Diagnostic Considerations
Carefully distinguish Proteus syndrome from other overgrowth disorders, particularly Klippel-Trenaunay syndrome, hemihyperplasia/lipomatosis syndrome, and neurofibromatosis type 1. [36] Several other syndromes can also be considered in the differential diagnosis [24] ; these are discussed below.
Vascular syndromes
The classic definition of Klippel-Trenaunay syndrome is the triad of vascular stain, soft tissue and/or bony hypertrophy, and venous varicosities. It often involves vascular malformation involving the lower or upper limbs, but usually only 1 limb is affected. The vascular (ie, capillary, lymphatic, and venous) malformations always exist in combination. Overgrowth is present at birth; commonly, this is more severe than that in Proteus syndrome. Moreover, Klippel-Trenaunay syndrome lacks subcutaneous tumors, palmar and/or plantar cerebriform hyperplasia, and cranial exostoses, which are usually found in Proteus syndrome patients. [37] The delayed onset of cerebriform hyperplasia often leads to the misdiagnosis of Proteus syndrome as Klippel-Trenaunay syndrome in neonates and infants. [24]
Parkes-Weber syndrome is a vascular malformation involving the upper and lower limbs. It is characterized by a diffuse capillary blushing, warmth, and underlying arteriovenous shunts.
Maffucci syndrome is characterized by hemangiomas and enchondromas.
Syndromes with pigmentation and lipomatosis
Neurofibromatosis type 1 involves café au lait macules, axillary freckling, Lisch nodules, and neurofibromas, rather than epidermal nevi and hamartomas.
Bannayan-Riley-Ruvalcaba syndrome, which is characterized by macrocephaly, lipomas, capillary malformations, and polyposis of the colon and rectum, does not cause asymmetric growth, cranial exostoses, epidermal nevi, or palmar or plantar changes.
Patients with hemihyperplasia lipomatosis syndrome lack the progressive overgrowth seen in patients with Proteus syndrome.
Encephalocraniocutaneous lipomatosis has been considered a circumscribed form of Proteus syndrome, although some authors believe that Proteus syndrome and encephalocraniocutaneous lipomatosis are different entities. [38]
Conditions with local gigantism
a. Macrodystrophica lipomatosa- caused by the proliferation of mesenchymal elements that result in local gigantism. Biopsy shows adipose tissue dispersed in mesh-like fibrous tissue. [39]
b. Other causes of local gigantism are hemangiomatosis, lymphangiomatosis and fibrolipohamartoma of the nerve sheath. [39]
Differential Diagnoses
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Epidermal nevus of the trunk follows the Blaschko lines.
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Cerebriform connective-tissue nevus on the plantar surface.
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Overall clinical aspect.
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Proteus syndrome with hemihypertrophy of the limbs.
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Proteus syndrome with gigantism of the feet and macrodactyly.
