Proteus-like syndrome

Overview

Proteus-like syndrome is a rare congenital condition characterized by features similar to those of Proteus syndrome, including asymmetrical, disproportionate overgrowth of bones, skin, and other tissues. However, individuals with Proteus-like syndrome do not meet the full clinical criteria for a diagnosis of classic Proteus syndrome and may lack the characteristic AKT1 gene mutation. The term "Proteus-like" is used to describe a spectrum of overgrowth disorders that mimic Proteus syndrome in presentation but differ in genetic cause and clinical progression. Because of this overlap and ambiguity, Proteus-like syndrome is often considered a diagnosis of exclusion, applied when other well-defined overgrowth syndromes have been ruled out.

Causes

The exact cause of Proteus-like syndrome is currently unknown. Unlike classic Proteus syndrome, which is caused by a somatic mosaic mutation in the AKT1 gene, individuals with Proteus-like syndrome may not have identifiable mutations in this gene. The syndrome is thought to result from other, yet unidentified, post-zygotic somatic mutations that affect genes involved in cell growth, differentiation, or proliferation.

Potential contributing mechanisms may include:

• Somatic mosaicism: A mutation that occurs after fertilization, resulting in a mixture of mutated and normal cells

• Disruption in growth regulation pathways: Abnormal signaling in pathways such as PI3K-AKT-mTOR may still be involved, as seen in other overgrowth disorders

• Sporadic occurrence: The condition is not inherited and typically arises de novo

Ongoing research is aimed at identifying the molecular and genetic basis of Proteus-like syndromes to better classify and treat these conditions.

Symptoms

The symptoms of Proteus-like syndrome are highly variable and depend on the extent and location of tissue overgrowth. The presentation resembles Proteus syndrome but often lacks hallmark features such as cerebriform connective tissue nevi. Common symptoms include:

Overgrowth and Asymmetry

• Disproportionate, asymmetrical overgrowth of limbs, digits, or facial structures

• Asymmetry may become more apparent over time and can affect multiple body parts

• Overgrowth is typically non-hereditary and progressive

Cutaneous and Soft Tissue Findings

• Thickened skin or localized hyperplasia

• Lipomas or other soft tissue masses

• Vascular malformations or skin discoloration

Musculoskeletal Abnormalities

• Limb length discrepancies

• Spinal curvature (scoliosis or kyphosis)

• Joint instability or reduced range of motion

Neurological and Other Features

• Macrocephaly or craniofacial asymmetry

• Developmental delay or mild intellectual disability (in some cases)

• Ocular anomalies or hearing abnormalities

Not all individuals with Proteus-like syndrome display all of these features, and the severity can range from mild to disabling.

Diagnosis

Diagnosis of Proteus-like syndrome is clinical and often challenging. It is based on the presence of features consistent with overgrowth disorders in the absence of definitive genetic confirmation for known syndromes like classic Proteus syndrome.

• Clinical examination: Detailed assessment of overgrowth patterns, asymmetry, and other dysmorphic features

• Imaging studies: X-rays, MRI, or CT scans to evaluate soft tissue and skeletal overgrowth, vascular anomalies, and internal involvement

• Genetic testing: Typically shows no mutation in AKT1; broader testing may be performed to exclude other conditions such as PIK3CA-related overgrowth spectrum (PROS), Klippel–Trénaunay syndrome, or PTEN Hamartoma Tumor Syndrome

• Exclusion of other syndromes: Proteus-like syndrome is diagnosed when a patient shows some, but not all, features of Proteus syndrome and does not meet criteria for other defined overgrowth disorders

Because of the diagnostic complexity, evaluation by a clinical geneticist or specialist in overgrowth syndromes is often recommended.

Treatment

There is no cure for Proteus-like syndrome, and treatment is focused on symptom management, improving functional outcomes, and monitoring for complications. Management is individualized and multidisciplinary.

Medical Management

• Monitoring and managing overgrowth: Regular assessments to monitor the progression of overgrowth and organ involvement

• Pain management: For joint and musculoskeletal discomfort associated with tissue overgrowth

• Experimental therapies: mTOR or PI3K inhibitors (e.g., sirolimus, alpelisib) are being studied in related overgrowth conditions and may have future applications

Surgical Interventions

• Orthopedic surgery: To correct bone overgrowth, limb length discrepancies, or spinal deformities

• Plastic or reconstructive surgery: May improve function or appearance in affected areas

• Excision of soft tissue masses: If lipomas or vascular malformations cause discomfort or restrict movement

Supportive and Rehabilitative Care

• Physical and occupational therapy to improve mobility and manage joint issues

• Psychological support for body image concerns and social challenges

• Special education support if developmental delays are present

Prognosis

The prognosis for individuals with Proteus-like syndrome is highly variable, depending on the extent and progression of overgrowth and associated complications. Many individuals live relatively normal lives with appropriate medical and surgical support, while others may experience chronic pain, functional impairments, or social challenges due to disfigurement.

Unlike classic Proteus syndrome, which is associated with significant risks such as thromboembolic events and tumor development, Proteus-like syndrome often follows a milder course. However, because the condition can progress over time, regular follow-up with a multidisciplinary team is essential. Early intervention and ongoing monitoring can greatly improve quality of life and reduce complications.