Pathophysiology: Proteus syndrome is caused by an activating somatic mosaic mutation in AKT1, a gene which encodes the well-studied serine/threonine kinase PKB/Akt .1,2 Akt is the key mediator of the PI3K signaling pathway. In response to a growth signal (e.g. IGF, EGF) and the autophosphorylation of a receptor tyrosine kinase, PI3K is recruited and activated, generating PIP¬3 molecules at the lipid membrane. These partially activate Akt and also activate PDK1/2, which complete the Akt activation. Akt signaling effects many pathways , most notably: inhibiting BAD and other mediators of apoptosis, inhibiting GSK3β inhibition of β-catenin activity, activating MDM2 to suppress p53, and inhibiting TSC1/2 inhibition of mTOR (Figure 1). The exact effect of the Proteus Akt point mutation on these pathways is not well-characterized, and is likely tissue specific. Overactivation of these or related signaling pathways results in cellular overgrowth and tumor susceptibility as seen in Proteus syndrome as well as in related hamartomatous and hyperplastic diseases such as Beckwith-Wiedemann (IGF-2), CLOVES syndrome (PI3KCA), Cowden disease and SOLAMEN syndrome (PTEN), neurofibromatosis type I (NF1), tuberous sclerosis (TSC1/2), and Peutz-Jeghers syndrome (LKB1) (Figure 2).
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Note: prior to 2011, and occasionally still, the term Proteus syndrome may be used to refer to phenotypically similar PI3K-AKT-mTOR mutation syndromes, though these are now better referred to as Proteus-like, or separate disorders (e.g. SOLAMEN, CLOVES).1 Epidemiology: Proteus syndrome is exceedingly rare. Few more than 200 cases have ever been described in literature, with an estimated incidence of less than 1 per 1,000,000 live births, though the disease may be underdiagnosed if not severe (i.e. the somatic mutation occurs later in development ), or mistaken for other hamartoma syndromes.3,4 Diagnostic tests: A preliminary clinical diagnosis can be made based on the appearance of clinical symptoms. The most definitive diagnostic test is to sequence the 14q32.33 AKT1 gene in an affected tissue region for a c.49G>A, p.Glu17Lys mutation (a point mutation of guanine to adenine, resulting in glutamate instead of lysine after translation).1 Testing of blood or unaffected tissue is not an effective method in most cases, and there are no known circulating biomarkers.5 Symptoms and physical signs: The key finding in the …show more content…
The most recent diagnostic criteria by Cohen et al. includes a number of specific benign tumors and malformations common with the condition. Some key specific criteria include cerebriform connective tissue nevi, hemihyperplasia with bone deformity , and dysregulated adipose and vascular tissue (Figure 3). The tumors caused by the disease are largely benign, and include lipomas, ovarian cystadenomas, monomorphic parotid adenomas , and meningiomas, though many other tumors benign and malignant have been reported. Facial involvement of the disease is associated with intellectual disability (Figure 4). Only about 20% of patients with Proteus syndrome have premature deaths. Some of the main causes are pulmonary embolism caused by deep vein thrombosis associated with arterio-venous malformation, and respiratory and central nervous system deaths due to lung and brain malformation.1,4,5
Basic treatment: Proteus syndrome has no cure, and no accepted pharmaceutical therapy targeting the disease mechanism. Sirolimus (Rapamycin) has been proposed for suppression of mTOR, though there are potential severe side effects with long term therapy. There are currently no clinical trials for drug therapies. ArQule, in collaboration with the NIH Human Genome Research Institue, has begun preclinical trials on small molecule
Note: prior to 2011, and occasionally still, the term Proteus syndrome may be used to refer to phenotypically similar PI3K-AKT-mTOR mutation syndromes, though these are now better referred to as Proteus-like, or separate disorders (e.g. SOLAMEN, CLOVES).1 Epidemiology: Proteus syndrome is exceedingly rare. Few more than 200 cases have ever been described in literature, with an estimated incidence of less than 1 per 1,000,000 live births, though the disease may be underdiagnosed if not severe (i.e. the somatic mutation occurs later in development ), or mistaken for other hamartoma syndromes.3,4 Diagnostic tests: A preliminary clinical diagnosis can be made based on the appearance of clinical symptoms. The most definitive diagnostic test is to sequence the 14q32.33 AKT1 gene in an affected tissue region for a c.49G>A, p.Glu17Lys mutation (a point mutation of guanine to adenine, resulting in glutamate instead of lysine after translation).1 Testing of blood or unaffected tissue is not an effective method in most cases, and there are no known circulating biomarkers.5 Symptoms and physical signs: The key finding in the …show more content…
The most recent diagnostic criteria by Cohen et al. includes a number of specific benign tumors and malformations common with the condition. Some key specific criteria include cerebriform connective tissue nevi, hemihyperplasia with bone deformity , and dysregulated adipose and vascular tissue (Figure 3). The tumors caused by the disease are largely benign, and include lipomas, ovarian cystadenomas, monomorphic parotid adenomas , and meningiomas, though many other tumors benign and malignant have been reported. Facial involvement of the disease is associated with intellectual disability (Figure 4). Only about 20% of patients with Proteus syndrome have premature deaths. Some of the main causes are pulmonary embolism caused by deep vein thrombosis associated with arterio-venous malformation, and respiratory and central nervous system deaths due to lung and brain malformation.1,4,5
Basic treatment: Proteus syndrome has no cure, and no accepted pharmaceutical therapy targeting the disease mechanism. Sirolimus (Rapamycin) has been proposed for suppression of mTOR, though there are potential severe side effects with long term therapy. There are currently no clinical trials for drug therapies. ArQule, in collaboration with the NIH Human Genome Research Institue, has begun preclinical trials on small molecule