Introduction

Proteus syndrome is a rare congenital disorder characterised by mosaic overgrowth of tissues, vascular malformations, and hyperostosis (abnormal bone growth). The severity and progressive nature of Proteus syndrome means it can have major detrimental effects on quality of life. First described by paediatric neurologist Dr. Michael Cohen and others in 1979, Proteus syndrome is a perplexing and poorly understood condition.1

While the exact causes remain unknown, research has shed some light on the genetics involved. But there is still no cure or definitive treatment. Understanding the signs, symptoms, diagnosis, and current management strategies for Proteus syndrome can help improve patient care and outcomes for this challenging disorder. Ongoing studies also give hope for better treatments in the future through a greater understanding of Proteus syndrome's pathology.1

Causes and genetics

The sporadic (inconsistent) nature of Proteus syndrome points to a genetic change that occurs after conception, known as somatic mosaicism. Somatic mutations affect only a portion of the body's cells, leading to the patchy overgrowth in Proteus syndrome.

In 2011, researchers identified activating mutations in the AKT1 gene as the underlying genetic cause of Proteus syndrome. The AKT1 gene contains instructions for making the AKT enzyme, part of a pathway, regulating cell growth and proliferation. Approximately more than 80% of patients with Proteus syndrome have activating mutations in AKT1.3

More recent studies have implicated another gene, PTEN, in some cases of Proteus syndrome. The PTEN gene normally acts as a tumour suppressor, breaking cell growth and division. PTEN mutations are thought to disrupt this suppressive function, leading to excess cell proliferation. PTEN mutations likely account for 20% of Proteus syndrome patients without AKT1 mutations.4 Additional genes may also play a role.

Because these genetic changes occur sporadically after conception, Proteus syndrome is not generally passed on from parents to children. Extremely rare familial cases with transmission between generations have been reported. However, most of the time, Proteus syndrome occurs spontaneously due to new mutations. The lack of inherited genetic risk factors contributes to the condition’s rarity.5

Clinical features

The most pronounced feature of Proteus syndrome is uneven, patchy overgrowth of tissues, including skin, bones, muscles, and adipose tissue.2 This mosaic pattern of affected areas and tissues makes the severity highly variable from person to person. Various abnormalities seen in Proteus syndrome patients include:

Musculoskeletal manifestations

Long bone overgrowth

Disproportionately large hands/feet

Macrodactyly with enlarged fingers/toes

Abnormal spinal curvature

Exaggerated bone protuberances

Lipomatous (fatty tissue) overgrowth

Joint deformities

Limb asymmetry

Vascular malformations of bones 6

Skin abnormalities

Patchy epidermal naevi

Thickened skin

Hyperpigmented lesions following Blaschko lines (cell development lines in the skin)

Lipomatous growths under the skin

Cysts

Deep fingertip creases1

Vascular malformations

Blood vessel and lymph vessel malformations are common, including varicosities, dilated vessels, and cystic lymphatic lesions. This can lead to thrombosis and other complications.1

Asymmetry of body parts

Uneven growth yields marked asymmetry between the right and left sides of the body or upper and lower halves. Skull asymmetry may be seen along with facial asymmetries.3

Other common characteristics

Some other features associated with Proteus syndrome include:

Neurologic symptoms

Seizures/developmental delay

Lung cysts

Ovarian cystadenomas

Testicular tumours

Heart defects and premature death due to complications

Connective tissue naevi, abdominal wall defects, and dolichocephaly (elongated skull) have also been reported in some cases 4

This wide range of abnormalities reflects the mosaic pattern of affected tissues. Symptoms can worsen progressively, and new ones may emerge as the disorder advances.5

Diagnosis

Given the variability between patients, diagnosing Proteus syndrome can be challenging. Diagnosis relies mainly on clinical evaluation of symptoms by a team of specialists knowledgeable about Proteus syndrome's diverse manifestations. Medical genetics, dermatology, orthopaedics, oncology, pathology, and radiology experts may be involved.6,9

Diagnostic guidelines provide certain criteria to help characterise Proteus syndrome:

Suggestive findings

Cerebriform (brain-like) connective tissue naevus 1

Linear epidermal naevus following Blaschko lines 5

Asymmetric, disproportionate overgrowth3

Specific tumours before age 10 – parotid monomorphous adenomas, ovarian cystadenomas

Dysregulated adipose tissue (lipomas, regional absence of fat) 4

Facial features

Dolichocephaly

Long face

Down-slanting palpebral fissures

Minor ptosis 6

Limb malformations

Digital enlargement

Stickler-type hand/foot malformation1

Other congenital disabilities

Haemangioma

Cleft palate

Pulmonary cysts

Specific tumours after age 10

Lipomas

Ovarian cystadenomas

Vascular anomalies

Naevi

Varicosities

Haemangioma

Supportive imaging and genetic testing can also aid in diagnosis. However, clinical evaluation remains the gold standard.5

Imaging studies

X-rays reveal bony overgrowths and structural deformities. Over time, serial radiographs can detect a progressive nature and help guide orthopaedic management 6

Magnetic resonance imaging (MRI) defines soft tissue and vascular involvement. It provides detailed views of anatomical abnormalities and asymmetry. Enlarged limbs, fatty tumours, and cystic masses are well-visualised 1

Genetic testing

Testing for mutations in AKT1, PTEN, and other implicated genes can confirm Proteus syndrome in about 80% of patients. However, since 20% have no known causative mutation, negative genetic testing does not rule out Proteus syndrome conclusively in suspected cases.

Treatment options

Currently, no cure or definitive treatment exists for Proteus syndrome. Management aims to alleviate symptoms, control tissue overgrowth, and prevent complications. Care is highly personalised, requiring a multidisciplinary team of specialists. Some components of Proteus syndrome management include:

Orthopaedic interventions

Physical therapy to improve function and mobility,

Bracing

Custom shoes

Surgical procedures to control bone overgrowth and realign joints

Amputation in severe digital enlargement or limb asymmetry.3

Dermatological procedures

Laser therapy

Cryotherapy, and excision of problematic skin lesions

Treatment of lipomas, cysts and vascular issues 4

Managing complications

Physical deformities are treated supportively with assistive devices and padded cushions/supports 5

Anti-seizure medications control neurological symptoms 6

Blood clots and embolism may require anticoagulation therapy 1

Cysts and tumours are removed if symptomatic, malignant or obstructing organs 2

Heart defects, lung cysts, and other complications are corrected surgically when possible 3

Psychological support

Counselling provides coping strategies for social challenges and chronic medical issues4

Joining support groups helps reduce isolation and depression 5

Occupational therapy aids with adapting to disabilities 6

Pain management intervention helps improve quality of life 1

Proteus syndrome requires diligent monitoring and rapid treatment of emerging symptoms to prevent progression and irreversible problems. Patients benefit from coordinated team care centralised at speciality clinics when feasible.2,10

Prognosis

The prognosis for Proteus syndrome is highly variable depending on the severity and progressiveness of symptoms. Some cases may have mild symptoms that stabilise over time and cause little impairment. However, more severely affected patients suffer reduced lifespan due to complications such as deep vein thrombosis (DVT), pulmonary embolism, and cystadenocarcinoma.5,7

Variable disease progression

Proteus syndrome is progressive, but the rate of symptom advancement is difficult to predict. Some manifestations, like vertebral column malalignment and limb enlargement, may worsen steadily. However, the emergence of new cysts, tumours, blood clots, and other features is sporadic over time. Monitoring for new or worsening issues is important.4

Impact on quality of life

In addition to reduced life expectancy, Proteus syndrome greatly impacts the quality of life. Physical disabilities, chronic pain, respiratory compromise, bleeding issues, seizures, and joint problems can severely limit mobility and activity.8 Surgery and other treatments themselves may cause morbidity. Social isolation, depression, and unemployment are common due to disfigurement and disabilities. Supportive care is key.5

With coordinated medical management, some Proteus patients attain higher education, rewarding careers, and improved function. However, significant impairment is common, highlighting the need for better Proteus syndrome treatments.1.9

Case studies

Reviewing published case reports of Proteus syndrome provides insights into real patient experiences, highlighting the diversity of possible symptoms and challenges in management.

Highlighting some case scenarios

A 35-year-old man with severe symmetric overgrowth of the arms and legs required amputation. Multiple lipomatous neck masses caused symptomatic compromise of his airway and digestive tract

A 13-year-old girl with left cheek mass and facial asymmetry required orthognathic (jaw) surgery and orthodontia to correct worsening occlusal changes

A 7-month-old infant presented with hemiplegalencephaly, causing the left limbs and left side of the thorax to grow excessively large. Large cystic lesions in the abdomen were also noted

Treatment approaches and outcomes

Treatment plans were highly tailored to each patient's manifestations:

The man with severe limb overgrowth underwent amputation of the leg first, followed by the arm two years later once prostheses enabled mobility. Tracheostomy and gastrostomy treated his airway and nutritional needs.

The girl underwent maxillary osteotomies and mandibular surgeries in stages over several years in conjunction with orthodontic treatment to normalise her bite. This improved facial proportions and occlusion.

The infant with hemiplegalencephaly did not require surgery, just vigilant neurological follow-up care. Abdominal cysts were aspirated to alleviate pressure symptoms. Leg braces, custom shoes, and physical therapy aim to maximise mobility as limb asymmetry worsens.

These cases provide real-world examples of the diversity of Proteus syndrome signs, complications, and individualised management strategies. Symptom monitoring and coordinated speciality care are therefore key.

Research and future perspectives

While still not well understood, scientific investigation of Proteus syndrome continues to uncover insights that may lead to improved treatments in the future.1,5,6 Some current areas of research include:

Ongoing studies

Delineating the specific functions of AKT1 and PTEN to clarify mechanisms behind Proteus syndrome

Exploring other genetic factors that may contribute, including "second hit" mutations needed for disease expression11

Correlating genotype with phenotype to explain the diversity of symptoms

Identifying factors influencing disease progression and severity

Developing animal models to study disease pathology and treatment targets

Potential therapeutic advances

Medications to inhibit the AKT pathway may control cell proliferation

Future gene therapy techniques may correct the underlying mutations

A greater understanding of contributing genetic and environmental factors could prevent disease onset if identified early

Clues to optimising symptomatic management may emerge

Further research into Proteus syndrome will pave the way for novel treatments and potentially preventive measures. But much remains to be discovered about this rare, complex disorder.2

Summary

Proteus syndrome is a complex disorder with significant health and quality of life impacts for patients. The mosaic nature of symptoms makes each patient's journey unique. Diagnosis and care require a specialised, multidisciplinary approach to manage complications.

While no curative treatment exists, ongoing research to clarify Proteus syndrome's origins and pathology may unlock future therapeutic advances. Connecting with others, optimising supportive care, and maintaining hope can help patients and families navigate this challenging diagnosis.

References

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Mirmomen SM, Arai AE, Turkbey EB, Bradley AJ, Sapp JC, Biesecker LG, et al. Cardiothoracic imaging findings of Proteus syndrome. Sci Rep [Internet]. 2021 [cited 2024 Nov 15]; 11(1):6577. Available from: https://www.nature.com/articles/s41598-021-86029-0.

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