Proteus syndrome is a rare condition that can be loosely categorized as a hamartomatous disorder. It is a complex disorder with multisystem involvement and great clinical variability. Once thought to have neurofibromatosis, Joseph Merrick (also known as "the elephant man" and studied by Treves in the 1800s) is now, in retrospect, thought by clinical experts to actually have had Proteus syndrome.
This condition is characterized by various cutaneous and subcutaneous lesions, including vascular malformations, lipomas, hyperpigmentation, and several types of nevi. Cerebriform nevi are thought to be characteristic of the disorder. Progressive, asymmetrical limb overgrowth is pathognomonic, and patients have an unusual body habitus. Because cutaneous lesions tend to appear over time, the diagnosis may be delayed until late infancy, childhood, or even adulthood. Orthopedic complications often pose the most challenging medical problems, although vascular complications also contribute to overall morbidity. Severe disfigurement and social stigmatization are additional challenges that must be addressed.
Examples of various malformations and physical symptoms in Proteus syndrome are shown in the images below.
Patients and their families can be referred to the Proteus Syndrome Foundation.
A study by Lindhurst et al demonstrated that a somatic mutation in the AKT1 gene is causative for Proteus syndrome. The researchers performed exome sequencing of DNA from biopsies of affected tissues and compared this with DNA from normal tissues in these patients. AKT1 mutations were found in the affected tissues but not in the normal tissues. 
Proteus syndrome is caused by a somatic mutation rather than a germline one, meaning that only cells descended from the affected cell will display symptoms. This means that individuals with mutations later in development will generally have a less severe phenotype. The random nature of the somatic mutation explains the variability of presentation in patients with Proteus syndrome.
Proteus syndrome is believed to be exceedingly rare, with less than 100 confirmed affected individuals reported worldwide.  This suggests that prevalence is less than 1 case per 1,000,000 live births. However, this condition is also often misdiagnosed.
The following is noted in patients with Proteus syndrome:
Hemihyperplasia (asymmetrical overgrowth of the head, face, and digits) and soft tissue overgrowth are among the more significant medical complications. Some scientists have suggested that the bony overgrowth in Proteus syndrome is secondary to mesenchymal changes beginning during embryonic life, with formation of extra-large cartilage precursors. 
Soft tissue and bone overgrowth may slow after puberty.
Absent or decreased subcutaneous fat (lipohypoplasia) of the trunk or limbs may also be seen in patients with Proteus syndrome, contributing to the gracile appearance and well-recognized body habitus in severely affected individuals. 
Facial involvement may be associated with not only asymmetric mandibular growth, maxillary growth, or both, but also with premature dental eruption and idiopathic root resorption.
Eye findings may include strabismus as well as epibulbar dermoids or cysts; ocular findings are reported in more than 40% of affected individuals. 
Scoliosis or kyphoscoliosis may be severe and progressive, leading to respiratory compromise in some cases. Neck and trunk elongation with upper body wasting and leg muscle hypertrophy may contribute to overall abnormal body habitus and concomitant functional abnormalities.
Although less common, kidney or bladder problems may be identified in slightly less than 10% of affected individuals. Genitourinary problems described include hydronephrosis, renal cysts, asymmetry of the kidneys or bladder, and nephrogenic diabetes. 
Cutaneous and subcutaneous lesions can create significant cosmetic and functional problems. Benign growths, such as lipomas, connective tissue nevi, epidermal nevi, and vascular malformations, may be locally invasive and contribute greatly to morbidity.
Individuals with a larger number of skin manifestations are also more likely to have more severe involvement of other tissues.
Whereas ovarian cystadenomas are frequent enough in women with Proteus syndrome to be included as part of the diagnostic criteria, other fairly rare neoplasms have been identified in affected individuals. Meningiomas, various testicular tumors, and parotid monomorphic adenomas have been described.  More recently, a patient with Proteus syndrome was shown to have multiple spinal cord meningiomas. 
Cystic lung malformations are reported in slightly less than 10% of patients and are especially common in younger female patients. 
Learning disabilities or mental retardation occurs in a subset of patients. A particular facial phenotype often is associated with mental impairment with or without CNS malformations and seizures. Infantile seizures, specifically Ohtahara syndrome, have been described in several patients with Proteus syndrome in association with hemimegalencephaly. 
Race-, sex-, and age-related demographics
No racial or ethnic differences in disease occurrence are apparent. Classically, males have been thought to be more commonly affected than females, but new studies with genetically confirmed cases have not yet been published. 
The genetic mutation that causes Proteus Syndrome is a somatic mutation that occurs after conception and is propagated in one or more subsets of embryonic cells. The classic progressive, asymmetrical overgrowth may not be obvious at birth, which can delay diagnosis.
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