Proteus Syndrome

Excerpt

Clinical characteristics: Proteus syndrome is characterized by progressive segmental or patchy overgrowth most commonly affecting the skeleton, skin, adipose, and central nervous systems. In most individuals Proteus syndrome has modest or no manifestations at birth, develops and progresses rapidly beginning in the toddler period, and relentlessly progresses through childhood, causing severe overgrowth and disfigurement. It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism.

Diagnosis/testing: The diagnosis of Proteus syndrome is based on clinical criteria that include all three general characteristics (mosaic distribution of lesions, sporadic occurrence, progressive course) and additional specific clinical criteria. Identification of a mosaic, somatic, heterozygous pathogenic variant in AKT1 by molecular genetic testing can establish the diagnosis if the clinical criteria are inconclusive.

Management: Treatment of manifestations: Management of overgrowth is the chief concern; the approaches are diverse and include various orthopedic procedures to delay or halt linear bone growth; rehabilitation medicine care including physical and occupational therapy; correction of skeletal deformities such as scoliosis; dermatologic management of the skin manifestations, especially the cerebriform connective tissue nevi with pedorthic intervention as needed; monitoring for and treating deep vein thrombosis and pulmonary embolism; monitoring and treating bullous pulmonary disease; developmental intervention or special education for developmental delays; psychosocial counseling is warranted in most instances.

Surveillance: Monitoring should be tailored to individual presentation; routine monitoring for evidence of tumor development is by medical history and physical examination; periodic imaging is not indicated.

Agents/circumstances to avoid: Medications that increase the risk of deep vein thrombosis or are procoagulant; medications that increase growth (e.g., androgenic steroids or growth hormone).

Genetic counseling: All individuals with clinically confirmed Proteus syndrome known to these authors have been simplex occurrences caused by somatic mosaicism for the specific de novo pathogenic variant c.49G>A (p.Glu17Lys). It is hypothesized that a non-mosaic (i.e., germline) AKT1 c.49G>A pathogenic variant would be lethal in early development. There is no known risk to offspring of an affected individual; however, the number of affected individuals who have reproduced is very small. Thus, the risks to the parents of an affected child and to affected persons who do reproduce are not increased compared to the general population. Because Proteus syndrome is not inherited, prenatal testing is not indicated.