eMedicine Specialties > Dermatology > Pediatric Diseases

Proteus Syndrome

Author: Matthew J Mahlberg, MD, Resident Physician, Department of Dermatology, New York University School of Medicine
Coauthor(s): Mina Yassaee, University of Pennsylvania School of Medicine; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Contributor Information and Disclosures

Updated: Dec 10, 2008

Introduction

Background

Proteus syndrome (PS) is a sporadically occurring hamartomatous disorder associated with irregular asymmetric overgrowth of multiple body tissues and cell lineages. 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 1979.¹ In 1983, to stress the polymorphic nature of the clinical manifestations of Proteus syndrome, Wiedermann coined the term Proteus syndrome after the Greek god Proteus (meaning polymorphous), the "Old Man of the Sea" who could change his shape at will to avoid capture.²

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.³

Pathophysiology

Proteus syndrome is a rare, sporadic disease with patchy or mosaic manifestations. The etiology of Proteus syndrome remains unknown; however, the predominant hypothesis is that Proteus syndrome is caused by a postzygotic mosaic alteration in a gene that is lethal in the nonmosaic state.⁴ Chromosomal aberrations have not been demonstrated with routine cytogenetic studies, but the karyotype in 2 patients with Proteus syndrome showed structural abnormalities of chromosome 16 and chromosome 1 in a mosaic distribution, further supporting the hypothesis of somatic mutation.⁵ Several authors initially reported a common PTEN gene mutation in their patients; however, these patients were later determined to have a Proteuslike syndrome.⁶

The concept of a somatic mutation that involves tissue growth factors or their receptors can explain several aspects of Proteus syndrome, such as the mosaic distribution of lesions, its sporadic occurrence, the unaffected offspring from affected individuals, and the existence of discordant twins.^7,8 Despite the evidence implicating a somatic mutation, no causal gene mutations are yet known for Proteus syndrome.

Mortality/Morbidity

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.⁹

Race

Proteus syndrome has no predilection for any particular race.

Sex

The male-to-female ratio is 1.9:1 (n = 96).⁹

Age

At least some of the abnormalities associated with Proteus syndrome are present at birth or they appear in the first years of life. They usually progress until puberty.¹⁰ Notably, the cerebriform nevi typically do not manifest until age 2 years, on average, often delaying the correct diagnosis of Proteus syndrome.¹¹

Clinical

History

• Asymmetric hypertrophy of the face is apparent.
• Asymmetric hypertrophy of part or all of one or both limbs, particularly the digits, is noted.
• Asymmetric hypertrophy of the trunk is also typical.
• Patients have heterogeneous skin lesions, which may include palmoplantar cerebriform hyperplasia, soft subcutaneous tumors, epidermal nevi, vascular hamartomas, and hyperpigmented or hypopigmented areas.
• Many patients have normal intelligence, but mental retardation and seizures are reported. Mental retardation is found in approximately 30% of Proteus syndrome patients and is more common in patients with typical facial phenotype.⁹

Physical

• 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).¹¹ In some patients, the presenting symptom may be one or more of the many types of heterogeneous skin lesions that characterize Proteus syndrome. These include cerebriform connective-tissue nevi, epidermal nevi, vascular hamartomas, lipomas, and hyperpigmented or hypopigmented areas. Epidermal nevi and vascular malformations are considered group 1 lesions, while lipomas and cerebriform connective-tissue nevi generally occur later and are considered group 2.¹¹
  • Group 1 cutaneous lesions are characterized as follows:
    • 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.^13,14 See Media File 1. Epidermal nevi are found asymmetrically, scattered around the body. Histologic findings are acantholysis and hyperkeratosis in a clinical lesion consistent with an epidermal nevus.¹³
    • 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.⁷ In some patients, these vascular malformations have been noted to expand beyond proportionate growth.¹⁵ Prominence of the veins may be enhanced in areas of regional lipodystrophy.¹⁴
  • Group 2 cutaneous lesions are characterized as follows:
    • 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. One patient developed an isolated plantar cerebriform collagenoma who lacked the general diagnostic criteria for Proteus syndrome.¹⁶  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 Media File 2). 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.¹³ Lesions on the sole typically cause the most morbidity because they cause difficulty walking, are prone to ulceration and infection, and are malodorous.¹³ Histologically, the lesions consist of an irregular proliferation of highly collagenized fibrous tissue.^10,17
    • 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.¹³ Lipohypoplasia occurs as regions of skin with minimal fat, while dermal hypoplasia appears as depressed, red plaques in areas with prominent veins.
  • Cutaneous manifestations also include striking overgrowth anomalies, including asymmetric hypertrophy of the face, part or all of one or both limbs (particularly digits), the trunk, or any combination of these; often, hemihypertrophy of one side of the body results.¹⁸ See Media Files 3-5. These abnormalities can also be the first to attract the parents' attention and cause considerable anxiety. 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.¹³ Hypertrichosis and nail abnormalities are also seen.¹³
• 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.¹⁴ 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.¹³
  • Craniofacial abnormalities are common and progressive and include cranial hemihyperplasia, hyperostosis of the skull or external auditory canal, craniosynostosis, and unilateral condylar hyperplasia.⁷ 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.¹⁹
  • 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.^20,21 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.²² Renal cysts have also been described.⁹
  • 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. One report of intravesicular venous lesions was associated with life-threatening hematuria.²³
  • 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.^9,24
  • Additional features include asymmetric myopathy, congenital heart defects, malocclusion, hypodontia, and hypoplastic enamel.⁹ Immunodeficiency has been reported in one patient with Proteus syndrome.²⁵
• Proteus syndrome diagnostic criteria: In 2004, the following criteria had 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.¹²
  • 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 (as described above)

Causes

The etiology of Proteus syndrome is unknown, but a Proteuslike syndrome has been associated with PTEN mutations.

• The syndrome occurs sporadically in healthy families.
• Routine cytogenetic studies have not consistently revealed chromosomal aberrations.
• The concept of a somatic mutation that affects the production or regulation of tissue growth factors or their receptors could explain the sporadic occurrence, the random distribution of overgrowth, and the wide range of findings within the phenotype.

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