Bone malformations in Proteus syndrome: an analysis of bone structural changes and their evolution during growth

Abstract

The radiographic follow-up of a patient with Proteus syndrome is presented. Review of radiographs obtained at 3 years 10 months, 10 years, and 17 years 8 months indicated that the rate of growth in length of the oversized tubular bones of the hands was similar to that of the normal bones of the same hand. This observation supports the view that the primary lesion occurs in the early embryonic period, when the limb bud mesenchyme cells condense and cartilage differentiates producing oversized cartilage anlages, rather than being a defect of bone cell-mediated apposition and modelling processes of bone. Additional radiographs of the pelvis and spine were obtained at age 4 years 10 months and head CT at 8 years 10 months. This pathogenetic mechanism fits well with the hypothesis of somatic mosaicism, which is at present the most credible explanation for the aetiology of Proteus syndrome. Other skeletal malformations recognized as typical of the syndrome can be interpreted as secondary adaptations to the altered mechanical conditions induced by overgrowth of bones.

Molecular Regulation of Limb Growth

“…Similarly, gain-of-function and loss-of-function mutations in FGF receptors lead to skeletal dysplasias such as Apert (OMIM 101200), Carpenter (OMIM 201000), and Crouzon syndromes (OMIM 123500) but not to hamartomas or overgrowth. Moreover, mutations in each of the above genes lead to alterations in the rate of growth, yet this appears to be discordant with findings that the rate of skeletal growth is not altered in a condition such as Proteus syndrome 17 . Exactly how gene expression is regulated and how these different signaling molecules interact have yet to be elucidated.…”

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“…Cases of primary hyperostosis are rarer, while bone substance may be normal or not. 12 Hyperostoses may occur in various bones, even in the ear passage. [13][14][15] Typical alterations in the structure and morphology of blood vessels affect primarily the small blood vessels and capillaries.…”

Phenotype and Surgical Treatment in a Case of Proteus Syndrome With Craniofacial and Oral Findings

“…Somatic mutations arising early in ontogenesis are estimated to be the cause of the plethora of findings in Proteus syndrome (17). Progressive segmental overgrowth most commonly affects bones, skin, fat tissues, and central nervous system (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Skeletal enlargements such as macrodactyly, vetrebral anomalies (scoliosis), and hyperostosis usually get noticed firsts (1,2,8).…”