Proteus syndrome (ORPHA:744)
A rare complex overgrowth syndrome characterized by progressive overgrowth of the skeleton, skin, adipose, and central nervous systems.
Epidemiology
Approximately 200 cases of Proteus syndrome (PS) have been reported to date. The prevalence is estimated to be less than 1/1,000,000 live births.
Clinical description
Proteus syndrome presents in a wide range of severity and anatomic distribution. Individuals usually have no signs or symptoms at birth but onset of overgrowth typically occurs in the first 2 years of life. This often manifests as overgrowth of the hands or legs. Skeletal overgrowth is progressive and may involve the limbs, the skull, and spine. Cerebriform connective tissue nevi (CCTN) typically occur on the feet or hands during childhood beginning as small nodules that coalesce to the cerebriform lesion. Vascular malformations, most commonly venous or capillary, and epidermal nevi may occur in the first months of life and generally stabilize with time. Neurological features include hemimegalencephaly, developmental delay and intellectual disability. Additional features include cystic lung disease, and an increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). Tumors may arise in individuals and are mainly benign, particularly gonadal cystadenoma, parotid adenoma, and meningioma, but rare malignant tumors have been reported.
Etiology
Somatic activating variants in AKT1 are associated with Proteus syndrome. The most common is the c.49G>A (p.Glu17Lys) variant but others have been reported.
Diagnostic methods
Diagnosis should be based on phenotype and genotype. This dyadic approach has been proposed with use of a scoring system. The score includes the following features of Proteus syndrome: CCTN (5 points), asymmetric bony overgrowth (5 points), organ/visceral overgrowth (5 points), cystic lung disease (2 points), dysregulated adipose tissue (2 points), vascular malformations (2 points), tumors associated with Proteus syndrome (1 point), history of DVT or PE (2 points), and a facial phenotype (2 points). Presence of prenatal overgrowth or ballooning overgrowth (-5 points each) may favor a diagnosis of other than Proteus syndrome, such as PIK3CA-related overgrowth spectrum. In the absence of a somatic AKT1 variant, a score of 15 or greater indicates a clinical diagnosis of Proteus syndrome. If a somatic AKT1 variant is present, a score of 10 or greater indicates a diagnosis of AKT1- related Proteus syndrome. Genetic testing requires sampling of an affected tissue, such as a skin biopsy. Blood is not an appropriate source for genetic testing.
Differential diagnosis
Differential diagnoses include PIK3CA-related overgrowth spectrum disorders such as Klippel-Trenaunay syndrome and CLOVES syndrome, as well as other disorders of overgrowth such as PTEN hamartoma tumor syndrome (PHTS), neurofibromatosis type 1, Ollier disease, and Maffucci syndrome.
Antenatal diagnosis
Prenatal testing is not performed as PS is a mosaic disorder and not inherited.
Genetic counseling
Proteus syndrome is not thought to be inherited because the activating AKT1 variant is hypothesized to be lethal in the heterozygous state. There are reports of individuals with Proteus syndrome who have unaffected children.
Management and treatment
Treatment requires a multidisciplinary approach and must be tailored to an individual's unique presentation. Surgical interventions used to control overgrowth include physeal arrest, epiphysiodesis, and spinal fusion. Physical and occupational therapy is critical as custom designed orthotics or footwear may be necessary. Dermatological care along with management of malodor (if present) is needed for those with CCTN. Perioperative anticoagulation prophylaxis should be strongly considered as PE is the leading cause of death. Individuals should be counseled about the risk of tumor predisposition. Psychosocial counseling can be beneficial for individuals and their families. Targeted therapy using AKT inhibitors to mitigate disease progression is ongoing in clinical trials.
Prognosis
Prognosis varies depending on the severity of complications.

                            Last update: 
                            May 2024


                            - Expert reviewer(s): 
                            Dr Christopher OURS