Clinical Characterization of Skin Findings on the Hands in Proteus Syndrome

Background: Proteus syndrome is a progressive asymmetric overgrowth disorder caused by mosaic activating variants in AKT1. It most frequently affects the skin, soft tissues, bones, and central nervous system and increases the risk for certain tumors and venous thromboembolism. A hallmark feature is the progressive plantar cerebriform connective tissue nevus (CCTN). The natural history of skin manifestations of the hand in Proteus syndrome is less well characterized. Methods: A retrospective review of photography collected from 2000 through 2024 was conducted as part of an ongoing natural history of Proteus syndrome study (NCT00001403). Results: Clinical photography of the hands from 74 individuals (40 male, 34 female) with Proteus syndrome was reviewed. The average age at the earliest photograph was 13.2 (SD 8.8) years. Thirty-five individuals had serial photographs with an average total interval of 5.8 (SD 4.2) years. Connective tissue nevi (CTN) were present in 30 (41%) individuals. These were cerebriform in 16 individuals. Palmar CTN progression through the gradual expansion of nodules was universal in children. Epidermal nevi (EN) were present on the hands of 28 (39%) individuals and were generally stable. Enlargement of digits with nodules or plaques was seen in 45 (61%) individuals. Less frequent features included changes to the nails, dorsum of the hand, and vascular anomalies. Conclusion: There are a variety of skin manifestations on the hand in Proteus syndrome. Palmar CTN are often progressive whereas other lesions progress slowly or remain stable over time.