Proteus Syndrome (PS) is an extremely rare, sporadic disorder characterized by the progressive and asymmetric overgrowth of various tissues throughout the body. Named after the Greek sea god Proteus, who could change his shape at will, the condition results in a highly variable clinical presentation that changes and worsens over time. This overgrowth disorder is estimated to affect fewer than one in a million individuals worldwide.
The condition is not apparent at birth, as affected infants appear clinically unaffected. Abnormal growth typically begins subtly between six and eighteen months of age and progresses rapidly during childhood. Proteus Syndrome is defined by this unpredictable and disproportionate growth, which can affect the bones, skin, fatty tissues, and blood vessels.
Defining Characteristics and Clinical Presentation
The most striking feature of Proteus Syndrome is the disproportionate and asymmetrical overgrowth affecting the skeleton and soft tissues. This overgrowth often involves the limbs, skull, and spine, leading to limb length discrepancies, scoliosis, and cranial enlargement. These physical changes can severely impact mobility.
A highly specific feature is the cerebriform connective tissue nevus (CCTN), a skin lesion that appears primarily on the soles of the feet. This nevus has a convoluted, deeply grooved, and furrowed appearance, resembling the surface of a brain. Other dermatological findings include linear epidermal nevi, which are streaky, wart-like growths that follow the lines of embryonic development.
Abnormalities in adipose tissue are common, presenting either as localized fatty overgrowth (lipomas) or regional absence of fat (lipoatrophy). Skeletal involvement frequently includes hyperostosis, which is the excessive growth and thickening of bone. The combination of these varied and patchy tissue abnormalities underscores the segmental nature of the syndrome.
The Underlying Genetic Cause
The biological mechanism driving Proteus Syndrome is a post-conception error in a single gene, making it a non-inherited condition. The cause is a specific somatic activating mutation in the AKT1 gene. This gene provides instructions for making the AKT1 protein, a crucial component of a signaling pathway that regulates cell growth and proliferation.
The specific mutation, often designated c.49G>A (p.Glu17Lys), causes the AKT1 protein to be perpetually “switched on,” leading to uncontrolled cell growth. The mutation is termed somatic because it occurs in a body cell after fertilization, rather than being inherited. Consequently, the condition appears only in the descendants of the single cell where the initial mutation took place.
This distribution of mutant cells alongside normal cells is known as somatic mosaicism. The patchy, segmentally affected areas of the body correspond directly to the regions where cells carry the AKT1 mutation. The severity and pattern of the syndrome depend on when in embryonic development the mutation occurs.
Diagnosis and Differential Diagnosis
Diagnosing Proteus Syndrome relies on clinical features and genetic confirmation, given its rarity and variable presentation. Physicians use established clinical criteria, which include three mandatory general features: a mosaic distribution of lesions, a sporadic occurrence, and a progressive course of the disorder.
The presence of specific features is also scored, with the cerebriform connective tissue nevus (CCTN) carrying the highest diagnostic weight. Diagnosis is strongly supported if the patient meets the general criteria and exhibits the CCTN, or a combination of other specific findings like disproportionate overgrowth or specific benign tumors.
Genetic testing confirms the diagnosis by identifying the AKT1 mutation. Due to the condition’s mosaic nature, the mutation is only present in affected tissue. Therefore, a biopsy from an overgrown area, such as a skin lesion, is necessary for accurate testing, as a standard blood sample often fails to detect the mutation. The careful diagnostic process helps distinguish Proteus Syndrome from other overgrowth disorders, such as CLOVES syndrome, which are caused by mutations in different genes.
Therapeutic Management and Long-Term Care
Since there is no cure for Proteus Syndrome, therapeutic management focuses on controlling symptoms and preventing complications. A multidisciplinary team approach is necessary, involving specialists in orthopedics, plastic surgery, dermatology, and vascular medicine. The primary goal is to address progressive overgrowth and maintain function and mobility.
Orthopedic interventions often involve procedures like epiphysiodesis to halt the growth of longer limbs and correct bone length discrepancies. Surgical reduction of overgrown soft tissue or lipomas may be performed, though re-growth is a common challenge. Physical therapy and rehabilitation medicine are also central to managing skeletal and joint issues.
Individuals with Proteus Syndrome have an increased predisposition to developing deep vein thrombosis (DVT) and pulmonary embolism (PE). This heightened risk of blood clots is one of the most serious complications of the syndrome. Regular surveillance for thrombosis and the use of prophylactic measures are necessary components of long-term care.