Diagnostic Criteria

Consensus clinical diagnostic criteria for Proteus syndrome (PS) have been published . Suggestive Findings PS should be suspected in a proband with the following: • Distorting, progressive overgrowth, typically of postnatal onset, often resulting in asymmetric distortion of the skeletal architecture. Hemimegencephaly can be prenatal. • Cerebriform connective tissue nevi characterized by deep grooves and gyrations as seen on the surface of the brain • Linear verrucous epidermal nevus, a streaky, pigmented, rough nevus that often follows the lines of Blaschko and can be present anywhere on the body • Adipose dysregulation, including lipomatous overgrowth and lipoatrophy • Vascular malformations, including cutaneous capillary malformations, prominent venous patterning or varicosities, and lymphatic malformations • Overgrowth of other tissues, most commonly spleen, liver, thymus, and gastrointestinal tract • Tumors, most commonly meningiomas. Ovarian cystadenomas, breast cancer, parotid monomorphic adenoma, mesothelioma, and others have also been reported. • Bullous pulmonary degeneration • Dysmorphic facial features including dolichocephaly, long face, downslanting palpebral fissures, and/or minor ptosis, depressed nasal bridge, wide or anteverted nares, and open mouth at rest Establishing the Diagnosis The diagnosis of PS is established in a proband with ALL of the following three general criteria: • Mosaic distribution of lesions • Sporadic occurrence • Progressive course AND using the following positive (and negative) clinical criteria : • A score of ≥10 points in an individual with a mosaic AKT1 pathogenic variant • A score of ≥15 points in an individual without a mosaic AKT1 pathogenic variant* Note: The diagnosis of is established in an individual with a mosaic AKT1 pathogenic variant and a score of 2-9 using clinical criteria. *Individuals without a mosaic AKT1 pathogenic variant should be considered to have PS, not AKT1-related Proteus syndrome (AKT1-PS). However, the clinical criteria were intended to diagnose PS with confidence based only on clinical criteria, and individuals with these clinical criteria should be managed the same as those with AKT1-PS. Table 1. Positive and Negative Clinical Criteria Used in the Diagnosis of Proteus Syndrome Positive Clinical Criteria | Points Cerebriform connective tissue nevus | 5

Management Guidelines

No clinical practice guidelines for Proteus syndrome (PS) have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Proteus syndrome (PS), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended . Table 3. Proteus Syndrome: Recommended Evaluations Following Initial Diagnosis

Surveillance Guidelines

Individualized surveillance plans for the skeletal, pulmonary, soft tissue, and other manifestations of PS should be developed according to the individual's specific needs .

Table 5.

Proteus Syndrome: Recommended Surveillance

System/Concern | Evaluation | Frequency

Musculoskeletal

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