Proteus Syndrome

^{Three Comparative Hand Sculptures Representing Tissue Growth and Mosaic Structure in Proteus Syndrome (Generated by Artificial Intelligence)}

Proteus syndrome is a mosaic genetic disorder characterized by asymmetric, disproportionate, and progressive overgrowth of various tissues. This syndrome affects the skeletal system, skin, adipose tissue, and central nervous system. The disease typically presents with no symptoms at birth or with mild findings, and progresses from infancy through early childhood, leading to structural deformities in affected tissues. Growth abnormalities exhibit a patchy distribution across the body.

The disease was first described as a distinct clinical entity in 1979^【1】. It was named in 1983 after Proteus, a sea god in Greek mythology known for his ability to change shape, hence the term "Proteus syndrome"^【2】. Joseph Carey Merrick, who lived in 19th century England and was known as the "Elephant Man," is one of the most recognized historical and popular culture examples of this condition^【3】.

Proteus syndrome is classified among rare diseases in medical literature. Since its identification, approximately 200 to 250 confirmed cases have been reported worldwide, with an estimated 120 of these patients currently alive.^【4】 The genetic basis of the disease—a somatic mutation occurring during embryogenesis and not inherited from parents—prevents its heritability and is the primary reason for its low case count.

The cellular basis of Proteus syndrome lies in a somatic mutation occurring in a subset of cells during embryonic development. This mutation is caused by the c.49G>A (p.Glu17Lys) variant in the AKT1 gene^【5】. This mutation leads to constitutive activation of the PI3K/AKT/mTOR signaling pathway, which regulates cell proliferation and survival. Because the mutation does not affect germ cells and arises after embryogenesis, the disease is not inherited from parents to offspring.

The clinical presentation varies among individuals and progresses over time. Asymmetric and disproportionate overgrowth anomalies are observed throughout the body.

Skeletal abnormalities include gigantism of the limbs (arms, legs, hands, and feet) and cranial anomalies (macrocephaly). The bone overgrowth caused by the syndrome is irregular and calcified in structure. Asymmetric macrodactyly (excessive growth of fingers or toes) is also observed.

Skin manifestations include cerebriform connective tissue nevus (CCTN). Analysis of clinical reports indicates that these lesions appear on the soles of the feet in 80% of patients and on the palms in 20%^【6】. These lesions consist of grooved connective tissue resembling the convolutions of the brain. Patients also frequently exhibit epidermal nevi and vascular malformations of capillary, venous, or lymphatic origin.

The syndrome causes regional variations in adipose tissue distribution. Localized lipomas and fat accumulations occur in certain body areas, while lipohipoplasia (failure of adipose tissue development) is observed in other regions of the same patient.

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In Proteus syndrome, vascular malformations of capillary, venous, and lymphatic origin are observed. During the course of the disease, deep vein thrombosis (DVT) and pulmonary thromboembolism (PE) may develop. DVT is characterized by slowed blood flow and clot formation in the deep veins of the legs. Pulmonary thromboembolism, which occurs when clots from leg veins travel through the bloodstream and obstruct pulmonary arteries, imposes pressure on the right ventricle of the heart, leading to respiratory and circulatory failure.

The persistent activation of the signaling pathway regulating cell division increases the risk of neoplasia and tumor formation. Reported neoplastic lesions in patients include bilateral ovarian cystadenomas, monomorphic adenomas of the parotid gland, testicular tumors, and meningiomas^【7】. These neoplastic growths also follow the mosaic distribution pattern of the syndrome and exhibit regional development.

In some patients, neuromotor and cognitive development remains within normal limits. However, structural brain malformations such as hemimegalencephaly—where one hemisphere of the brain is abnormally enlarged—have been reported, along with intellectual disability and epileptic seizures^【8】.

Cystic or bullous lung changes may occur in the respiratory system. Disordered growth also affects internal organs, leading to asymmetric enlargement or cystic formations in the kidneys, spleen, and tonsils^【9】.

The diagnosis of Proteus syndrome is based on a comprehensive evaluation combining clinical findings with genetic test results.

For a diagnosis to be considered, three general criteria must all be met: mosaic distribution of lesions, sporadic occurrence of the disease, and progressive nature of the findings over time. In individuals meeting these general criteria, clinical assessment involves scoring specific signs categorized as A, B, and C. Category A includes cerebriform connective tissue nevus (CCTN); categories B and C include asymmetric overgrowth, tumors, and vascular malformations. For a definitive diagnosis, individuals with a confirmed AKT1 mutation must score at least 10 points on the specific criteria; those without a detected mutation must score at least 15 points^【10】.

Following clinical evaluation, diagnosis is confirmed by molecular testing at the cellular level. Genetic testing of biopsy samples from affected tissues must detect the c.49G>A (p.Glu17Lys) mutation in the AKT1 gene to complete the diagnostic process^【11】. Because mutant cells are rarely detected in blood samples, genetic testing directly targets lesional tissues.

Other syndromes characterized by asymmetric overgrowth and tissue anomalies may resemble Proteus syndrome clinically. The primary condition considered in differential diagnosis is the PIK3CA-Related Overgrowth Spectrum (PROS). CLOVES syndrome, which falls under the PROS umbrella and is characterized by congenital lipomatous overgrowth, vascular malformations, and skeletal anomalies, is a key differential. Although both syndromes arise from genetic defects in the PI3K/AKT/mTOR pathway, they are distinguished by the mutated gene—AKT1 in Proteus syndrome versus PIK3CA in PROS.

Other conditions excluded in differential diagnosis include Bannayan-Zonana syndrome, caused by mutations in the PTEN gene; Klippel-Trenaunay syndrome, which features vascular malformations; and isolated hemihyperplasia.

There is currently no curative treatment for Proteus syndrome. Management requires a multidisciplinary approach involving orthopedics, dermatology, genetics, and surgery.

Orthopedic surgery is performed to control asymmetric growth and deformities of the skeletal system. Epiphysiodesis (closure of growth plates) is preferred to correct limb length discrepancies, while corrective surgeries are used for scoliosis or macrodactyly. Local mass excisions and liposuction are employed for skin and adipose tissue overgrowths; however, postoperative recurrence of tumor-like structures and hypertrophic scarring are commonly observed. Airway deformities and vascular anomalies in these patients complicate anesthesia during surgical procedures.

Miransertib (MK-7075), an oral pan-AKT inhibitor targeting the PI3K/AKT/mTOR pathway, has been included in clinical trials to halt excessive tissue growth. Phase 1/2 MOSAIC clinical trials are evaluating the safety profile of miransertib. In these trials, the drug is administered at an initial dose of 15 mg/m² daily for the first three 28-day cycles, followed by 25 mg/m² daily thereafter^【12】. For PROS conditions caused by mutations at a different step in the same biological pathway, alpelisib-based medications have been approved and are in clinical use.

Prophylactic anticoagulant therapy is administered before and after surgical interventions to reduce the risk of deep vein thrombosis and pulmonary embolism. Strengthening patient communication and enhancing health literacy among caregivers through public information campaigns are important supportive measures.

The prognosis in Proteus syndrome varies depending on the distribution of mutant cells and the tissues affected. Clinical reports indicate that life expectancy ranges from 9 months to 29 years^【13】. Major causes of mortality include severe neurological involvement, progressive respiratory failure, and episodes of pulmonary thromboembolism.

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