eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Proteus Syndrome

Author: Beth A Pletcher, MD, Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey
Contributor Information and Disclosures

Updated: Mar 18, 2010

Introduction

Background

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.¹

This condition is characterized by various cutaneous and subcutaneous lesions, including vascular malformations, lipomas, hyperpigmentation, and several types of nevi. Partial gigantism with limb or digital overgrowth is pathognomonic, with an unusual body habitus and, often, cerebriform thickening of the soles of the feet. 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.¹

Examples of various malformations and physical symptoms in Proteus syndrome are shown in the images below.

Pathophysiology

Manifestations probably result from somatic mosaicism for a dominant lethal gene, but the gene locus has yet to be identified. Because hyperplasia and hypoplasia often occur together, another hypothesis suggests that the postzygotic event that results in these clinical manifestations is embryonic somatic recombination leading to at least 3 subsets of cells. These subsets include normal, overgrowth (pleioproteus), and atrophy (elattoproteus) cells. Reports of discordance for Proteus syndrome in monozygotic twins supports the theory that the condition arises postzygotically.²

Frequency

International

Proteus syndrome is believed to be exceedingly rare, with less than 100 confirmed affected individuals reported worldwide.³ This suggests that prevalence is less than 1 case per 1,000,000 live births.

Mortality/Morbidity

The following is noted in patients with Proteus syndrome:

• Hemihyperplasia (asymmetric overgrowth of the head, face, and digits) and soft tissue overgrowth are among the more significant medical complications. Lesions are identified at birth in more than 17% of patients.⁴ 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.⁵
• Soft tissue and bone overgrowth may slow after puberty.¹
• 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.⁶
• 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.⁴
• 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.⁴
• 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.³ More recently, a patient with Proteus syndrome was shown to have multiple spinal cord meningiomas.⁷
• Cystic lung malformations are reported in slightly less than 10% of patients and are especially common in younger female patients.⁴
• Intrathoracic or intra-abdominal lipomas occur and should be screened for because of the particularly aggressive nature of these lesions.^3,8
• Increased risk for thrombotic events such as deep vein thrombosis (DVT) or pulmonary embolism (PE) contribute to the overall morbidity and mortality, even in young children, and is reported to be one of the most common causes of death in affected individuals.⁹
• 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.¹⁰

Race

No racial or ethnic differences in disease occurrence are apparent.

Sex

Males are almost twice as likely to be affected as females and also appear to be at greater risk for thrombosis than females.⁴

Age

The genetic change or somatic event leading to this syndrome is likely to present shortly after conception and is propagated in one or more subsets of embryonic cells. Even so, the diagnosis may not be suspected in many individuals until later infancy or early childhood, depending on the degree of overgrowth or rate of cutaneous lesion appearance. A fetus was prenatally identified with ultrasound findings of a large right-sided mass and unusual hand configuration. However, in this case, the actual diagnosis was not made until postmortem examination.

Clinical

History

In cases of suspected Proteus syndrome, clinicians must carefully use the standard diagnostic criteria (as listed below) to preclude misdiagnosis. A literature review suggests that less than half of reported cases have clearly defined Proteus syndrome.⁴  This has led to speculation that a subset of patients with presumed Proteus syndrome have PTEN gene mutations, when, in fact, these individuals do not have enough diagnostic features warrant a diagnosis of Proteus syndrome.³ The following are the 3 general criteria necessary for clinical diagnosis without regard to specific clinical features:

• Lesions follow a mosaic distribution or pattern.
• Problems follow a progressive course.
• The disorder appears to be sporadic (ie, not inherited).

Diagnostic confirmation also requires the presence of manifestations listed under the following categories:

• Category A (1 required) - Connective tissue nevus
• Category B (2 required)
  • Epidermal nevus
  • Disproportionate overgrowth of one or more of the following: limbs, digits, cranium, vertebrae, external auditory meatus, spleen, or thymus
  • Bilateral ovarian cystadenomas or a parotid monomorphic adenoma in a patient younger than 20 years
• Category C (all 3 required)
  • Lipomas or focal atrophy of adipose tissue
  • Capillary, venous, or lymphatic malformation
  • Facial features including dolichocephaly, a long face, down-slanting palpebrae, ptosis, depressed nasal bridge, anteverted nares, and open mouth position while at rest

Physical

• When present at birth, asymmetric limb, digital, or cranial overgrowth may be a major diagnostic finding.
• Digital, limb, or cranial overgrowth usually involves both soft tissue and bone.
• Cranial or external auditory canal hyperostosis may be seen.
• Scoliosis associated with disproportionate vertebral growth is common.
• The combination of disproportionate overgrowth and focal atrophy can lead to a unique habitus characterized by wasting of upper arm muscles, an elongated thorax, an extremely gracile neck, and muscular hypertrophy of the thighs.
• Cystic lung malformations that lead to cystic pulmonary emphysema and restrictive lung disease secondary to severe scoliosis are relatively common. Recurrent pneumonias, shortness of breath, or reduced exercise tolerance may point to significant respiratory compromise.
• Organomegaly is less common but can also occur with splenomegaly or occasional thymus enlargement.
• The 6 most common skin findings include (from most to least frequent) lipomas, vascular malformations, connective tissue nevi, epidermal nevi, partial lipohypoplasia, and patchy dermal hypoplasia.
  • Connective tissue nevi are virtually pathognomonic and typically have a cerebriform contour. They often occur on the soles of the feet but can also be found on other areas.
  • Epidermal nevi tend to be the flat, soft variety.
  • Lipomas may be well demarcated or locally invasive with large intra-abdominal or intrathoracic lesions presenting serious medical concerns.
  • Vascular lesions may include capillaries, lymphatics, venules, or combinations of these. They tend to grow gradually over time and, unlike the more common capillary hemangiomas seen in the general population, rarely regress. Port wine stains or patchy hyperpigmentation may also be seen.
• Learning difficulties or mental retardation are seen in about 1 in 5 individuals with Proteus syndrome.
• Facial features that often coincide with poor mental development include a prominent occiput, ptosis with or without down-slanting palpebrae, upturned nose, and a long, narrow face.
• Seizures are reported in more than 10% of affected individuals.

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