Proteus syndrome
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Proteus syndrome is a rare disorder with a genetic background that can cause tissue overgrowth involving all three embryonic lineages. Patients with Proteus syndrome tend to have an increased risk of embryonic tumor development.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. . The clinical and
radiographic Radiography is an imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical radiography ("diagnostic" and "therapeut ...
symptoms of Proteus syndrome are highly variable, as are its orthopedic manifestations. Only a few more than 200 cases have been confirmed worldwide, with estimates that about 120 people are currently alive with the condition.Woman's 11-stone legs may be lost
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As attenuated forms of the disease may exist, there could be many people with Proteus syndrome who remain undiagnosed. Those most readily diagnosed are also the most severely disfigured. The syndrome is named after the Greek sea-god
Proteus In Greek mythology, Proteus (; Ancient Greek: Πρωτεύς, ''Prōteus'') is an early prophetic sea-god or god of rivers and oceanic bodies of water, one of several deities whom Homer calls the "Old Man of the Sea" ''(hálios gérôn)''. ...
, who could change his shape. The condition appears to have been first described in the American medical literature by Samia Temtamy and John Rogers in 1976. American pathologist Michael Cohen described it in 1979.


Signs and symptoms

Proteus syndrome causes an overgrowth of skin, bones, muscles, fatty tissues, and blood and
lymphatic vessel The lymphatic vessels (or lymph vessels or lymphatics) are thin-walled vessels (tubes), structured like blood vessels, that carry lymph. As part of the lymphatic system, lymph vessels are complementary to the cardiovascular system. Lymph vess ...
s. Proteus syndrome is a progressive condition wherein children are usually born without any obvious deformities. Tumors of skin and bone growths appear as they age typically in early childhood. The musculoskeletal manifestations are cardinal for the diagnosis of Proteus syndrome. The severity and locations of these various asymmetrical growths vary greatly but typically the skull, one or more limbs, and soles of the feet will be affected. There is a risk of premature death in affected individuals due to
deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...
and
pulmonary embolism Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain p ...
caused by the vessel malformations that are associated with this disorder. Because of carrying excess weight and enlarged limbs,
arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
and muscle pain may also be symptoms. Further risks may occur due to the mass of extra tissue. The disorder itself does not uniformly cause learning impairments: the distribution of intelligence deficits among those with Proteus syndrome appears higher than that of the general population, although this is difficult to determine with statistical significance. In addition, the presence of visible deformity may have a negative effect on the social experiences of the affected individual, causing cognitive and social deficits. Affected individuals are at increased risk for developing certain tumors including unilateral ovarian cystadenomas,
testicular tumor Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system. Symptoms may include a lump in the testicle, or swelling or pain in the scrotum. Treatment may result in infertility. Risk factors include an u ...
s, meningiomas, and monomorphic
adenoma An adenoma is a benign tumor of epithelial tissue with glandular origin, glandular characteristics, or both. Adenomas can grow from many glandular organs, including the adrenal glands, pituitary gland, thyroid, prostate, and others. Some adenom ...
s of the
parotid gland The parotid gland is a major salivary gland in many animals. In humans, the two parotid glands are present on either side of the mouth and in front of both ears. They are the largest of the salivary glands. Each parotid is wrapped around the ma ...
.
Hemimegalencephaly Hemimegalencephaly (HME), or unilateral megalencephaly, is a rare congenital disorder affecting all or a part of a cerebral hemisphere. It causes severe seizures, which are often frequent and hard to control. A minority might have seizure contro ...
is often found to be associated.


Orthopaedic features

The musculoskeletal manifestations of Proteus syndrome are frequent and recognizable. Patients tend to demonstrate a unique pattern of skeletal abnormalities. The orthopaedic features are usually bilateral, asymmetrical, progressive and involving all four limbs and spine. Affected patients usually have localized periarticular limb distortions, limb length discrepancy, and spine deformity. Patients with Proteus syndrome can have regular bone configuration and contours despite the bone enlargement. Patients can also exhibit deformation of the skull in the form of
dolichocephaly Dolichocephaly (derived from the Ancient Greek δολιχός 'long' and κεφαλή 'head') is a condition where the head is longer than would be expected, relative to its width. In humans, scaphocephaly is a form of dolichocephaly. Dolichoce ...
or elongated skull and facial abnormalities. Because of the rarity of the syndrome and the variability of signs, the orthopaedic management should be individualized.


Genetics

In 2011 researchers determined the cause of Proteus syndrome. In 26 of 29 patients who met strict clinical criteria for the disorder, Lindhurst ''et al.'' identified an activating mutation in
AKT1 RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT1'' gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains. It ...
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
in a mosaic state gene. Previous research had suggested the condition linked to PTEN on
chromosome 10 Chromosome 10 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 10 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
, while other research pointed to
chromosome 16 Chromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs (the building material of DNA) and represents just under 3% of the total DNA in cell ...
. Prior to the findings regarding AKT1 in 2011, other researchers expressed doubt regarding the involvement of PTEN or
GPC3 Glypican-3 is a protein that, in humans, is encoded by the ''GPC3'' gene. The ''GPC3'' gene is located on human X chromosome (Xq26) where the most common gene (Isoform 2, GenBank Accession No.: NP_004475) encodes a 70-kDa core protein with 580 ami ...
, which codes for
glypican 3 Glypican-3 is a protein that, in humans, is encoded by the ''GPC3'' gene. The ''GPC3'' gene is located on human X chromosome (Xq26) where the most common gene (Isoform 2, GenBank Accession No.: NP_004475) encodes a 70-kDa core protein with 580 ami ...
and may play a role in regulating cell division and growth regulation.


Diagnosis


Differential diagnosis

*
Macrodystrophia lipomatosa Macrodystrophia lipomatosa (ML) is a rare congenital disorder characterized by localised overgrowth of a part of an extremity or less commonly a whole extremity. The involvement of more than one extremity is even more uncommon. There is a slight pre ...
* Fibrolipomatous hamartoma *
Neurofibromatosis Neurofibromatosis (NF) is a group of three conditions in which tumors grow in the nervous system. The three types are neurofibromatosis type I (NF1), neurofibromatosis type II Neurofibromatosis type II (also known as MISME syndrome – multi ...
type 1 *
Klippel–Trénaunay syndrome Klippel–Trénaunay syndrome, formerly Klippel–Trénaunay–Weber syndrome and sometimes angioosteohypertrophy syndrome and hemangiectatic hypertrophy, is a rare congenital medical condition in which blood vessels and/or lymph vessels fail t ...
* Parkes Weber syndrome *
Sotos syndrome Sotos syndrome is a rare genetic disorder characterized by excessive physical growth during the first years of life. Excessive growth often starts in infancy and continues into the early teen years. The disorder may be accompanied by autism, mild ...
*
Hemangiomas A hemangioma or haemangioma is a usually benign vascular tumor derived from blood vessel cell types. The most common form, seen in infants, is an infantile hemangioma, known colloquially as a "strawberry mark", most commonly presenting on the ski ...


Classification

Many sources classify Proteus syndrome to be a type of
nevus Nevus (plural nevi) is a nonspecific medical term for a visible, circumscribed, chronic lesion of the skin or mucosa. The term originates from ''nævus'', which is Latin for "birthmark"; however, a nevus can be either congenital (present at bir ...
syndrome. The
lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...
s appear to be distributed in a mosaic manner. It has been confirmed that the disorder is an example of genetic
mosaicism Mosaicism or genetic mosaicism is a condition in multicellular organisms in which a single organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized ...
.


Treatment

A team of doctors in Australia have trial tested the drug
rapamycin Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosi ...
in the treatment of a patient said to have Proteus syndrome and have found it to be an effective remedy. However, the diagnosis of Proteus syndrome in this patient has been questioned by others. The Proteus syndrome research team in the
National Human Genome Research Institute The National Human Genome Research Institute (NHGRI) is an institute of the National Institutes of Health, located in Bethesda, Maryland. NHGRI began as the Office of Human Genome Research in The Office of the Director in 1988. This Office transi ...
at the
United States National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late 1 ...
have initiated a
Phase 0 The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
dose finding trial with the AKT1 inhibitor ARQ 092, which is being developed by the Arqule Corporation. In earlier tests on tissue and cell samples obtained from patients, ARQ 092 reduced
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of AKT and downstream targets of AKT in as little as two hours. The Phase 0 trial opened in November 2015. This trial is based on
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
data showing inhibition of AKT1 in
cell lines An immortalised cell line is a population of cells from a multicellular organism which would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cells ...
from patients with Proteus syndrome.


Notable cases

In a 1986 article in the ''
British Medical Journal ''The BMJ'' is a weekly peer-reviewed medical trade journal, published by the trade union the British Medical Association (BMA). ''The BMJ'' has editorial freedom from the BMA. It is one of the world's oldest general medical journals. Origi ...
'', Michael Cohen and J.A.R. Tibbles put forward the theory that
Joseph Merrick Joseph Carey Merrick (5 August 1862 – 11 April 1890), often erroneously called John Merrick, was an English man known for having severe deformities. He was first exhibited at a freak show under the stage name "the Elephant Man" and then wen ...
(an Englishman known as the "Elephant Man") had Proteus syndrome. However, the exact condition had by Joseph Merrick is still not known with certainty.– Spiring P (2001). "The Improbable Elephant Man". ''Biologist'' (London) 48(3) 104.
in
The Sunday Telegraph ''The Sunday Telegraph'' is a British broadsheet newspaper, founded in February 1961 and published by the Telegraph Media Group, a division of Press Holdings. It is the sister paper of ''The Daily Telegraph ''The Daily Telegraph'', kn ...

– BBC News
– ''Eurekalert!''The Daily Telegraph
 Mandy Sellars has been diagnosed by some doctors as having this condition. Her legs and feet have grown at a disproportionate rate since birth. However, in 2013, Sellars' case was profiled on British television in a special called ''Shrinking My 17 Stone Legs'', in which it was determined that Sellars' condition was not, in fact, Proteus syndrome, but rather the often-misdiagnosed
PIK3CA-related overgrowth spectrum PIK3CA-related overgrowth spectrum (PROS) is an umbrella term for rare syndromes characterized by malformations and tissue overgrowth caused by somatic mutations in PIK3CA gene. In PROS diseases individuals malformations are seen in several differe ...
, a syndrome caused by a PIK3CA gene mutation.


See also

*
Epidermal nevus syndrome Epidermal nevus syndrome (also known as "Feuerstein and Mims syndrome", and "Solomon's syndrome"Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. .) is a rare disease that was first described in 19 ...
*
Mosaic (genetics) Mosaicism or genetic mosaicism is a condition in multicellular organisms in which a single organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized ...
*
Overgrowth syndrome Overgrowth syndromes in children constitute a group of rare disorders that are characterised by tissue hypertrophy. Individual overgrowth syndromes have been shown to overlap with regard to clinical and radiologic features. The details of the gene ...
*
List of radiographic findings associated with cutaneous conditions Many conditions of or affecting the human integumentary system have associated features that may be found by performing an x-ray or CT scan of the affected person. See also * List of cutaneous conditions * List of contact allergens * List of ...


References


External links


GeneReviews/NCBI/NIH/UW entry on PTEN Hamartoma Tumor Syndrome (PHTS)
{{Multiple abnormalities Congenital disorders Syndromes with tumors Rare syndromes Genodermatoses Genetic disorders with OMIM but no gene