Proteus syndrome

What is Proteus syndrome

Proteus syndrome is a rare condition characterized by progressive overgrowth of the bones, skin, adipose tissue and central nervous system 1). Organs and tissues affected by Proteus syndrome grow out of proportion to the rest of the body. The overgrowth is usually asymmetric, which means it affects the right and left sides of the body differently. Newborns with Proteus syndrome have few or no signs of the condition. Overgrowth becomes apparent and progresses rapidly between the ages of 6 and 18 months and gets more severe with age, causing severe overgrowth and disfigurement. It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism.

In people with Proteus syndrome, the pattern of overgrowth varies greatly but can affect almost any part of the body. Bones in the limbs, skull, and spine are often affected. The condition can also cause a variety of skin growths, particularly a thick, raised, and deeply grooved lesion known as a cerebriform connective tissue nevus. This type of skin growth usually occurs on the soles of the feet and is hardly ever seen in conditions other than Proteus syndrome. Blood vessels (vascular tissue) and fat (adipose tissue) can also grow abnormally in Proteus syndrome.

Some people with Proteus syndrome have neurological abnormalities, including intellectual disability, seizures, and vision loss. Affected individuals may also have distinctive facial features such as a long face, outside corners of the eyes that point downward (down-slanting palpebral fissures), a low nasal bridge with wide nostrils, and an open-mouth expression. For reasons that are unclear, affected people with neurological symptoms are more likely to have distinctive facial features than those without neurological symptoms. It is unclear how these signs and symptoms are related to abnormal growth.

Other potential complications of Proteus syndrome include an increased risk of developing various types of noncancerous (benign) tumors and a type of blood clot called a deep venous thrombosis (DVT). DVTs occur most often in the deep veins of the legs or arms. If these clots travel through the bloodstream, they can lodge in the lungs and cause a life-threatening complication called a pulmonary embolism. Pulmonary embolism is a common cause of death in people with Proteus syndrome.

Proteus syndrome is caused by AKT1 gene mutations that occur during early development, the disorder is not inherited and does not run in families.

Proteus syndrome is a rare condition with an incidence of less than 1 in 1 million people worldwide. Only a few hundred affected individuals have been reported in the medical literature 2).

Researchers believe that Proteus syndrome may be over-diagnosed, as some individuals with other conditions featuring asymmetric overgrowth have been mistakenly diagnosed with Proteus syndrome. To make an accurate diagnosis, most doctors and researchers now follow a set of strict guidelines that define the signs and symptoms of Proteus syndrome.

The diagnosis of Proteus syndrome is based on published clinical diagnostic criteria that include all three general characteristics (mosaic distribution of lesions, sporadic occurrence, progressive course) and additional specific clinical criteria 3). Identification of a mosaic, somatic, heterozygous pathogenic variant in AKT1 by molecular genetic testing can establish the diagnosis if the clinical criteria are inconclusive.

Confirming a diagnosis of Proteus syndrome can be difficult and the interpretation of the clinical diagnostic criteria is controversial. The identification of the causative gene variant in AKT1 can allow molecular diagnosis, although this too can be challenging. The gene alteration is uncommonly present in the blood and therefore DNA diagnostic testing must generally be performed on biopsies of affected tissues. Other diagnostic techniques that may be used in evaluation may include plain x-rays (radiography), computed tomography (CT) scans for skull lesions, high resolution CT scan of the lungs for pulmonary cysts and magnetic resonance imaging (MRI) of the brain, abdomen, pelvis and limbs. Ultrasound is used to detect scrotal or ovarian masses and can be used to evaluate deep vein thromboses.

The treatment of Proteus is directed toward the specific symptoms that are apparent in each individual. Multiple orthopedic procedures are usually necessary to try and control the rapid overgrowth associated with Proteus syndrome. Surgery may be necessary when overgrowth interferes with joint function or causes scoliosis or angular deformities. Surgery to reduce overgrown tissues or body parts may be indicated. Epiphysiodesis (removal or ablation of growth plates in bones) may be especially useful to prevent or treat the skeletal overgrowth of Proteus syndrome.

Patients with Proteus syndrome undergoing surgical procedures must be closely monitored because surgery may predispose affected individuals to deep vein thrombosis. When undergoing surgery, affected individuals should be considered for prophylaxis to prevent blood clots (antithrombotic prophylaxis) or treatment for blood clots once they develop.

Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Figure 1. Proteus syndrome

Proteus syndrome

Footnote: Thirty-year old male with Proteus syndrome. (A) Cranial hyperostosis involving his right frontoparietal bones. (B) Bony overgrowth with ulnar deviation of his bilateral 2nd fingers. (C) Lateral view of his right leg shows bony hemihyperplasia and vascular malformations—venous varicosities. (D) Frontal view of his legs shows venous varicosities, bony overgrowth of his right leg. (E) Dorsolateral view of left foot, and (F) plantar view of left foot with cerebriform connective tissue nevus (CCTN).

[Source 4) ]

Figure 2. Proteus Syndrome in a 12-Year-Old Boy

Proteus Syndrome in a 12-Year-Old Boy
[Source 5) ]

We have a child with Proteus syndrome. What are the chances our next child will also have Proteus syndrome?

It is very important to talk about questions like this with a geneticist or genetic counselor, because having the right diagnosis for your child is very important in answering this question. The chances for a person with Proteus syndrome to have an affected sibling are low, much less than 1/100 or 1 percent. Adults with Proteus syndrome have never had any affected children.

What medical problems can Proteus syndrome cause?

Proteus syndrome can affect any part of the body but commonly affects the bones and skin. Overgrowth of a bone can cause orthopedic problems, and overgrowth of the skin can cause cosmetic and other concerns. Less commonly, individuals with Proteus syndrome have lung problems that require monitoring. Many children and adults with Proteus syndrome have normal intelligence and have good general health. Children and adults with Proteus syndrome are at risk to get a type of blood clot called a deep vein thrombosis (DVT), which can cause a serious problem called a pulmonary embolism. It is important for doctors caring for people with Proteus syndrome to be aware of this risk.

It is important to realize that every person with Proteus syndrome is different and that no two people with this condition will have the same medical concerns.

How can I help my child or my family cope with Proteus syndrome?

Proteus syndrome is a rare condition that can cause physical differences and changes over time. Many parents and families are frustrated by how long it can take to get a diagnosis and how hard it can be to find a doctor with experience treating this condition. Even after a family has a diagnosis, it can be very difficult to explain this condition to others or answer rude and unwelcome questions, and some children struggle to adapt to physical challenges or differences.

Every family of a child with a rare condition faces unique challenges and has a unique set of strengths. Learning more about the condition and talking with other parents are two things that many families say are helpful. Older children and teens can find connecting with other children with similar concerns to be very helpful, and many children with chronic illnesses say that sharing their thoughts about their condition with another young person their age makes them feel less alone and more understood. Sibilngs of children with health concerns have their own unique emotional needs, and there are a growing number of resources, such as Sibshops [http://www.siblingsupport.org/sibshops], available to them.

Proteus syndrome causes

Proteus syndrome results from a mutation in the AKT1 gene. This genetic change is not inherited from a parent; it arises randomly in one cell during the early stages of development before birth. As cells continue to grow and divide, some cells will have the mutation and other cells will not. This mixture of cells with and without a genetic mutation is known as mosaicism.

The AKT1 gene helps regulate cell growth and division (proliferation) and cell death. A mutation in this gene disrupts a cell’s ability to regulate its own growth, allowing it to grow and divide abnormally. Increased cell proliferation in various tissues and organs leads to the abnormal growth characteristic of Proteus syndrome. Studies suggest that an AKT1 gene mutation is more common in groups of cells that experience overgrowth than in the parts of the body that grow normally.

In some published case reports, mutations in a gene called PTEN have been associated with Proteus syndrome. However, many researchers now believe that individuals with PTEN gene mutations and asymmetric overgrowth do not meet the strict guidelines for a diagnosis of Proteus syndrome. Instead, these individuals actually have condition that is considered part of a larger group of disorders called PTEN hamartoma tumor syndrome. One name that has been proposed for the condition is segmental overgrowth, lipomatosis, arteriovenous malformations, and epidermal nevus (SOLAMEN) syndrome; another is type 2 segmental Cowden syndrome. However, some scientific articles still refer to PTEN-related Proteus syndrome.

Proteus syndrome symptoms

Proteus syndrome may affect bone and connective tissue, fatty tissues, skin, central nervous system and internal organs (viscera). The specific symptoms and severity varies greatly from patient to patient. In some patients, affected individuals may exhibit only a few, mild symptoms of Proteus syndrome, making diagnosis challenging.

Proteus syndrome may affect bone and connective tissue, fatty tissues, skin, central nervous system and internal organs (viscera). The specific symptoms and severity varies greatly from person to person. Some affected individuals may exhibit only a few, mild symptoms of Proteus syndrome, making diagnosis extremely difficult.

Most affected individuals are born without any noticeable symptoms. Some patients can have brain overgrowth apparent at birth. Overgrowth usually begins between 6-18 months. The specific affected areas of the body vary greatly from patient to patient. Bone, connective tissue and fat are the most commonly affected tissues in the body.

Overgrowth associated with Proteus syndrome is irregular, disproportionate, and may affect one side of the body such as only one foot and not the other (asymmetric). Overgrowth of bone (hyperostosis) may occur affecting the skull, the long bones of the arms and legs, and the feet and hands. Overgrowth in Proteus syndrome is usually severe and typically deforms bones to the point that they are unrecognizable. The spine may be affected, resulting in scoliosis – a condition in which the spine is abnormally curved. Progressive, bony overgrowth eventually affects the joints limiting range of motion. Ultimately, an affected joint may become significantly overgrown and locked in place (immobilized).

In childhood, affected individuals may develop abnormal skin conditions including localized areas of severe fatty overgrowth especially affecting the stomach or the arms and legs. In some, benign tumors consisting of fatty tissue (lipomas) may develop. In addition to fatty tissue overgrowth, some affected individuals may develop areas of fatty tissue loss (atrophy) especially in the chest.

Affected children may also develop a raised, rough (verrucous) lesion (epidermal nevus) that is usually rough and dark brown or brownish-black. An epidermal nevus may be present at birth. Another skin lesion known cerebriform connective tissue nevus (CCTN) may occur. Cerebriform connective tissue nevus – this is a very distinct type of skin overgrowth seen almost exclusively in people with Proteus syndrome. This slow-growing lesion is most often found on the feet and less commonly on the hands. It is not present at birth and is made up of thickened, abnormally firm subcutaneous tissue. The skin may develop deep grooves or furrows.

Malformations of various blood vessels (vascular malformations) are common in Proteus syndrome. The capillaries, veins, and lymph vessels can be affected. The capillaries are tiny blood vessels that connect arteries and veins. Veins are blood vessels that take blood to the heart. Lymph vessels are part of the lymphatic system, the circulatory network of vessels, ducts and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body.

Individuals with Proteus syndrome may be at risk for developing blood clots in the legs a condition known as deep vein thrombosis (DVT). The legs may become painful and swollen and blood vessels in the legs may be visibly enlarged. In some, a piece of a DVT may break off and travel up the bloodstream toward the lungs, where it may cause a pulmonary embolism. A pulmonary embolism is the lodging of a clot within the pulmonary artery, which can potentially cause breathlessness, a sudden pain the chest, exhaustion, or life-threatening complications such as high blood pressure of the pulmonary artery.

Additional findings can occur in Proteus syndrome including abnormal enlargement of certain internal organs such as the spleen, thymus, colon, and other tissues.

Affected individuals also have a predisposition of developing a wide variety of tumors, most of which are benign. The tumors most often associated with Proteus syndrome are bilateral ovarian cystadenomas, a group of rare salivary gland tumors known as monomorphic adenomas, and meningiomas.

Less common findings in Proteus syndrome include malformations of the central nervous system such as overgrowth of half of the brain (hemimegalencephaly). In some patients, intellectual disability may be present and seizures have been reported as well. Individuals with these abnormalities may also have distinct facial features including a long face, downward slanting eyelid folds (palpebral fissures), droopy eyelids (ptosis), low bridge of the nose, wide nostrils (nares), and a long narrow head (dolichocephaly). The reason for the association of neurological and facial abnormalities is unknown.

Some individuals with Proteus syndrome may develop cystic lung disease, kidney or urinary abnormalities, and eye abnormalities such as crossed eyes (strabismus) or benign cysts or tumors of the eyeballs (epibulbar cysts or dermoids).

Proteus syndrome diagnosis

The diagnosis of Proteus syndrome is based on clinical criteria that include three general characteristics and a specific symptom checklist. A mutation in the AKT1 gene can be identified in more than 90% of people meeting the diagnostic criteria.

There are three general characteristics or features that must be present for doctors to consider a diagnosis of Proteus syndrome 6):

  1. Mosaic distribution: This means that the areas of overgrowth are patchy and that only some body parts show signs of overgrowth while others are unaffected.
  2. Sporadic occurrence: This means that no one else in the affected person’s family has similar features of overgrowth.
  3. Progressive course: This means that the overgrowth has noticeably altered the appearance of the affected body parts over time or that new areas of overgrowth have appeared over time.

If a person has all three of these general characteristics in addition to some specific characteristics, doctors may consider a diagnosis of Proteus syndrome.

The specific characteristics are grouped into three categories: A, B, and C.

  • One from category A; OR
  • Two from category B; OR
  • Three from category C

A diagnosis of Proteus syndrome requires all three general features to be present and either one feature from Category A, or two features from Category B, or three features from Category C 7):

  • Category A: Cerebriform connective tissue nevus, which are skin lesion characterized by deep grooves and gyrations as seen on the surface of the brain.
  • Category B:
    • Patches of skin caused by an overgrowth of cells in the outermost layer of skin (Linear epidermal nevus). Linear epidermal nevus is a streaky skin pigmentation that is often brown. This skin change sometimes has a rough or velvety texture.
    • Asymmetric, disproportionate overgrowth (at least one of the following):
      • Limbs
      • Hyperostosis of the skull
      • Hyperostosis of the external auditory canal
      • Megaspondylodysplasia
      • Viscera: spleen/thymus
      • Specific tumors before being 20 years old of age
      • Bilateral ovarian cystadenoma (a type of benign tumor in the ovary)
      • Parotid monomorphic adenoma (a benign tumor in s salivary gland)
  • Category C
    • Abnormal growth and/or distribution of fat (dysregulated fatty tissue overgrowth) (either of the following):
      • Fatty tumours (lipomas)
      • Lack of fat under the skin (regional lipohypoplasia)
      • Vascular malformations (differences in the blood vessels, veins, or capillaries or vessels of the immune system called the lymphatic vessels)
      • including one of the following:
      • Capillary malformation
      • Venous malformation
      • Lymphatic malformation
      • Lung bullae
      • Facial features (all of the following):
      • A long and narrow head (dolichocephaly)
      • Long face
      • Down slanting palpebral fissures and/or minor dropping of the eyelids (ptosis)
      • Depressed nasal bridge
      • Wide or opening nares
      • Open mouth at rest

Proteus syndrome treatment

Each person with Proteus syndrome will have different medical needs that require individualized treatment. Many patients with Proteus syndrome are followed by several specialists such as a geneticist, a pediatrician, a dermatologist, and others 8).

Treatment of the overgrowth include orthopedic procedures to delay or stop linear bone growth and correction of skeletal deformities such as scoliosis. Developmental intervention or special education is suggested for developmental delays. Because any organ or tissue can be affected, the affected person should be monitored for any possible complication. The following are recommended: monitoring for and treating vascular problems, such as blood clot (thrombus) that forms within a vein (vein thrombosis) and blockage of an artery in the lungs by a blood clot (pulmonary embolism); monitoring and treating the lung disease; and routine monitoring for evidence of tumor development with management of the skin problems, especially for the lesions known as cerebriform connective tissue nevi 9).

Overgrowth

Overgrowth is an ongoing issue for many individuals with Proteus syndrome. The management is complex and highly dependent on the nature of the overgrowth, which can vary substantially.

For overgrowth of tubular bones, epiphysiostasis and epiphysiodesis should be the mainstays of management. One intervention that the authors have found to be detrimental to individuals with Proteus syndrome is distraction osteotomy (so-called Ilizarov procedure) performed on the normal (shorter) limbs. Readers are referred to a review and conference report for more details on this complex issue 10).

The skeletal overgrowth of Proteus syndrome can result in significant biomechanical and functional compromise. Because of this, ongoing and comprehensive rehabilitation medicine care, including physical and occupational therapy, is important for many individuals. In addition, many individuals with Proteus syndrome develop substantial needs for custom-designed footwear or orthotics due to leg-length inequality or plantar cerebriform connective tissue nevi.

Refer to an orthopedist if scoliosis is identified on clinical and/or radiographic examination. Scoliosis surgery is high-risk in individuals with Proteus syndrome. The authors are aware of individuals who have died from DVT and PE, with prophylactic anticoagulation. In spite of this risk, such surgery is indicated because the progressive nature of the scoliosis can lead to fatal restrictive lung disease. Scoliosis in individuals with Proteus syndrome can advance extremely rapidly, and attentive and frequent monitoring is warranted 11).

Cerebriform connective tissue nevi

Cerebriform connective tissue nevi (CCTN). Individuals with Proteus syndrome who develop large plantar cerebriform connective tissue nevi should receive regular dermatologic care and attention to manage malodor (a potential complication of difficulty with cleanliness of the deepening of the sulci in late adolescence) and other concerns, such as pressure ulcerations. Large plantar cerebriform connective tissue nevi can also contribute to problems with shoe fit and often warrant pedorthic intervention as mentioned above. Surgical removal of a cerebriform connective tissue nevus has been successfully accomplished in at least two individuals.

Overgrowth of lipomatous tissue

Overgrowth of lipomatous tissue / lipoatrophy. Management of the overgrowth of adipose tissue is challenging because the areas of adipose overgrowth are not encapsulated and discrete (in contrast to lipomas) and, therefore, can be difficult to resect and commonly regrow after surgical debulking. The authors generally recommend open surgical approaches over liposuction because the highly vascularized lipomatous overgrowth in some individuals can result in difficult-to-control hemorrhaging and/or chronically weeping lymphatics.

Deep vein thrombosis (DVT) and pulmonary embolism (PE)

Deep vein thrombosis (DVT) and pulmonary embolism (PE). The authors 12) recommend emergent evaluation of individuals who develop symptoms of DVT (e.g., palpable subcutaneous rope-like mass, swelling, erythema, pain, and distal venous congestion) or PE (e.g., shortness of breath, chest pain, and cough which may include hemoptysis). Because individuals with PE can be asymptomatic, it is recommended that an individual with a DVT be evaluated for PE regardless of symptoms.

Evaluation for DVTs. In the absence of cardiopulmonary compromise, consider the D-dimer assay and/or ultrasonographic evaluation.
Evaluation of PE. High-resolution chest CT (so called spiral CT) with contrast is recommended. Ventilation-perfusion nuclear medicine scanning may be appropriate in some individuals.

Treatment of DVT and PE should follow recommended anticoagulation guidelines for these disorders. The authors recommend hematologic evaluation and consultation for consideration of anticoagulant prophylaxis for individuals undergoing surgery or other procedures that may predispose to DVT/PE.

Tumors

It is impractical to screen for tumors with imaging in individuals with Proteus syndrome because the tumors are so heterogeneous. Instead, a primary care clinician should evaluate the individuals regularly (every 6-12 months) and elicit signs and symptoms of malignancy (e.g., pain, unexpected growths, signs of obstruction or compression). If these are elicited, an imaging evaluation of that organ system should be undertaken.

Bullous pulmonary disease

Pulmonary evaluation is recommended for individuals with bullous pulmonary disease, and resection of large bullous lesions may be indicated in some individuals. Bullous disease in the context of scoliosis can pose significant and complex challenges for appropriate management.

Psychometric and learning evaluation

Developmental evaluation for consideration of intervention or special education for those individuals with developmental delays is indicated.

Psychosocial issues

Psychosocial counseling is certainly warranted in most instances. Although Proteus syndrome is exceedingly rare, a robust support group infrastructure exists and many families find this very helpful.

Surveillance

Individualized surveillance plans for the skeletal, pulmonary, soft-tissue, and other manifestations of Proteus syndrome should be developed according to the individual’s specific needs.

Because of the predisposition to a range of tumors (most of which are benign) individuals with Proteus syndrome should be monitored by their primary care provider with regular evaluations including a directed medical history and examination; periodic imaging is not indicated.

Agents/Circumstances to Avoid

Medications that increase the risk of DVT or are procoagulant should be avoided. Medications that increase growth (e.g., androgenic steroids or growth hormone) should be avoided.

Proteus syndrome life expectancy

Life expectancy of Proteus syndrome is 9 months to 29 years, according to the severity of the abnormalities 13). The fourth leading cause of premature death is pulmonary thromboembolism and respiratory failure, which are predisposed by vascular malformations, surgical convalescence, and (in extreme cases of deformity) by restricted mobility 14). Benign neoplasms associated with the syndrome include lipomas, ovarian cystadenomas, and monomorphic adenoma of the parotid gland; malignant neoplasms include papillary adenocarcinoma of testicles, mesothelioma of the tunica vaginalis, and peritoneal mesothelioma 15).

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