Proteus-like syndrome (ORPHA:2969)
A rare genetic disease characterized by patients presenting with a multitude of clinical features of Proteus syndrome without meeting the diagnostic criteria for the disease.
Epidemiology
The prevalence is unknown. There have been only 7 case reports of patients with proteus-like syndrome; 5 out of 7 were confirmed to have a germline pathogenic PTEN variant.
Clinical description
Proteus-like syndrome has the clinical features of Proteus syndrome but lacks some of the required criteria necessary for diagnosis. The main clinical features include skeletal overgrowth, hamartomous overgrowth of multiple tissues, cerebriform connective tissue nevi, vascular malformations and linear epidermal nevi.
Etiology
Mutations in the PTEN gene are found in more than half of Proteus-like syndrome cases, making them a part of the PTEN harmatoma tumor syndrome (PHTS) group. To date, mutations in AKT1 have not been reported in Proteus-like patients. It is possible that Proteus-like patients will have somatic mosaic or germline mutations in genes encoding other components of the phosphatidylinositol 3-kinase signaling pathway.
Diagnostic methods
Clinical diagnosis can be made using the Proteus syndrome clinical criteria. Individuals who present with clinical features but do not meet the clinical criteria for Proteus syndrome are diagnosed clinically as having Proteus-like syndrome. Germline genetic testing for a pathogenic PTEN variant can confirm a genetic diagnosis of Proteus-like syndrome.
Differential diagnosis
The differential diagnosis includes Proteus syndrome and PTEN hamartoma tumor syndromes (PHTS) such as Cowden syndrome.
Antenatal diagnosis
Antenatal diagnosis is in theory possible if the pathogenic variant has previously been identified in the family. It has not been described in the literature.
Genetic counseling
Inheritance is autosomal dominant in those with a PTEN mutation, with a high de novo rate. Genetic counseling should be offered to at-risk family members to inform them of their health risks and the 50% transmission risk for each pregnancy.
Management and treatment
Germline PTEN pathogenic variants predispose to a wide spectrum of benign and malignant tumors and surveillance recommendations for PTEN carriers including Proteus-like syndrome, have been described under the term of PTEN hamartoma tumor syndrome (PHTS) and Cowden syndrome. Management and surveillance for Proteus-like syndrome with a germline PTEN pathogenic variant would be as described for PHTS, which includes the following: 1) annual comprehensive physical examination starting at age 18 or 5 years before youngest age of diagnosis of cancer in the family, with attention to thyroid exam; 2) yearly dermatological exam for children and adults; 3) yearly thyroid ultrasound from the time of diagnosis; 4) monthly breast self-examination from age 18, clinical breast examination annually from age 25, and annual MMG staring from age 30-35; 5) endometrial cancer screening by biopsy can be considered starting age 35; 6) colonoscopies starting from age 35 and repeating every 5 years; 7) management tailored to clinical presentation and personalized follow-up with annual clinical review has been suggested in literature. More data is required to optimize screening and management for Proteus-like syndrome patients.
Prognosis
Prognosis could be dependent on the risk associated with the development of cancer.

                            Last update: 
                            December 2023


                            - Expert reviewer(s): 
                             Manasadevi KARTHIKEYAN  - Dr Joanne NGEOW