Proteus Syndrome

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 19th century) 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.[1] 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.[2, 3]

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

Patient education

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.[4]

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.

Frequency

International

Proteus syndrome is believed to be exceedingly rare, with less than 100 confirmed affected individuals reported worldwide.[5] This suggests that prevalence is less than 1 case per 1,000,000 live births. However, this condition is also often misdiagnosed.

Mortality/Morbidity

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.[6]

• 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.[7]

• 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.[8]

• 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.[8]

• 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.[5] More recently, a patient with Proteus syndrome was shown to have multiple spinal cord meningiomas.[9]

• Cystic lung malformations are reported in slightly less than 10% of patients and are especially common in younger female patients.[8]

• Intrathoracic or intra-abdominal lipomas occur and should be screened for because of the particularly aggressive nature of these lesions.[5, 10]

• 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.[11, 12]

• 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.[13]

A study by Sapp et al indicated that in individuals with Proteus syndrome, the probability of death by age 22 years is 25%. However, the report also found evidence of a postadolescence moderation of the disease process and resulting reduction in the mortality rate.[14]

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.[8]

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.

In cases of suspected Proteus syndrome, clinicians must carefully use the standard diagnostic criteria (as listed below) to preclude misdiagnosis. These criteria can guide the decision to order AKT1 testing.

The following are the 3 general criteria necessary for clinical diagnosis without regard to specific clinical features (when patients meet the strict clinical criteria, there is a >90% positive predictive value in the genetic testing):

• 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 findings from category A, B, or C.

Category A

Connective tissue nevus is required.

Category B

Two of the following are 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 three of the following are required:

• Lipomas or focal atrophy of adipose tissue

• Capillary, venous, or lymphatic malformation or lung bullae

• Facial features including dolichocephaly, a long face, down - slanting palpebrae, ptosis, depressed nasal bridge, anteverted nares, and open mouth position while at rest

The following are characteristics of Proteus syndrome:

• 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

Cutaneous findings include the following:

• 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

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.

AKT1 testing should be offered to patients suspected of having Proteus syndrome. A punch biopsy of affected tissue is ideal, but a skin scraping of epidermal nevi has been noted to be effective.[16] Because the mutation is somatic, peripheral blood testing is not high yield in diagnosis.

Platelet studies may be indicated for patients with numerous vascular malformations or splenomegaly, especially those with a history of easy bruising or petechiae. A coagulation workup may be indicated preoperatively for patients with Proteus syndrome in light of the apparent increased risks for thrombotic events such as deep vein thrombosis (DVT) or pulmonary embolism (PE).

See the list below:

• Radiography

  • A baseline skeletal survey is recommended for all individuals at the time of diagnosis, with follow-up radiography as necessary.

  • Consider anteroposterior (AP) and lateral spine radiography for an affected child with clinical evidence of scoliosis or kyphosis.

  • Radiography of enlarged digits or limbs may be necessary if orthopedic intervention is considered.

• MRI or CT scanning[15]

  • MRI or CT scanning may help evaluate intracranial anatomy, especially cranial asymmetry that might be associated with cerebral cortex overgrowth. MRI of the head is also an important screening tool for intracranial malformations in children with seizures or developmental delay.[17]

  • A 3-dimensional CT scan may be very useful in evaluating bony overgrowth of the cranium or facial structures; however, both soft tissue and bony involvement are typical for the related hemihyperplasia.

  • MRI of the thorax, abdomen, or extremities may be necessary to define the boundaries of a subcutaneous lesion such as a vascular malformation or lipoma that extends deep into soft tissues. Abdominal and thoracic MRIs are vital screening tools even when clinical symptoms are absent because undiagnosed internal lipomas can cause future problems.

  • High-resolution chest CT scanning may especially help identify pulmonary cystic malformations, which may be suspected in patients with recurrent pneumonias, atelectasis, or respiratory compromise.[17] Postprocessing CT densitovolumetry may also help to more clearly delineate the extent of cystic lung involvement in patients with pulmonary manifestations.[18]

  • Multidetector CT with intravenous contrast may be used to identify a PE when this becomes a clinical concern.[17]

See the list below:

• Electroencephalography is indicated for any patient with a history or symptoms suggesting seizures.

• Pulmonary function tests may help evaluate patients with respiratory symptoms.

• Venograms, Doppler studies, or ventilation/perfusion (V/Q) studies may be helpful diagnostic tools in patients with symptoms suggestive of DVT or PE.

See the list below:

• Connective tissue nevi resemble tightly compacted, collagen-rich connective tissue.

• Epidermal nevi generally exhibit a combination of hyperkeratosis, parakeratosis, acanthosis, and papillomatosis. Clinically they may appear to be somewhat streaky; may be tan, brown, or dark brown; and are generally well-circumscribed, papular, pebbly lesions.[5]

• Lipomas, whether invasive or well circumscribed, are made up of benign-appearing, mature adipocytes. Lipomas in Proteus syndrome tend to not be encapsulated and can lead to local invasion, most often occurring with lesions located in or on the thorax or abdomen.[5] Even lesions that clinically resemble lipomas may not just contain fatty components, and pathologic findings range from simple lipomas to more complex lipohamartomas.[19]

• Vascular malformations are of the single-channel type, with capillaries, venules, lymphatics, or combinations of these noted within the lesions. They tend to be lined with flat epithelium and growth tends to mirror the patient’s own somatic growth; however, unlike sporadic vascular lesions that may regress over time, this seldom, if ever, occurs in patients with Proteus syndrome. To add to the confusion, vascular lesions in Proteus syndrome frequently contain lymphatic elements and are therefore sometimes classified as lymphatic malformations or lymphovenous malformations.[19]

• Tissue resected from enlarged digits generally has a hamartomatous appearance with less organized connective tissue elements; hyaline cartilaginous nodules may also be seen.[19]

The mainstays of treatment for Proteus syndrome include early identification of serious medical problems and the use of prophylactic and symptomatic treatment.

• Hemihyperplasia

  • Medical approaches are limited and should be considered in the context of functional improvement.

  • Leg length discrepancy can create a host of secondary morbidities and needs to be addressed by an experienced orthopedist.

  • Macrodactyly can make it difficult for the patient to write, hold objects, dress, eat, or find comfortable footwear.

• Hemifacial macrosomia or macroglossia

  • These present cosmetic concerns and may affect dental occlusion and mastication.

  • Augment routine dental and orthodontic care with a maxillofacial surgeon or craniofacial team consultation as indicated.

• Scoliosis: Early recognition may permit nonsurgical attempts to halt progression.

• Cutaneous and subcutaneous lesions: Periodic evaluation is essential since lipomas and vascular malformations may have local or even systemic effects.

• Cutaneous vascular markings and malformations: Laser treatment is useful for removing cutaneous vascular markings and malformations, such as port wine stains and capillary hemangiomas. It is not yet effective for permanently removing café au lait spots or melanin-related hyperpigmentation.

• Although no consistently successful way to treat epidermal nevi has been established, individual reports have noted success with various approaches such as CO 2 or ruby lasers, dermatome excision followed by phenol peel, cryotherapy, keratolytics, and even intralesional steroid injection.[20]

• Secondary thrombocytopenia: This may be indicated by a history of easy bruising or presence of petechiae.

• Thrombosis: Aggressive management of thrombosis may be lifesaving in patients who present with calf or leg pain, a palpable cord, and shortness of breath or respiratory distress. Physicians who care for individuals with Proteus syndrome should be made aware of the potential thrombotic risks; hematologic evaluation prior to elective surgery should also be considered.[5]

• Internal lesions: MRIs of the chest and abdomen can reveal internal lesions such as lipomas or pulmonary cysts. Undetected, these can cause very serious problems before becoming symptomatic.

 

Preoperative coagulation studies may provide guidance for perioperative and postoperative management of patients with Proteus syndrome. Some clinicians have suggested serious consideration of prophylactic anticoagulation prior to elective surgery; however, this decision must be made on an individual basis while exploring the risks and benefits and in the context of the patient’s clinical circumstances (including laboratory studies and the anticipated surgery).[11]

Progressive scoliosis may require orthopedic intervention. Exceptionally large digits may require surgical reduction or even amputation in extreme circumstances so that the patient can wear shoes or use their hand.

Hemifacial macrosomia or macroglossia may require surgical intervention if airway obstruction, feeding difficulties, or severe malocclusion is present. These complex situations often require a coordinated, multidisciplinary team approach with input from a craniofacial surgeon, orthodontist, and dentist.

Although any competent surgeon can resect large or invasive cutaneous or subcutaneous lesions, plastic surgical consultation is advisable for cosmetically important areas such as the face. Subcutaneous lesions impinging on vital structures, obstructing vision, or growing rapidly deserve immediate attention. Laser lipolysis using a 980-nm laser diode is a more recent addition to the treatment armamentarium and has been used successfully in a child to reduce the size of a large lipomatous lesion.[21] This approach may be shown in the future to have advantages over surgical excision or liposuction for specific types of lesions.

Internal lipomas or cystic lung malformations may also require surgical resection.

A study by Crenshaw et al indicated that lower-limb discrepancy (LLD) in children with Proteus syndrome can be diminished, with few complications, through surgery. The investigators reported that by the time patients in the study underwent their first operation, the average LLD was 5.0 cm. Among the patients who needed no overcorrection, LLD at the last clinical encounter averaged 2.6 cm. Essential parts of the surgical protocol included careful monitoring, rapid mobilization, deep venous thrombosis prophylaxis, and the use of sequential compression devices. Two of the study’s eight patients developed mild knee valgus, which was successfully treated with standard guided growth techniques.[22]

See the list below:

• An orthopedist is a vital team member who must address the functional significance of both hemihyperplasia and scoliosis.

• A craniofacial surgeon or surgical team can address cranial asymmetry or hemifacial macrosomia.

• A general or plastic surgeon can address resection of cutaneous or subcutaneous lesions when necessary.

• A neurosurgeon can address CNS lesions such as cortical overgrowth, with or without hydrocephalus. Patients undergoing complex craniofacial procedures can also benefit from a neurosurgeon's operative expertise.

• A dermatologist can evaluate and monitor subcutaneous and cutaneous lesions and can perform biopsies when necessary.

• An ophthalmologist can closely monitor strabismus or orbital asymmetry in a patient with ocular involvement.

• A dentist can address dental anomalies and an orthodontist can treat malocclusion.

• A geneticist and genetic counselor can provide the patient and family with additional information about the diagnosis, diagnostic testing, proposed genetic mechanisms, and recurrence risks. Family planning options and prenatal diagnosis are also addressed in this clinical setting.

• A developmental pediatrician can evaluate a child with learning disabilities or developmental delays. This specialist makes recommendations for ongoing therapy and school interventions.

• A psychologist or trained mental health professional can assist a child or adolescent with significant disfigurement, if adjustment problems arise. Social stigmatization is a major obstacle for many children and adults. Both patients and family members may benefit from ongoing psychotherapy. Clinicians should be especially aware of how parents of affected children are coping and should consider referral for psychological support as needed. Peer support for affected older teens and adults is available from the Proteus Syndrome Organization.[23]

See the list below:

• In the absence of surgery, encourage patients to participate in all activities as fully as possible.

• Patients who undergo spinal fusion or other major surgical procedures need to confer with their surgeons about acceptable activities.

Drug therapy is not currently a component of the standard of care for Proteus syndrome (see Treatment). However, a study by Lindhurst et al indicated that ARQ 092 reduces the abnormally increased phosphorylation of the protein kinase Akt occurring in cells and tissues with the AKT1 E17K Proteus syndrome mutation. This suggests that the agent, which is under investigation as a cancer therapy, may also offer a treatment for Proteus syndrome.[24]

See the list below:

• Although patients need comprehensive primary care, Proteus syndrome is so rare and complex that an experienced subspecialist, such as a geneticist, should serve as medical coordinator. Annual examinations focusing on common complications and disease progression with appropriate subspecialty referrals are in order.

• Numerous authors have advocated for a team approach in the management of the myriad complications that can occur in patients with Proteus syndrome.

• Guidelines developed for ongoing patients evaluations were published in 1999 and are still appropriate today.[25] These include the following:

  • Serial clinical photography to document progression or nonprogression

  • Skeletal survey at the time of diagnosis and subsequently as clinically indicated

  • MRIs of affected areas as well as the chest and abdomen to identify silent but potentially serious internal lesions

  • Dermatology consultation to address cutaneous lesions

  • Orthopedic consultation to monitor bony overgrowth with surgical intervention as needed

  • Routine pediatric or adult primary care follow-ups annually for a comprehensive examination (may also include gynecologic examinations for female patients)

  • Other consultations as needed (See Consultations.)

  • Referral to a family or peer support group (See Patient Education.)

See the list below:

• Hospitalization may be necessary for major surgical procedures in patients with Proteus syndrome.

See the list below:

• Hemihyperplasia, asymmetric overgrowth of limbs or digits, and megalospondylodysplasia

• Scoliosis with or without unusual habitus

• Macrocephaly, macroglossia, and cranial or auditory canal hyperostosis

• Connective tissue nevi, epidermal nevi, lipomas, or vascular malformations

• Clinically silent but locally invasive internal lipomas or vascular malformations

• Pulmonary cystic malformations

• Deep vein thrombosis (DVT), pulmonary embolism (PE), or both

• Splenomegaly or thymic enlargement

• Ovarian cystadenomas, testicular tumors, or parotid adenomas

• Strabismus

• Dental anomalies

• Learning disabilities or mental retardation

See the list below:

• Although data on long-term survival are not currently available, complications (eg, CNS malformations, severe and progressive scoliosis, thrombotic events, invasive internal lesions) are likely to contribute to premature death in a subset of affected individuals.

• Prompt attention to complications and early detection of potential problems may significantly reduce overall morbidity and mortality.