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. [7] 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. [7]
General criteria are as follows:
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Mosaic distribution of lesions
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Sporadic occurrence
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Progressive course
Specific criteria are as follows:
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Category A - Cerebriform connective-tissue nevus
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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)
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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). [24] Café au lait spots and areas of hypopigmentation or hyperpigmentation with a linear or whorled arrangement are also hallmarked skin findings in persons with Proteus syndrome. [11] Hypertrichosis and nail abnormalities are also seen. [11] 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. [11, 25] 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. [11] 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.
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 throughout a patient's lifetime without regression. [22] In some patients, these vascular malformations have been noted to expand beyond proportionate growth. [26] Prominence of the veins may be enhanced in areas of regional lipodystrophy. [25]
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. [11] Lesions on the sole typically cause the most morbidity because they cause difficulty walking, are prone to ulceration and infection, and are malodorous. [11] Histologically, the lesions consist of an irregular proliferation of highly collagenized fibrous tissue. [23, 27]
Papules and nodules over palms and soles; discrete nodules over digits, eyelids, perinasal skin and lips may be seen. These non-cerebriform connective tissue nevus may progress to cerebriform nevus over time. [28]
Nail abnormalities that are seen with proteus syndrome are brachonychia, nail ridging, onychoschizia, leukonychia and onycholysis. Dental enamel hypoplasia, dental pits, asymmetric tooth and overgrowth of gingival oral mucosa and tongue may be seen. [28]
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. [11] 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. [25] 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. [11]
Craniofacial abnormalities are common and progressive and include cranial hemihyperplasia, hyperostosis of the skull or external auditory canal, craniosynostosis, and unilateral condylar hyperplasia. [22] 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. [29]
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. [6, 30] 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. [31] Renal cysts have also been described. [2]
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. [32, 33]
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. [2, 34]
Additional features include asymmetric myopathy, congenital heart defects, malocclusion, hypodontia, and hypoplastic enamel. [2] Immunodeficiency has been reported in one patient with Proteus syndrome. [35]
Clinical overview images
See the images below.
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Epidermal nevus of the trunk follows the Blaschko lines.
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Cerebriform connective-tissue nevus on the plantar surface.
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Overall clinical aspect.
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Proteus syndrome with hemihypertrophy of the limbs.
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Proteus syndrome with gigantism of the feet and macrodactyly.
