Proteus syndrome

Overview

Proteus syndrome is an extremely rare and complex genetic disorder characterized by overgrowth of various tissues in the body, including bones, skin, connective tissue, and blood vessels. The condition is highly variable and affects each person differently, often resulting in asymmetrical and progressive overgrowth that can lead to significant physical deformities and medical complications. The syndrome is named after the Greek god Proteus, who could change his shape, reflecting the diverse and evolving nature of the condition. Proteus syndrome affects fewer than 1 in 1 million people worldwide and often becomes apparent in early childhood.

Causes

Proteus syndrome is caused by a mosaic mutation in the AKT1 gene, which plays a critical role in cell growth, proliferation, and survival. The mutation occurs post-zygotically, meaning it arises after fertilization and is not inherited from either parent. As a result, only some cells in the body carry the mutation, which explains the patchy, asymmetrical distribution of symptoms.

The AKT1 gene mutation leads to abnormal activation of the PI3K-AKT signaling pathway, promoting uncontrolled cellular growth and overproduction of tissues. Because the mutation is mosaic, it cannot be passed on to future generations and occurs sporadically. No environmental factors or family history are linked to the development of Proteus syndrome.

Symptoms

The clinical features of Proteus syndrome are highly variable and may affect multiple body systems. Symptoms typically emerge within the first two years of life and progress over time. Common signs and manifestations include:

General Characteristics

• Asymmetrical and disproportionate overgrowth of body parts (e.g., limbs, skull, spine)

• Progressive deformities due to continued tissue and bone enlargement

• Normal development at birth with overgrowth becoming evident later

Skin and Soft Tissue

• Cerebriform connective tissue nevi (brain-like ridged skin lesions, often on soles or palms)

• Thickened skin, wart-like lesions, or hyperpigmented patches

• Subcutaneous tumors or lipomas (benign fatty growths)

Musculoskeletal and Skeletal

• Overgrowth of long bones, spine, skull, or jaw (often unilateral)

• Scoliosis or kyphosis (spinal curvature)

• Joint abnormalities and limited mobility

Vascular and Neurological

• Vascular malformations including venous malformations and capillary anomalies

• Deep vein thrombosis (DVT) and risk of pulmonary embolism

• Seizures, developmental delays, or cognitive impairments in some cases

Other Possible Features

• Macrocephaly (enlarged head)

• Facial asymmetry and overgrowth of facial bones

• Ocular anomalies (strabismus, epibulbar dermoids)

Not every individual with Proteus syndrome exhibits all symptoms, and the severity can vary widely.

Diagnosis

Diagnosis of Proteus syndrome can be challenging due to its rarity and variable presentation. It is primarily based on clinical features and confirmed by genetic testing. Diagnostic steps include:

• Clinical evaluation: Assessment of asymmetrical and progressive overgrowth patterns, especially in multiple tissue types

• Diagnostic criteria: Established criteria include mosaic distribution of lesions, progressive course, and involvement of multiple systems

• Imaging studies: X-rays, CT scans, or MRIs to assess internal and skeletal overgrowth, vascular malformations, and soft tissue masses

• Genetic testing: Identification of the mosaic AKT1 gene mutation in affected tissue samples confirms the diagnosis

• Differential diagnosis: Ruling out similar disorders such as Klippel–Trénaunay syndrome, neurofibromatosis, and congenital lipomatous overgrowth syndromes

Because the AKT1 mutation is mosaic, it may not be detectable in blood samples; testing affected tissue is often required for confirmation.

Treatment

There is no cure for Proteus syndrome, and treatment focuses on managing symptoms, preventing complications, and improving quality of life. Care is highly individualized and typically involves a multidisciplinary team of specialists.

Medical Management

• Anticoagulation therapy: To reduce the risk of deep vein thrombosis and pulmonary embolism

• Pain management: Using medications and physical therapy to relieve discomfort due to overgrowth or joint problems

• Sirolimus or mTOR inhibitors (experimental): May help reduce abnormal cell growth by targeting the PI3K-AKT-mTOR pathway

Surgical Interventions

• Orthopedic surgery: To correct skeletal deformities or limb length discrepancies

• Tumor removal: Excision of lipomas or other overgrown soft tissue masses if they cause pain or limit function

• Vascular surgery: For symptomatic or complicated vascular malformations

Supportive Care

• Physical and occupational therapy to improve mobility and function

• Psychological support for coping with visible disfigurement and social challenges

• Regular monitoring for new or worsening symptoms, including imaging and lab tests

Prognosis

The prognosis of Proteus syndrome varies greatly depending on the extent and severity of tissue overgrowth and associated complications. Some individuals may lead relatively normal lives with appropriate medical and surgical management, while others may face significant disability and health challenges. Major risks include life-threatening thromboembolic events, airway obstruction due to overgrowth, and complications from organ involvement or tumor development.

With advances in genetic testing and improved management strategies, early diagnosis and intervention can significantly improve outcomes and quality of life. Lifelong follow-up and coordinated care are essential due to the progressive and unpredictable nature of the condition.