Proteus syndrome (PS) is characterized by rapidly progressive disproportionate overgrowth with a strong bony component and pathognomonic “cerebriform” connective tissue growths on the skin, especially on the soles of the feet and palms of the hands. In addition, circumscribed adipose tissue hyperplasia, epidermal nevi, and vascular malformations (slow-flow) are most common.
Unfortunately, many vaguely similar-looking circumscribed hyperplasia phenotypes have been ill defined, especially in the older literature. Thus they were often subsumed under the term Proteus syndrome or “Proteus-like syndromes.” However, Proteus syndrome in the narrow sense has been clearly defined.
(according to Biesecker et al., 1999, Turner et al., 2004)
(All must be met): mosaic distribution, disproportionate progression of hyperplasia after birth, sporadic occurrence.
Either category A or two of B or three of C must be met.
|Category A: Cerebriform mixed connective tissue nevus (CMCTN)|
|Category B:||Category C:|
|Epidermal nevus||1. Dysregulation of the adipose tissue|
|Asymmetric, disproportionate overgrowth||either/or:|
|1 or more of the following:||(a) Lipomatosis/lipomas|
|(b) Hyperostosis of skull||(b) Regional lipoatrophy|
|(c) Hyperostosis of external auditory canal||2. Vascular malformations|
|(d) Vertebral body||1 or more:|
|(e) Viscera: spleen/thymus||(a) Capillary|
|Specific tumors before 20th birthday.||(b) Venous|
|1 of:||(c) Lymphatic|
|(a) Bilateral cystadenomas of the ovary||3. Pulmonary cysts|
|(b) Parotid adenomas||4. Facial phenotype|
Proteus syndrome occurs sporadically (not familial). It is based on a genetic mosaic. The cause is a somatic (present only in affected tissue) autosomal dominant gain-of-function mutation (c.49G>A, p.Glu17Lys) in the AKT1 oncogene. Mutation-related constitutive activation of AKT1 leads to overactivation of the PI3K (phosphatidylinositol-3- kinase)/AKT/mTOR pathway and causes enhanced cell growth and anti-apoptosis.
The presentation is highly variable (“protean” = easily changeable) and multiform.
The regional overgrowth with a strong skeletal component usually begins to become apparent in the second half of the first year or in the first half of the second year of life and is disproportionately progressive in phases during childhood. The result is often considerably asymmetric overgrowth. Hands and feet are particularly affected, but long tubular bones such as humerus and femur, vertebral bodies, skullcap, auditory canals, etc., may also be involved. Radiological characteristics are enlargement and irregular ossification of affected bones as well as increasing periosseous soft tissue calcification, especially near the joints, accompanied by massive changes in the shape of the bone. In the spine, asymmetrically osseous hyperplasia of massively enlarged vertebral bodies (hemimegaspondylodysplasia) leads to asymmetric scoliosis.
Cerebriform mixed connective tissue nevi (CMCTN) are almost pathognomonic skin appearances; they occur more frequently on the soles of the feet ("moccasin sole"), but also in the palm of the hand, and are characterized by a cerebriform, i.e., reminiscent of the brain surface, garland-shaped proliferation of connective tissue.
Localized adipose tissue hyperplasias occur particularly on the trunk and sometimes infiltrate the muscles. Epidermal nevi appear as skin-colored to gray-brown, slightly raised striated skin changes with velvety soft, sometimes papillomatous surfaces.
The vascular malformations may involve capillaries (CM), veins (VM), and/or lymphatic vessels (LM), so they are always slow-flow malformations. However, these are not constant features of Proteus syndrome.
In Proteus syndrome, cystic changes to the lung tissue are common, some of which may enlarge and lead to pneumonia or pneumothorax.
Tumors: Unlike other syndromes associated with specific tumors, Proteus syndrome has a small but significantly increased risk of various tumors, most of which are benign. In particular, meningiomas, ovarian cystadenomas, and parotid monomorphic adenomas have been observed in several individuals with Proteus syndrome.