Summary

Proteus syndrome (PS) is a sporadic disorder affecting tissue derived from any germinal layer and resulting in tissue overgrowth in a mosaic pattern. The clinical manifestations are highly variable and include macrodactyly, vertebral abnormalities, and asymmetric limb overgrowth and length discrepancy. Hyperostosis, overgrowth of viscera (spleen, thymus), abnormal and disproportionate fat distribution, asymmetric muscle development, connective-tissue nevi, epidermal nevi, and vascular malformations may also be seen. The incidence of bilateral ovarian cystadenomas and parotid monomorphic adenoma is higher in these patients than in the general population. Thrombo embolic manifestations and pulmonary cystic malformations are also more frequent in PS patients. PS is characterized by calcified connective tissue, and elongation of long bones with abnormal thinning. These features indicate that the condition may be caused by a somatic alteration in a gene, but no specific gene mutation has yet been identified. Although germline PTEN mutations (the PTEN gene is responsible for Bannayan-Zonana syndrome) have been found in some PS cases, this mutation was not identified in most reported patients, and it seems unlikely to have a major role in the etiology of PS. The most plausible genetic theory for explaining the characteristics of this syndrome is Happle's somatic mosaic hypothesis: autosomal lethal genes may survive only in a mosaic state. This would explain the genetic basis of syndromes such as PS, which are often characterized by sporadic occurrence, distribution of lesions in a scattered or asymmetrical pattern, variable extent of involvement and lack of diffuse involvement of entire organs. As a result of the variability of the symptoms, the rate of misdiagnosis in PS is high: a recent study revealed that among the 205 PS cases reported in the literature, only 97 strictly met the diagnostic criteria published in 1998 by the American National Institute of Health. The presence of connective tissue nevi was considered almost pathognomonic for the syndrome, although they are not present in all cases. Other combinations of manifestations (e.g., epidermal nevus, disproportionate overgrowth, specific tumors) were suggested to meet the diagnostic criteria. Moreover, patients with PS were also reported to have a higher incidence of premature death, scoliosis, megaspondyly, central nervous system abnormalities, tumors, otolaryngologic complications, pulmonary cystic malformations, dental and ophthalmogic complications. The cases that met the criteria were more often males, the abnormal growth was described as asymmetric, distorting, and relentless. However, although the manifestations of Proteus syndrome are highly variable, accurate diagnosis is possible if standard diagnostic criteria are followed and if disease features are assessed in comparison with those found in similar syndromes. Differential diagnosis includes mainly Klippel-Trenaunay syndrome and hemihyperplasia/lipomatosis syndrome. Up to now, the diagnosis and management of the disease depend heavily on clinical evaluation and imaging. Follow-up is multidisciplinary and health care providers should keep in mind the risk of deep venous thrombosis and pulmonary embolism.

Expert reviewer(s)

• Pr Didier LACOMBE