Proteus syndrome (PS) is an exceptionally rare, sporadic disorder characterized by the progressive, disproportionate overgrowth of various tissues in the body. With an estimated incidence of less than one case per ten million people, the condition typically begins to manifest in infancy, between six and eighteen months of age. The name is derived from the Greek sea god Proteus, who could change his shape, reflecting the highly variable presentation of the syndrome. PS involves abnormal growth patterns and a predisposition to developing certain types of tumors, requiring specialized medical attention.
Defining Physical Characteristics
The manifestations of this condition are highly variable and almost always follow an asymmetric, or patchy, distribution across the body. The overgrowth can affect nearly any tissue, including the skin, bones, muscles, fatty tissues, and vascular structures. This disproportionate growth often leads to macrodactyly, or gigantism, of the limbs and digits, resulting in significant limb length discrepancies.
A nearly unique finding is the cerebriform connective tissue nevus (CCTN), a thick, raised, and deeply grooved lesion that often occurs on the soles of the feet, resembling the surface of the brain. The skin can also display linear epidermal nevi, which appear as streaky, slightly raised skin changes with a velvety texture. Adipose tissue is often dysregulated, presenting both as localized overgrowth (lipomas) and areas of focal atrophy.
Skeletal abnormalities are prominent and progressive, frequently involving the spine, skull, and long bones. Disproportionate vertebral growth can lead to severe scoliosis, while overgrowth of the skull bones may result in macrocephaly or a dolichocephalic (elongated) head shape. Vascular malformations, which include capillary, venous, and lymphatic types, are also a common feature of the syndrome.
Affected individuals have an increased susceptibility to developing tumors, most of which are benign. Consistently reported tumors include bilateral ovarian cystadenomas, meningiomas, and parotid monomorphic adenomas.
The Underlying Genetic Cause
Proteus syndrome is caused by a somatic activating mutation in the \(AKT1\) oncogene, specifically the c.49G→A (p.Glu17Lys) variant. This mutation occurs after conception and is not inherited, meaning it is only present in some cells of the body.
This mechanism is known as somatic mosaicism, where the genetic alteration occurs early in embryonic development in a single cell. As the embryo grows, only the descendants of that mutated cell carry the \(AKT1\) variant, creating a mix of genetically normal and genetically altered cells. The location and proportion of the mutated cells determine the specific pattern and severity of the overgrowth.
The \(AKT1\) gene produces the AKT1 kinase, a protein that regulates cell proliferation and survival. The activating mutation causes the AKT1 protein to be constitutively active, meaning it is constantly “on.” This over-activation leads to the unchecked signaling of the PI3K/AKT/mTOR pathway, a master regulator of cell growth. This cellular dysregulation drives the abnormal and excessive tissue growth characteristic of the syndrome.
Diagnostic Confirmation
Diagnosis of Proteus syndrome is challenging due to its extreme rarity and the broad variability of clinical features among affected individuals. The diagnosis historically relies on a set of established clinical criteria, which require the presence of three general features: mosaic distribution of lesions, a progressive course, and a sporadic (non-inherited) occurrence.
These general criteria must be accompanied by a combination of specific major and minor clinical features, such as the pathognomonic cerebriform connective tissue nevus or a specific number of other overgrowth and tumor types. Clinical suspicion guides the decision to proceed with molecular testing.
Genetic testing provides the definitive confirmation by identifying the \(AKT1\) mutation in a mosaic state. Because the mutation is only present in affected tissues, the genetic test requires deep sequencing of a biopsy sample taken from an overgrown or affected area, such as a skin lesion or tumor. Standard blood-based genetic tests are often negative, as the mutation may not be present in a large enough fraction of blood cells to be detected.
Comprehensive Management Strategies
Since there is currently no cure for Proteus syndrome, management focuses on a multidisciplinary, symptomatic approach to address the progressive overgrowth and complications. Orthopedic specialists are often involved early to manage skeletal issues, including the correction of scoliosis and the reduction of limb length discrepancies. Surgical procedures like epiphysiodesis, which slows the growth of a longer bone, or the use of spinal bracing are employed to maintain mobility and function.
Management of the soft tissue overgrowth, such as the large lipomatous masses, often requires open surgical debulking, though the highly vascular nature of the tissue can pose surgical difficulties. Regrowth of the masses is a frequent issue following these procedures.
A particularly serious risk is the predisposition to deep vein thrombosis (DVT) and pulmonary embolism (PE), which represents a major cause of mortality in patients. Aggressive monitoring, prompt evaluation of any potential symptoms, and prophylactic anticoagulation, especially around the time of surgery, are routinely implemented to mitigate this life-threatening risk.
Targeted therapeutic options are currently under investigation, focusing on the dysregulated growth pathway. Drugs known as mTOR inhibitors, such as sirolimus, are being studied in clinical trials for their potential to slow or halt the excessive cell proliferation. Beyond physical interventions, psychological and supportive care is also provided to help patients and their families manage the impact of the progressive disfigurement and associated social challenges.