The PTCH germ line mutations in NBCCS patients are either inherited from an affected parent or Vorinostat HDAC due to de novo events in a parental germ cell. The truncating germ line mutation found in our patient is likely to abolish the function of one copy of PTCH. However, it can not be completely excluded that a severely truncated form of the protein is produced that might interfere with the normal PTCH gene product, causing some kind of clinical phenotype. Tumorigenesis starts if inactivation of the second, normal PTCH allele by either loss-of-heterozygosity or point mutation occurs by chance in a single cell (two-hit mutagenesis). The resulting reactivation of the hedgehog/PTCH pathway not only causes basal cell carcinoma, but also contributes to the formation of tumors such as medulloblastoma and rhabdomyosarcoma [5].

Furthermore, several recent studies found evidence for an involvement of hedgehog signalling and PTCH in tumorigenesis of the GI- tract. Animal studies have shown that hedgehog signalling is crucial for the normal development of the gut [6]. Reactivation of this pathway is therefore likely to start uncontrolled cell growth, and it has already been demonstrated that hedgehog signalling is widely active in sporadic gut-derived tumors [7]., Ligand-dependent activation of the hedgehog/PTCH pathway by various external stimuli such as injury of the GI epithelium by acid, alcohol or Helicobacter pylori infection has been identified as the main pathomechanism underlying this observation [8].

The coexistence of a PTCH germ line mutation and a rare small bowel adenocarcinoma in our patient might indicate that a two-hit mutational inactivation of PTCH is a second though probably rare pathomechanism in GI malignancies. A highly unusual finding in our patient were the spindle-cell masses in the small bowel that displayed a high degree of cellular inhomogenity. Leiomyomatosis in the GI-tract has been reported occasionally in syndromes such as neurofibromatosis type 1 and tuberous sclerosis, but without the neural cell component found in our patient [9-11]. It is therefore tempting to speculate that reactivation of the PTCH/hedgehog pathway might have induced the growth of spindle cells in the GI-tract of our patient. The variability of cell types present can be explained by the important role of sonic hedgehog signalling in the activation and differentiation of progenitor cells.

Hedgehog signalling has shown to promote the development of neural crest cells that are capable of multilineage differentiation. These cells give rise not only to neurons and glial cells but also to different types of mesenchymal cells Entinostat including smooth muscle and connective tissue cells [11]. This role in the development of multipotent progenitor cells fits with the coexistence of neural and smooth muscle cells seen in the immunohistochemical analysis of the spindle-cell nodules.