Proteus syndrome

Alternate names

Hemihypertrophy and macrocephaly; Partial gigantism of hands and feet, nevi, hemihypertrophy, macrocephaly; Partial gigantism-nevi-hemihypertrophy-macrocephaly syndrome

Definition

Proteus syndrome is a rare condition characterized by overgrowth of the bones, skin, and other tissues. Organs and tissues affected by the disease 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 between the ages of 6 and 18 months and gets more severe with age.

Epidemiology

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.

Researchers believe that Proteus syndrome may be overdiagnosed, 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.

Cause

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.

Inheritance

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

Signs and symptoms

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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Abnormal form of the vertebral bodies
• Abnormal subcutaneous fat tissue distribution(Abnormal fat tissue distribution below the skin)
• Arteriovenous malformation
• Asymmetry of the thorax(Asymmetric chest)
• Cachexia(Wasting syndrome)
• Capillary hemangioma(Strawberry birthmark)
• Decreased muscle mass
• Disproportionate tall stature
• Epidermal nevus
• Irregular hyperpigmentation
• Kyphosis(Hunched back)
• Lipoma(Fatty lump)
• Lower limb asymmetry(Left and right leg differ in length or width)
• Lymphangioma
• Macrodactyly(Finger overgrowth)
• Melanocytic nevus(Beauty mark)
• Scoliosis
• Skeletal dysplasia
• Subcutaneous nodule(Firm lump under the skin)
• Upper limb asymmetry(Unequal size of arms)
• Vascular skin abnormality

30%-79% of people have these symptoms

• Abnormal lung lobation
• Bronchogenic cyst
• Calvarial hyperostosis(Overgrowth of skullcap)
• Dolichocephaly(Long, narrow head)
• Finger syndactyly
• Generalized hyperkeratosis
• Hypertelorism(Wide-set eyes)
• Lymphedema(Swelling caused by excess lymph fluid under skin)
• Macrotia(Large ears)
• Multiple cafe-au-lait spots
• Pulmonary embolism(Blood clot in artery of lung)
• Round face(Circular face)
• Thrombophlebitis
• Visceral angiomatosis

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: 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. Sporadic occurrence: This means that no one else in the affected person’s family has similar features of overgrowth. 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. 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: 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) 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

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. 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.

NIH genetic and rare disease info

• NIH info on Proteus syndrome

Proteus syndrome is a rare disease.

Proteus syndrome Resources
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