Dermatologic Manifestations of Proteus Syndrome 

Updated: Jun 26, 2018
Author: Megan Barry, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Proteus syndrome (PS) is a sporadically occurring hamartomatous disorder associated with irregular asymmetric overgrowth of multiple body tissues and cell lineages.[1] Most malformations in patients with Proteus syndrome have a mesodermal origin. Characteristic plurifocal overgrowths (partial or regional gigantism) can involve any structure of the body but most commonly involve the bone, connective tissue, and fat. Although some evidence of this syndrome was published in the medical literature as early as 1907, the modern medical description of the disease is attributed to Cohen and Hayden, who identified the syndrome in 1979.[2] In 1983, to stress the polymorphic nature of the clinical manifestations of the disorder, Wiedermann named it "Proteus syndrome" after the Greek god Proteus, who could change his shape at will to avoid capture.[3]

Perhaps the most famous case of Proteus syndrome is that of Joseph Merrick, the "Elephant Man" described by Sir Frederick Treves in 1884, who was made famous by a stage play and movie of the same name. Although first thought to have neurofibromatosis, Merrick is now believed to have had Proteus syndrome. Preserved castings of his soles show cerebriform cutaneous hyperplasia, a characteristic finding in persons with Proteus syndrome.[4]

Pathophysiology

Proteus syndrome is a rare, sporadic disease with patchy or mosaic manifestations.[5] In 2011, the New England Journal of Medicine published a paper by Lindhurst et al naming a mutation in AKT1 as the cause of Proteus syndrome.[6] Twenty-nine patients with Proteus syndrome were studied, and 26 were found to have activation of AKT protein in the affected tissues. All unaffected patients were negative for the activating mutation.

Patients with Proteus syndrome have a somatic mutation, meaning that the mutation arises randomly during development of the fetus after fertilization. Only tissues that descend from the mutated cell have the AKT activation and, therefore, have phenotypic abnormalities. Patients who have mutation at an earlier stage of development will then have more severe clinical symptoms.

The mutated AKT1 is constitutively activated as a result of phosphorylation. AKT is part of the PI3K/AKT/MTOR pathway, which regulates apoptosis of tissues. Activation of AKT leads to lack of apoptosis and overgrowth of tissues.

While PTEN was previously thought to be implicated in this disorder, this is no longer thought to be the case. Patients with PTEN mutation are now thought to have Proteus-like syndrome.[7, 8]

Etiology

Proteus syndrome is a rare, sporadic disease with patchy or mosaic manifestations. In 2011, the New England Journal of Medicine published a paper by Lindhurst et al naming a mutation in AKT1 as the cause of Proteus syndrome.[6, 9] Twenty-nine patients with Proteus syndrome were studied, and 26 were found to have activation of AKT protein in the affected tissues. All unaffected patients were negative for the activating mutation.

Patients with Proteus syndrome have a somatic mutation, meaning that the mutation arises randomly during development of the fetus after fertilization. Only tissues that descend from the mutated cell have the AKT activation and, therefore, have phenotypic abnormalities. Patients who have mutation at an earlier stage of development will then have more severe clinical symptoms.

The mutated AKT1 is constitutively activated as a result of phosphorylation. AKT is part of the PI3K/AKT/MTOR pathway, which regulates apoptosis of tissues. Activation of AKT leads to lack of apoptosis and overgrowth of tissues.

While PTEN was previously thought to be implicated in this disorder, this is no longer thought to be the case. Patients with PTEN mutation are now thought to have Proteus-like syndrome.[7, 8]

Epidemiology

Frequency

Around 100 cases have been reported in the literature.[10]

Race

Proteus syndrome has no predilection for any particular race.

Sex

The male-to-female ratio is 1.9:1 (n = 96).[11]

Age

At least some of the abnormalities associated with Proteus syndrome can be present at birth or appear in the first years of life. Frank asymmetry or overgrowth is present in less than 18%. Symptoms usually progress until puberty, when there seems to be a plateau.[12] Notably, the cerebriform nevi typically do not manifest until age 2 years, on average, often delaying the correct diagnosis of Proteus syndrome.[13]

Prognosis

Patients with Proteus syndrome have difficulty ambulating because of toe macrodactyly, scoliosis, and joint instability, with frequent hip dislocations, expansive subcutaneous tumors, and compression neuropathies due to intraneural hamartomas. Some patients may have persistent atelectasis, pneumonia, or symptoms of pulmonary insufficiency. Mental retardation is present in approximately 30% of patients. Premature death has been reported in 20% of Proteus syndrome patients, most often related to deep venous thrombosis leading to pulmonary embolus, postoperative complications, or pneumonia.[11, 14]

The disease is progressive but somewhat variable in prognosis. With appropriate medical and surgical care, patients with Proteus syndrome may age normally.[15] However, despite treatment efforts, Proteus syndrome may result in extreme musculoskeletal, cutaneous, and visceral deformities.[16]

 

Presentation

History

Patients present with the characteristic abnormalities of Proteus syndrome, many of which are not present at birth. By definition, these findings are progressive and asymmetric. This is a sporadic disorder, and the patients would not have family history of similar disorder.

Physical Examination

The intrinsic variability of the clinical features may result in overdiagnosis. Diagnostic criteria and guidelines for differential diagnosis and patient evaluation have been established.[17] Only those manifestations believed to have diagnostic value are considered because of the tremendous variability in the manifestations of Proteus syndrome among and within patients.

Proteus syndrome diagnostic criteria

In 2004, the criteria below have been revised from the original description in 1999. Diagnosis requires the presence of all general criteria and various specific criteria, including the presence of the category A criterion or 2 category B criteria or 3 category C criteria.[17]

General criteria are as follows:

  • Mosaic distribution of lesions

  • Sporadic occurrence

  • Progressive course

Specific criteria are as follows:

  • Category A - Cerebriform connective-tissue nevus

  • Category B - Epidermal nevus; asymmetric, disproportionate overgrowth (limbs, skull, external auditory meatus, vertebrae, and/or viscera); and specific tumors that occur in the second decade (ie, ovarian cystadenoma, parotid monomorphic adenoma)

  • Category C - Dysregulated adipose tissue (lipomas, regional lipohypoplasia), vascular malformations (capillary, venous, and/or lymphatic), lung cysts, and facial phenotype

Cutaneous manifestations

Virtually all patients with Proteus syndrome have at least one type of cutaneous lesion, of which several different types have been reported. Skin lesions can generally be classified into 2 groups, those that are congenital or neonatal in onset and are stable (group 1) and those that are postnatal and progressive (group 2).[13]  Café au lait spots and areas of hypopigmentation or hyperpigmentation with a linear or whorled arrangement are also hallmark skin findings in persons with Proteus syndrome.[18] Hypertrichosis and nail abnormalities are also seen.[18] See the images below.

Group 1 cutaneous lesions

Epidermal nevi are a common finding in patients with Proteus syndrome. These manifest at birth as tan-to-brown, flat-topped, hyperkeratotic or verrucous papules, which run in a linear or whorled pattern along the lines of Blaschko.[18, 19] See the image below. Epidermal nevi are found asymmetrically, scattered around the body. Histologic findings are acantholysis and hyperkeratosis in a clinical lesion consistent with an epidermal nevus.[18] A research letter by Wieland et al describes finding AKT1 mutation in skin scraping samples of epidermal nevi in children with Proteus syndrome. Nonsyndromic epidermal nevi are not found to have this mutation.

Epidermal nevus of the trunk follows the Blaschko Epidermal nevus of the trunk follows the Blaschko lines.

Vascular malformations are another common cutaneous finding usually present at birth. These anomalies can be of venous, capillary, or lymphatic origin and include nevus flammeus, angiokeratomas, cavernous hemangiomas, superficial and deep lymphangiomas, and varicosity of the superficial veins. These lesions are developmental abnormalities and grow proportionately through a patient's lifetime without regression.[10] In some patients, these vascular malformations have been noted to expand beyond proportionate growth.[20] Prominence of the veins may be enhanced in areas of regional lipodystrophy.[19]

Group 2 cutaneous lesions

Cerebriform connective-tissue nevus is one of the most common and characteristic features of Proteus syndrome, although its presence is not required for diagnosis and its presence alone is not pathognomonic for Proteus syndrome. These nevi have a relatively delayed onset, making the diagnosis difficult in neonates and infants.

Cerebriform nevi occur as well-demarcated, skin-colored plaques with a cerebriform or rugated appearance (see image below). Most often, they occur on the palms or soles but have also been noted on the forearm, on the trunk, and inferior to the nasal ala.[18] Lesions on the sole typically cause the most morbidity because they cause difficulty walking, are prone to ulceration and infection, and are malodorous.[18] Histologically, the lesions consist of an irregular proliferation of highly collagenized fibrous tissue.[12, 21]

Cerebriform connective-tissue nevus on the plantar Cerebriform connective-tissue nevus on the plantar surface.

Proteus syndrome patients have adipose tissue abnormalities, resulting in lipomas and areas of lipohypoplasia. Lipomas occur as hamartomatous masses consisting of subcutaneous tissue or a variable combination of adipose, lymphatic, and hemangiomatous components (eg, lipolymphohemangiomas) and are the second most frequent type of skin findings that characterize Proteus syndrome. The soft subcutaneous tumors can affect any area of the body but are most common on the head, abdomen, groin, or legs. They appear as soft, skin-colored nodules or tumors. Patchy areas of lipohypoplasia or dermal hypoplasia are also observed in some patients.[18] Lipohypoplasia occurs as regions of skin with minimal fat, while dermal hypoplasia appears as depressed, red plaques in areas with prominent veins.

Noncutaneous manifestations

The most characteristic noncutaneous findings in patients with Proteus syndrome involve skeletal overgrowth and include corporal hemihypertrophy, partial gigantism of hands and/or feet, and skeletal anomalies such as long-bone overgrowth and scoliosis.[19] Overgrowth of the hands, feet, or both was universal in one series of 24 patients with Proteus syndrome. Arm or leg overgrowth is nearly always present.[18]

Craniofacial abnormalities are common and progressive and include cranial hemihyperplasia, hyperostosis of the skull or external auditory canal, craniosynostosis, and unilateral condylar hyperplasia.[10] Hyperostosis and unilateral condylar hyperplasia are common, while cranial hemihyperplasia and craniosynostosis are rare. A facial phenotype with dolichocephaly, long face, down-slanting palpebral fissures, ptosis, low nasal bridge, wide or anteverted nares, and open mouth at rest has been associated with mental retardation and seizures. Not all patients with Proteus syndrome have this facial phenotype.[22]

Specific tumors have been noted to occur with increased frequency in patients with Proteus syndrome. In addition to being found subcutaneously, lipomas infiltrate muscle and internal organs, including the heart, pancreas, spinal cord, and pharynx.[23, 24] Other tumors noted to occur in several patients include ovarian cystadenomas, testicular tumors, and parotid adenomas. Other benign neoplasms, such as bronchial hamartomas and multiple meningiomas, have been reported.

Cystic lung disease is found in approximately 10% of patients with Proteus syndrome and can lead to significant morbidity; with rapid progression, it can be fatal.[25] Renal cysts have also been described.[11]

Visceral overgrowth is noted, most often of the spleen or thymus.

Internal vascular malformations of the gastrointestinal tract, spleen, kidneys, and testicles have been reported. Two reports have documented intravesicular vascular lesions, one of which was associated with life-threatening hematuria.[26, 27]

Many ocular manifestations are reported in patients with Proteus syndrome. The most commonly recorded include strabismus, nystagmus, and epibulbar tumors. Other ocular defects include a high degree of myopia, retinal pigmentary abnormalities, retinal detachment, cataracts, posterior segment hamartomas, retinal coloboma, heterochromia irides, and glaucoma.[11, 28]

Additional features include asymmetric myopathy, congenital heart defects, malocclusion, hypodontia, and hypoplastic enamel.[11] Immunodeficiency has been reported in one patient with Proteus syndrome.[29]

Clinical overview images

See the images below.

Overall clinical aspect. Overall clinical aspect.
Proteus syndrome with gigantism of the feet and ma Proteus syndrome with gigantism of the feet and macrodactyly.
Proteus syndrome with hemihypertrophy of the limbs Proteus syndrome with hemihypertrophy of the limbs.

Complications

Sequelae in patients with Proteus syndrome include ambulatory difficulty due to toe macrodactyly, scoliosis, and joint instability, with frequent hip dislocations.

Dysregulated adipose growth can result in aggressive, infiltrating lipomas that can involve adjacent structures.

Pulmonary complications are a frequent cause of morbidity and mortality in Proteus syndrome patients.

 

DDx

Diagnostic Considerations

Carefully distinguish Proteus syndrome from other overgrowth disorders, particularly Klippel-Trenaunay syndrome, hemihyperplasia/lipomatosis syndrome, and neurofibromatosis type 1.[30] Several other syndromes can also be considered in the differential diagnosis[13] ; these are discussed below.

Vascular syndromes

The classic definition of Klippel-Trenaunay syndrome is the triad of vascular stain, soft tissue and/or bony hypertrophy, and venous varicosities. It often involves vascular malformation involving the lower or upper limbs, but usually only 1 limb is affected. The vascular (ie, capillary, lymphatic, and venous) malformations always exist in combination. Overgrowth is present at birth; commonly, this is more severe than that in Proteus syndrome. Moreover, Klippel-Trenaunay syndrome lacks subcutaneous tumors, palmar and/or plantar cerebriform hyperplasia, and cranial exostoses, which are usually found in Proteus syndrome patients.[31] The delayed onset of cerebriform hyperplasia often leads to the misdiagnosis of Proteus syndrome as Klippel-Trenaunay syndrome in neonates and infants.[13]

Parkes-Weber syndrome is a vascular malformation involving the upper and lower limbs. It is characterized by a diffuse capillary blushing, warmth, and underlying arteriovenous shunts.

Maffucci syndrome is characterized by hemangiomas and enchondromas.

Syndromes with pigmentation and lipomatosis

Neurofibromatosis type 1 involves café au lait macules, axillary freckling, Lisch nodules, and neurofibromas, rather than epidermal nevi and hamartomas.

Bannayan-Riley-Ruvalcaba syndrome, which is characterized by macrocephaly, lipomas, capillary malformations, and polyposis of the colon and rectum, does not cause asymmetric growth, cranial exostoses, epidermal nevi, or palmar or plantar changes.

Patients with hemihyperplasia lipomatosis syndrome lack the progressive overgrowth seen in patients with Proteus syndrome.

Encephalocraniocutaneous lipomatosis has been considered a circumscribed form of Proteus syndrome, although some authors believe that Proteus syndrome and encephalocraniocutaneous lipomatosis are different entities.[32]

Differential Diagnoses

 

Workup

Imaging Studies

Imaging studies are useful in helping to establish the diagnosis of Proteus syndrome and in tracking the progression of the disease. The following imaging studies may be useful:

  • Radiography of the skull, vertebral column, long bones, and pelvis: The most characteristic forms of overgrowth are macrodactyly, clinodactyly, asymmetrical hypertrophy of a limb, vertebral body abnormalities, and hyperostosis.[23]

  • Comparative radiographic study of the hands and feet: The most characteristic non-cutaneous features are progressive asymmetric macrodactyly, hemihypertrophy of any part of the skeleton, scoliosis and spinal canal stenosis, macrocephaly, and exostoses, especially of the skull.

  • Intracranial MRI: This is an essential initial examination to evaluate for malformations of the CNS that may be associated with mental retardation or seizures. Such findings may include multiple meningiomas, polymicrogyria, and periventricular heterotopias.

  • Abdominal MRI: Even in the absence of symptoms, abdominal MRI is important to exclude intra-abdominal lipomas. If present, these can behave aggressively, invading adjacent structures.

  • High-resolution chest CT scanning: This examination may be useful in evaluating pulmonary cystic malformations.

Other Tests

See the list below:

  • Skin biopsy: Skin biopsy should be considered to confirm the clinical diagnosis of a cerebriform connective-tissue nevus. See Proteus syndrome diagnostic criteria, category A, in Physical.

  • Genetic testing is available for the AKT1 gene.

  • Electroencephalography: Although most patients appear to be of normal intelligence, mental retardation may occur. Seizures have also been reported.

Procedures

The ongoing evaluation of the patient with Proteus syndrome should include the following procedures[17] :

  • Serial clinical photography

  • Consultation with a dermatologist, followed by biopsy if indicated

  • Consultation with an orthopedic surgeon, followed by surgical treatment if indicated

  • Ongoing treatment from a geneticist, pediatrician, or both

  • Consultations with a neurologist and an ophthalmologist

  • Referral to family support group

Histologic Findings

The histologic findings in Proteus syndrome are specific to the particular type of lesion. The histology of cerebriform connective-tissue nevi and epidermal nevi are discussed in History and Physical, along with a description of their clinical manifestations.

 

Treatment

Medical Care

The aim of medical treatment is to minimize the physical and psychosocial consequences of Proteus syndrome; this requires a multidisciplinary approach.[33]

Antithrombotic prophylaxis should be considered if the patient is undergoing a surgical procedure because the patient's vascular malformations predispose them to deep venous thromboses and fatal pulmonary emboli.[34]

Cystic pulmonary lesions should be followed closely because they may progress to pneumonia, atelectasis and potentially pulmonary insufficiency. Pulmonary hamartomas can impair respiratory function. One report describes the successful reduction in hamartoma size with rapamycin therapy.[35]

Cerebriform connective-tissue nevi are of considerable concern for patients, especially when present on the plantar surfaces, making walking uncomfortable. Conservative medical treatment for cerebriform connective-tissue nevi includes (1) keeping the feet clean and dry, (2) regularly applying antibacterial lotion to reduce odor, (3) closely monitoring for ulceration and infection, and (4) using orthotic devices. Attempts at surgical excision have led to poor outcomes; therefore, surgery is not recommended.[18]

Surgical Care

Preoperative evaluation should include assessment of the airway anatomy and pulmonary reserve because of the frequent presence of tonsillar hypertrophy and pulmonary cysts.[36]

Plastic surgeons and orthopedic surgeons can correct some skeletal defects. Epiphysiodesis can help correct asymmetric epiphyseal growth, and reduction osteotomy can be used to shorten long bones. Spinal fusion for overgrown vertebrae may prevent the development of severe kyphoscoliosis and the risk of pulmonary compromise.[10, 33]

Subcutaneous tumors should be removed in the early stages.[37]

Gonadal deformities (ovarian or testicular) should be managed aggressively because of the high incidence of neoplastic transformation.[36] The Medscape Testicular Cancer Resource Center and Ovarian Cancer Resource Center may be of interest.

Consultations

Consult a dermatologist.

Consult a plastic surgeon for the correction of defects.

Consult an orthopedic surgeon for the correction of skeletal deformities.

Ophthalmologists and neurologists may be helpful because many ocular manifestations and CNS anomalies associated with seizures or developmental delays are reported in patients with Proteus syndrome.

Referral to psychologist or psychiatrist is important for patients and for their families. The disease creates an isolating social stigma associated with having a very rare, progressive, disfiguring condition. Symptoms of depression have been reported in 23% of parents of affected children.[38]