys variant (Lindhurst 2011)
Cerebriform naevusMost heavily weighted diagnostic criterion - usually plantar
1% to ~50%Mutant-allele admixture in affected tissues - the signature of mosaicism
DVT / PEStriking predisposition; a significant source of mortality
Core features
Genetics
PatternSomatic (mosaic) AKT1 c.49G>A, p.Glu17Lys gain-of-function variant; present only in affected tissues; not inherited; ubiquitous expression is embryonic-lethal in a mouse model.
Treatment
Cutaneous
PatternCerebriform connective-tissue naevus (characteristically plantar), epidermal naevi, lipomas and regional adipose dysregulation, vascular malformations (capillary, venous, lymphatic).
Treatment
Overgrowth
PatternProgressive, disproportionate, distorting overgrowth of limbs, digits, skull, spine and soft tissues, typically with modest or no manifestations at birth and rapid progression from the toddler period.
Treatment
Risks
PatternDeep vein thrombosis and pulmonary embolism; progressive cystic/bullous lung disease; a range of tumours (ovarian cystadenomas, parotid adenomas, meningiomas and others); orthopaedic deformity and limb-length discrepancy.
Treatment
Critical Must-Knows
- PROTEUS SYNDROME is a rare mosaic overgrowth disorder caused by a somatic activating variant in AKT1 (c.49G>A, p.Glu17Lys), proved by exome sequencing of affected versus unaffected tissue from the same patients: 26 of 29 patients in the defining study carried the variant, with mutant-allele admixtures from 1% to about 50% in affected tissues. It is not inherited; no confirmed vertical transmission or sib recurrence has been reported.
- The clinical signature is PROGRESSIVE, DISPROPORTIONATE and DISTORTING overgrowth, usually asymmetric and patchy (mosaic distribution), typically with modest or no manifestations at birth, rapid progression from the toddler period, and relentless progression through childhood. The pathognomonic-weighted cutaneous feature is the CEREBRIFORM CONNECTIVE-TISSUE NAEVUS - a firm, ridged, brain-like plaque most often on the plantar surface - though it is not completely specific, having been described (histologically confirmed) in mosaic PIK3CA overgrowth as well.
- DIAGNOSIS is dyadic: all three general criteria (mosaic distribution of lesions, sporadic occurrence, progressive course) plus a weighted point score of phenotypic attributes integrated with molecular testing of AFFECTED TISSUE - a score of at least 10 points with a mosaic AKT1 pathogenic variant, or at least 15 points without one, establishes Proteus syndrome; a mosaic AKT1 variant with a score of 2-9 is designated AKT1-related overgrowth spectrum.
- ORTHOPAEDIC relevance includes asymmetric limb overgrowth with limb-length discrepancy, macrodactyly, scoliosis, exostoses, hip dysplasia, genu valgum, joint contractures and hindfoot deformity. In the dedicated leg-length-discrepancy case series (8 patients), guided growth with tension-band plates and epiphyseal arrest reduced discrepancy with few complications; deep-vein-thrombosis prophylaxis, sequential compression devices and rapid mobilisation were integral parts of the surgical protocol.
- SYSTEMIC risks dominate the natural history: a striking predisposition to deep vein thrombosis and pulmonary embolism (a significant source of mortality), progressive cystic lung disease that progresses faster in children, and a range of tumours. Targeted therapy is emerging: the pan-AKT inhibitor miransertib achieved a 50% reduction in phosphorylated AKT in affected tissue at 5 mg/m2/day in five of six patients in a phase 0/1 pharmacodynamic study, with a decrease in a cerebriform naevus and reduced pain in children.
Clinical Pearls
- “Mosaic AKT1 c.49G>A (p.Glu17Lys); not inherited; test AFFECTED tissue, not blood.
- “Cerebriform connective-tissue naevus (usually plantar) is the most heavily weighted criterion - but not absolutely specific (also reported with mosaic PIK3CA).
- “Overgrowth is progressive, disproportionate and distorting; orthopaedic workload = limb-length discrepancy, macrodactyly, scoliosis, contractures.
- “Deep vein thrombosis/pulmonary embolism predisposition changes perioperative planning; avoid procoagulant drugs, growth hormone and androgenic steroids.
- “Progressive cystic lung disease, faster in children; tumour surveillance by history and examination.
Mosaic, Progressive and Dangerous - Not Just Big
Recognise the pattern
Progressive, disproportionate, distorting overgrowth in a mosaic (patchy, asymmetric) distribution, with a cerebriform connective-tissue naevus (usually plantar), is the clinical signature. The variant is in affected tissue only - a blood test may be normal.
The clots can kill
Proteus syndrome carries a striking predisposition to deep vein thrombosis and pulmonary embolism, and pulmonary embolism is a significant source of mortality. Perioperative thromboprophylaxis and rapid mobilisation are not optional in these patients.
Overview, Epidemiology & Historical Context
Proteus syndrome is an ultra-rare mosaic overgrowth disorder in which a somatic activating variant in AKT1 drives progressive, disproportionate and distorting overgrowth of the skeleton, skin, adipose tissue and other tissues. Because the variant arises after fertilisation and is confined to the cells that descend from the mutant progenitor, the distribution is patchy and asymmetric, the severity is highly variable, and the disorder is not inherited.
- How rare: an estimated prevalence of less than 1 in 1,000,000 live births is quoted in the case literature; no robust population incidence was retrievable, and the condition is best described as ultra-rare.
- Natural history in outline: most affected individuals have modest or no manifestations at birth; overgrowth develops and progresses rapidly beginning in the toddler period and progresses relentlessly through childhood, causing severe overgrowth and disfigurement (GeneReviews, Biesecker & Sapp).
- Historical note: Tibbles and Cohen (1986) marshalled the evidence that Joseph Merrick, the nineteenth-century "Elephant Man", had Proteus syndrome rather than neurofibromatosis - citing his macrocephaly, skull hyperostosis, long-bone hypertrophy, and thickened skin and subcutaneous tissue of the hands and feet including plantar hyperplasia and lipomas. The disorder had earlier been misattributed to neurofibromatosis, and misdiagnosis of Proteus syndrome remained common enough that Cohen (2005) made diagnostic criteria the centrepiece of his update.
- Why the name matters clinically: the defining behaviour is change - lesions that are present evolve, enlarge and distort over time. A static congenital asymmetry is not Proteus syndrome, and the general criterion of a progressive course exists precisely to separate it from the congenital, non-progressive overgrowth of the PIK3CA-related overgrowth spectrum.
Genetics & Pathophysiology
One Variant, Mosaic Distribution, Pathway Activation
Lindhurst and colleagues (2011) performed exome sequencing of DNA from biopsy samples of affected and unaffected tissue from the same patients and identified a somatic activating mutation in AKT1 - c.49G>A, encoding p.Glu17Lys - in 26 of 29 patients with Proteus syndrome. Mutant-allele admixtures in affected tissues and cell lines ranged from 1% to approximately 50%, mutant cell lines showed greater AKT phosphorylation than controls, and the study concluded that Proteus syndrome is caused by this somatic activating variant, proving the long-standing somatic-mosaicism hypothesis and implicating PI3K-AKT pathway activation in the overgrowth and tumour susceptibility.
- Why it is mosaic, and why it has to be. The variant is lethal when ubiquitous: in a mouse model, ubiquitous expression of the same Akt1 p.(E17K) allele caused embryonic lethality, with embryos showing fewer visible blood vessels, more haemorrhages, and a primitive capillary network that failed to remodel into hierarchical vasculature (Lindhurst 2020). Survival to birth therefore requires that only a fraction of cells carry the variant - which is exactly the mosaicism seen clinically.
- The pathway. AKT1 kinase sits in the PI3K-AKT-mTOR growth and survival pathway; the p.Glu17Lys variant constitutively activates it, driving proliferation and inhibiting apoptosis in the affected cell population. The same pathway is activated upstream by somatic PIK3CA variants in the PIK3CA-related overgrowth spectrum (PROS) - fibroadipose overgrowth, CLOVES syndrome, megalencephaly-capillary malformation and isolated macrodactyly - which is why these disorders overlap phenotypically and must be distinguished (Lindhurst 2012; Keppler-Noreuil 2014).
- Practical consequence for diagnosis. Because the variant is confined to affected tissue and the admixture can be as low as 1%, molecular confirmation requires sampling affected tissue (biopsy of overgrown or naevus tissue, or affected surgical specimens); a negative blood result does not exclude the diagnosis.
Why Mosaicism Is Obligatory
Q: Why is Proteus syndrome always mosaic and never inherited?
A: The causal AKT1 c.49G>A p.Glu17Lys variant is a constitutive activator of the PI3K-AKT pathway. In a conditional mouse model, ubiquitous expression of the same allele was embryonic-lethal, with a primitive cutaneous capillary network that failed to remodel into normal vasculature. Only embryos in which a minority of cells carry the variant survive - hence every patient is a mosaic, the lesions are patchy and asymmetric, and there are no confirmed instances of vertical transmission or sib recurrence. Counselling a family about recurrence risk means saying the risks to parents and siblings are not increased over the general population.
Diagnosis: Criteria, the Cerebriform Naevus & the Differential
General criteria (all three required):
- Mosaic distribution of lesions
- Sporadic occurrence
- Progressive course
Specific features are then scored. The original phenotype-only criteria were developed at an NIH workshop in March 1998 and published by Biesecker and colleagues (1999); they were updated in 2006. After the discovery of the causal mosaic AKT1 variant and the characterisation of the overlapping PIK3CA-related overgrowth spectrum, Sapp and colleagues (2019) re-evaluated the criteria and proposed a weighted, point-based system integrated with molecular testing - a "dyadic" gene-phenotype approach:
Proteus syndrome (AKT1-related)
- Requirements
- All three general criteria plus a clinical score of at least 10 points in an individual with a mosaic AKT1 pathogenic variant, or at least 15 points without one
AKT1-related overgrowth spectrum
- Requirements
- A mosaic AKT1 pathogenic variant with a clinical score of 2-9 points
Neither designation
- Requirements
- An individual whose only manifestation is an AKT1 c.49G>A-positive tumour
The most heavily weighted specific criterion has always been the cerebriform connective-tissue naevus.
Orthopaedic Manifestations
The Orthopaedic Workload
Reviewing the available literature on 61 reported patients, Stricker (1992) found that patients with Proteus syndrome commonly develop macrodactyly, limb overgrowth, spinal deformity, hip dysplasia, genu valgum, exostoses, joint contractures and hindfoot deformities. The overgrowth distorts rather than simply enlarges: limbs become asymmetric, digits grotesque, spines progressively scoliotic, and joints stiff or malaligned.
- Limb-length discrepancy (LLD). Asymmetric limb overgrowth produces progressive discrepancy. In the dedicated surgical series (Crenshaw 2018 - see Evidence), the average LLD was 3.4 cm (range 0.4-7.0) at presentation and had grown to 5.0 cm (range 1.8-10.0) by the time of first surgery - direct evidence that the discrepancy progresses and that timing matters.
- Macrodactyly and local gigantism. Fingers and toes enlarge disproportionately; debulking, osteotomy, ray resection or amputation may be needed for function, shoe wear or pain. In the older combined series of Klippel-Trénaunay-Weber and Proteus patients (Guidera 1993), surgical treatment consisted of epiphysiodesis, osteotomies, debulking procedures and amputation, with mixed results - the authors concluded that conservative or supportive treatment should be the primary mode of orthopaedic care.
- Spinal deformity. Progressive scoliosis and kyphoscoliosis are well recognised and can be driven by vertebral overgrowth and chest-wall asymmetry; surveillance and standard deformity principles apply, with the caveat that progression can be unpredictable.
- Other. Hip dysplasia, genu valgum, exostoses, joint contractures and hindfoot deformity round out the musculoskeletal picture; craniofacial bony overgrowth, testicular and parotid masses, and macrodactyly all appear in the modern case literature.
Overgrowth Is Progressive - Document, Monitor and Time the Intervention
The mistake is to treat the deformity as static. In the Crenshaw series the mean leg-length discrepancy grew from 3.4 cm at presentation to 5.0 cm by first surgery, and patients went on to need up to five procedures each. The practical discipline is: measure the discrepancy serially, project it to skeletal maturity, and time guided growth or epiphyseal arrest accordingly - while building deep-vein-thrombosis prophylaxis, sequential compression devices and rapid mobilisation into every surgical plan, because the thromboembolic risk is part of the disease, not an incidental anaesthetic consideration.
Management
Multidisciplinary, Staged, and Built Around the Risks
- Confirm the diagnosis dyadically: three general criteria plus weighted point score, integrated with mosaic AKT1 testing of affected tissue; classify AKT1-variant patients with low scores as AKT1-related overgrowth spectrum rather than forcing the label.
- Orthopaedics: orthopaedic procedures to delay or halt linear bone growth (guided growth, epiphyseal arrest), correction of skeletal deformities such as scoliosis, debulking or ray resection/amputation for macrodactyly, with rehabilitation medicine, physiotherapy and occupational therapy throughout.
- Skin: dermatological management, especially pedorthic intervention for the cerebriform plantar naevus (footwear, pressure distribution, skin care).
- Thromboembolism: avoid procoagulant drugs, growth hormone and androgenic steroids; perioperative DVT prophylaxis, sequential compression and rapid mobilisation; treat established DVT/PE.
- Lungs: pulmonology surveillance of cystic lung disease, which progresses faster in children.
- Tumours: surveillance by history and examination; treat tumours per surgeon/oncologist.
- Development and psychosocial: developmental intervention, special education and psychosocial counselling are warranted in most individuals.
Systemic Complications: Thromboembolism, Lung Disease & Tumours
The predisposition is striking and is a leading cause of death. GeneReviews lists a "striking predisposition to deep vein thrombosis and pulmonary embolism" among the defining clinical characteristics, and the pulmonary literature identifies pulmonary embolism as a significant source of mortality. The substrate is anatomical: capillary, venous and lymphatic malformations with prominent varicosities, and dilated conducting veins (an enlarged inferior vena cava, saphenous varicosities and enlarged leg arteries and veins are documented in imaged cases), compounded by orthopaedic surgery and immobilisation.
Management implications (GeneReviews):
- Agents/circumstances to avoid: medications that increase the risk of deep vein thrombosis or are procoagulant; medications that increase growth (androgenic steroids, growth hormone).
- Perioperatively: the orthopaedic LLD series built DVT prophylaxis, sequential compression devices and rapid mobilisation into its surgical protocol as integral elements.
- When it happens: evaluate and treat deep vein thrombosis and pulmonary embolism conventionally; a published adult case of pulmonary embolism in Proteus syndrome underlines that the risk does not stop at skeletal maturity. Chronic thromboembolic disease can also produce pulmonary hypertension, and precapillary pulmonary arterial hypertension without chronic emboli has been reported - dyspnoea in these patients warrants detailed investigation.
Guidelines, Registries & Global Practice
There is no disease-specific guideline, registry or validated surveillance schedule for Proteus syndrome; no randomised trial exists for any intervention. The authoritative synthesis used worldwide is the peer-reviewed GeneReviews chapter (Biesecker & Sapp, 2012, updated 2023), maintained by the group that defined the diagnostic criteria, and the 2019 dyadic diagnostic framework (Sapp et al.), which is designed to be applied anywhere that clinical assessment and molecular testing of affected tissue are available. Management is delivered by multidisciplinary teams - clinical genetics, paediatrics, orthopaedics, dermatology, pulmonology, vascular medicine and rehabilitation - and case reports from every inhabited continent (including the Kenyan and Indian cases underpinning this page's sourced images) describe the same pattern of progressive distorting overgrowth, cerebriform naevi and thromboembolic risk, with care constrained mainly by access to molecular diagnostics and to orthopaedic and pulmonary surveillance. The global messages are uniform: the disorder is mosaic and not inherited, the overgrowth is progressive, test affected tissue, and plan every operation around the thromboembolic risk.
Mnemonics & Memory Aids
Mnemonic
PROTEUS
P
Progressive, disproportionate, distorting overgrowth (the course is a general criterion)
R
Ridged cerebriform connective-tissue naevus - plantar; most heavily weighted, not absolutely specific
O
Overgrowth is MOSAIC - patchy, asymmetric; test affected tissue (1% to ~50% admixture)
T
Thromboembolism - DVT/PE predisposition; prophylaxis and rapid mobilisation around surgery
E
E17K - AKT1 c.49G>A p.Glu17Lys, PI3K-AKT pathway; not inherited (no vertical transmission)
U
Unusual tumours - ovarian cystadenoma, parotid adenoma, meningioma; surveillance by history and examination
S
Skeleton - limb-length discrepancy, macrodactyly, scoliosis; staged guided growth; avoid growth hormone, androgens, procoagulants
Hook:PROTEUS: Progressive overgrowth, Ridged plantar naevus, mOsaic AKT1, Thromboembolism, E17K, Unusual tumours, Skeleton.
Mnemonic
SCORE-10/15Dyadic Diagnosis
S
Sporadic
General criterion 1 - occurs sporadically, no inheritance
C
Course progressive
General criterion 2 - lesions progress over time
O
One mosaic pattern
General criterion 3 - mosaic distribution of lesions
R
Result integrated
Phenotype score integrated with mosaic AKT1 testing of affected tissue
E
Eligibility thresholds
≥10 points WITH mosaic AKT1 variant, or ≥15 points WITHOUT, = Proteus syndrome; 2-9 with the variant = AKT1-related overgrowth spectrum
Hook:Sporadic, Course progressive, One mosaic pattern, Result integrated, Eligibility 10/15 - all three general criteria plus the weighted score, married to the gene.
MCQ Practice Points
- The causal lesion is a somatic (mosaic) AKT1 c.49G>A, p.Glu17Lys gain-of-function variant - found in 26 of 29 patients in the defining study; it is not inherited, and ubiquitous expression is embryonic-lethal in a mouse model, which is why the disorder is always mosaic.
- Molecular confirmation requires affected tissue; mutant-allele admixtures range from 1% to ~50%, so blood can be negative.
- Diagnosis is dyadic: three general criteria (mosaic, sporadic, progressive) plus a weighted point score integrated with molecular testing - ≥10 points with a mosaic AKT1 variant or ≥15 without; 2-9 points with the variant = AKT1-related overgrowth spectrum.
- The cerebriform connective-tissue naevus (usually plantar) is the most heavily weighted criterion but not absolutely specific - it has been reported, histologically confirmed, with mosaic PIK3CA.
- Orthopaedic manifestations: macrodactyly, limb overgrowth, limb-length discrepancy, spinal deformity, hip dysplasia, genu valgum, exostoses, contractures, hindfoot deformity (Stricker 1992, 61-patient review).
- LLD surgery evidence: Crenshaw 2018 - tension-band-plate guided growth and epiphyseal arrest; mean LLD 3.4 cm at presentation → 5.0 cm at first surgery → 2.6 cm at last follow-up; DVT prophylaxis integral.
- Systemic risks: DVT/PE (a significant mortality source), progressive cystic lung disease (faster in children: Cystic Lung Score +5.6/year vs +1.6 in adults), and a range of tumours (ovarian cystadenoma, parotid adenoma, meningioma, immature teratoma).
- Avoid: procoagulant/DVT-risk medications, growth hormone and androgenic steroids.
- Targeted therapy: miransertib (oral allosteric pan-AKT inhibitor) - 5 mg/m2/day gave ≥50% pAKT reduction in affected tissue in 5/6 patients (phase 0/1); early sirolimus case report exists. Neither is standard of care.
Clinical Decision Scenarios
Practise clinical reasoning and management decisions out loud
Viva scenarioStandard
Asymmetric Overgrowth and a Ridged Sole
Clinical prompt
“A 7-year-old boy presents with progressive asymmetric overgrowth of the right leg and a thickened, folded, brain-like plaque on the sole of the foot. What is the likely diagnosis, how do you confirm it, and what must you think about before any operation?”
Viva scenarioChallenging
The Discrepancy That Keeps Growing
Clinical prompt
“An 11-year-old with molecularly confirmed Proteus syndrome has a leg-length discrepancy that has increased from 3 cm to 6 cm over two years, progressive scoliosis and macrodactyly of two toes. Outline your orthopaedic strategy and the evidence behind it.”
Exam day cheat sheet
Proteus Syndrome - Exam Day Cheat Sheet
Genetics
- Mosaic (somatic) AKT1 c.49G>A, p.Glu17Lys - 26/29 patients (Lindhurst 2011)
- Allele admixture 1% to ~50% in affected tissue - TEST AFFECTED TISSUE, not blood
- Not inherited; no confirmed vertical transmission; ubiquitous expression embryonic-lethal (mouse)
Diagnosis
- General criteria (all three): mosaic distribution, sporadic occurrence, progressive course
- Dyadic score: >=10 points with mosaic AKT1 variant, or >=15 without; 2-9 with variant = AKT1-related overgrowth spectrum
- Cerebriform connective-tissue naevus (usually plantar) = most heavily weighted criterion, NOT absolutely specific (mosaic PIK3CA overlap)
- Differential: PROS/CLOVES (PIK3CA), Klippel-Trénaunay, PTEN hamartoma tumour syndrome, hemihyperplasia
Orthopaedic
- Macrodactyly, limb overgrowth, LLD, scoliosis, hip dysplasia, genu valgum, exostoses, contractures, hindfoot deformity
- LLD: serial measurement, project to maturity; tension-band-plate guided growth → epiphyseal arrest (Crenshaw 2018: 3.4→5.0 cm pre-op, 2.6 cm at final)
- Older mixed series: mixed surgical results - conservative/supportive care is the default; operate for defined functional goals
Systemic risks
- DVT/PE predisposition - significant mortality source; prophylaxis + rapid mobilisation around every operation
- Progressive cystic lung disease - faster in children (CLS +5.6/yr vs +1.6/yr adults)
- Tumours: ovarian cystadenoma, parotid adenoma, meningioma, immature teratoma - surveillance by history/examination, not blanket imaging
- Avoid procoagulant drugs, growth hormone, androgenic steroids
Targeted therapy
- Miransertib (pan-AKT inhibitor): 5 mg/m2/day → >=50% pAKT reduction in 5/6 (phase 0/1, Keppler-Noreuil 2019)
- One-year case report: improved mobility, reduced cerebriform naevus, stable MRI (Biesecker 2020)
- Early sirolimus case report (Weibel 2021); no targeted agent is standard of care
Evidence & Key Studies
Evidence
A mosaic activating mutation in AKT1 associated with the Proteus syndrome
Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. • N Engl J Med (2011)
Key Findings:
- Exome sequencing of DNA from biopsy samples of affected tissue compared with unaffected tissue from the same patients identified a somatic activating AKT1 mutation (c.49G>A, p.Glu17Lys).
- 26 of 29 patients with Proteus syndrome carried the variant; confirmation used a custom restriction-enzyme assay across 158 samples from 29 patients.
- Mutant-allele admixtures in tissues and cell lines ranged from 1% to approximately 50% - the quantitative signature of mosaicism.
- Mutant cell lines showed greater AKT phosphorylation than controls; paired single-cell clones differing only in mutation status differed in AKT phosphorylation.
- The authors concluded the syndrome is caused by this somatic activating AKT1 mutation, proving the somatic-mosaicism hypothesis and implicating PI3K-AKT pathway activation in the overgrowth and tumour susceptibility.
Clinical implication: The molecular anchor of the entire topic: one recurrent mosaic variant, present only in affected tissue, at admixtures low enough that blood testing can miss it - biopsy affected tissue for confirmation.
Limitation: A molecular association study, not a natural-history cohort: it defines cause, not prognosis. Three of 29 patients did not carry the detectable variant, so clinical criteria retain a role.
Evidence
A dyadic genotype-phenotype approach to diagnostic criteria for Proteus syndrome
Sapp JC, Buser A, Burton-Akright J, Keppler-Noreuil KM, Biesecker LG • Am J Med Genet C Semin Med Genet (2019)
Key Findings:
- Phenotype-based criteria dated from 1999 and were updated in 2006; the causal mosaic AKT1 c.49G>A p.E17K variant and the PIK3CA-related overgrowth spectrum required their re-evaluation.
- Proposes a weighted, point-based system for phenotypic attributes integrated with molecular results.
- Designations: AKT1-related Proteus syndrome (score >=10 with, or >=15 without, a mosaic AKT1 variant) versus AKT1-related overgrowth spectrum (mosaic AKT1 variant with score 2-9).
- A patient whose only manifestation is an AKT1 c.49G>A-positive tumour receives neither designation.
Clinical implication: The current diagnostic framework: the label now rests on the gene-phenotype dyad, not on the cerebriform naevus or any single feature.
Limitation: A criteria proposal by the NIH group that defined the field, not an externally validated classification; thresholds are expert-derived.
Evidence
Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation
Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, Cohen MM Jr • Am J Med Genet (1999)
Key Findings:
- Report of the March 1998 NIH workshop that produced the original recommendations for diagnostic criteria, differential diagnosis and patient evaluation.
- Recognised the disorder as highly variable and apparently mosaic, with diagnostic confusion aggravated by a lack of longitudinal natural-history data.
- Established the general criteria (mosaic distribution, sporadic occurrence, progressive course) and specific criteria structure on which later systems built.
Clinical implication: The historical source of the three general criteria and the feature-scoring approach still embedded in the dyadic system.
Limitation: Pre-molecular: written twelve years before the AKT1 variant was discovered, so its criteria are phenotype-only and have been superseded by the 2019 dyadic proposal.
Evidence
Molecular heterogeneity of the cerebriform connective tissue nevus in mosaic overgrowth syndromes
Keppler-Noreuil KM, Burton-Akright J, Lindhurst MJ, Shwetar J, Sapp JC, Darling T, Biesecker LG • Cold Spring Harb Mol Case Stud (2019)
Key Findings:
- The cerebriform connective-tissue naevus was the most heavily weighted specific criterion in the pre-molecular diagnostic criteria.
- Two individuals with connective-tissue naevi and general attributes of Proteus syndrome had mosaic PIK3CA variants, not AKT1.
- Their plantar lesions showed the firm ridges-and-furrows morphology of a CCTN, histologically confirmed in one.
- Conclusion: CCTNs are not specific to Proteus syndrome; diagnosis should not rest on the CCTN alone but on the full criteria plus genetic analysis of affected tissue.
Clinical implication: Tempers the exam shorthand that the plantar cerebriform naevus is 'pathognomonic': it is the most heavily weighted clue, not an absolute one.
Limitation: Two patients: it demonstrates imperfect specificity, not the frequency with which PIK3CA disease produces a true CCTN.
References
- Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011;365(7):611-619. doi:10.1056/NEJMoa1104017. PMID: 21793738
- Biesecker LG, Sapp JC. Proteus Syndrome. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 2012 Aug 9 [updated 2023 May 25]. PMID: 22876373
- Sapp JC, Buser A, Burton-Akright J, Keppler-Noreuil KM, Biesecker LG. A dyadic genotype-phenotype approach to diagnostic criteria for Proteus syndrome. Am J Med Genet C Semin Med Genet. 2019;181(4):565-570. doi:10.1002/ajmg.c.31744. PMID: 31692258
- Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, Cohen MM Jr. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet. 1999;84(5):389-395. doi:10.1002/(SICI)1096-8628(19990611)84:5<389::AID-AJMG1>3.0.CO;2-O. PMID: 10360391
- Keppler-Noreuil KM, Burton-Akright J, Lindhurst MJ, Shwetar J, Sapp JC, Darling T, Biesecker LG. Molecular heterogeneity of the cerebriform connective tissue nevus in mosaic overgrowth syndromes. Cold Spring Harb Mol Case Stud. 2019;5(4):a004036. doi:10.1101/mcs.a004036. PMID: 31371346
- Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, et al. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet. 2012;44(8):928-933. doi:10.1038/ng.2332. PMID: 22729222
- Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, Parker VE, Blumhorst C, Darling T, et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014;164A(7):1713-1733. doi:10.1002/ajmg.a.36552. PMID: 24782230
- Lindhurst MJ, Li W, Laughner N, Shwetar JJ, Kondolf HC, Ma X, et al. Ubiquitous expression of Akt1 p.(E17K) results in vascular defects and embryonic lethality in mice. Hum Mol Genet. 2020;29(20):3350-3360. doi:10.1093/hmg/ddaa216. PMID: 33030203
- Crenshaw MM, Goerlich CG, Ivey LE, Sapp JC, Keppler-Noreuil KM, Scott AC, Biesecker LG, Tosi LL. Orthopaedic management of leg-length discrepancy in Proteus syndrome: a case series. J Pediatr Orthop. 2018;38(3):e138-e144. doi:10.1097/BPO.0000000000001121. PMID: 29329145
- Stricker S. Musculoskeletal manifestations of Proteus syndrome: report of two cases with literature review. J Pediatr Orthop. 1992;12(5):667-674. PMID: 1517432
- Guidera KJ, Brinker MR, Kousseff BG, Helal AA, Pugh LI, Ganey TM, Ogden JA. Overgrowth management in Klippel-Trenaunay-Weber and Proteus syndromes. J Pediatr Orthop. 1993;13(4):459-466. doi:10.1097/01241398-199307000-00009. PMID: 8396594
- Ours CA, Buser A, Hodges MB, Chen MY, Sapp JC, Gochuico BR, Biesecker LG. Quantification of Proteus syndrome-associated lung disease. Orphanet J Rare Dis. 2024;19(1):44. doi:10.1186/s13023-023-03013-9. PMID: 38321508
- Mathavan A, Mathavan A, Vahdatpour C, Eagan C, Kalra SS, Ataya A. Precapillary pulmonary arterial hypertension in a patient with Proteus syndrome. Pulm Circ. 2022;12(2):e12098. doi:10.1002/pul2.12098. PMID: 35783033
- Duarte Santos C, Lizardo Gracio R, Costa Pires T, Gonzalez Santos M, Rodrigues RJ, Magalhaes M, Mota Ponte A. Proteus syndrome: a rare case in an adult ward. Eur J Case Rep Intern Med. 2021;8(4):002554. doi:10.12890/2021_002554. PMID: 33987133
- Gordon PL, Wilroy RS, Lasater OE, Cohen MM Jr. Neoplasms in Proteus syndrome. Am J Med Genet. 1995;57(1):74-78. doi:10.1002/ajmg.1320570117. PMID: 7645604
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