Paralleling the high frequency of KIT mutations in sporadic GIST, most reported inherited GISTs have involved families with germline mutations in the KIT gene, commonly in exon 11, which encodes the juxta-membrane domain. In addition to the development of GISTs, these families manifest variable clinical phenotypes that typically also include hyperpigmentation, urticaria pigmentosa, and dysphagia. The specific KIT exon 11 deletion mutation described in the first family with an identified germline mutation in familial GIST, does not seem to be required for the familial GIST syndrome as a similar clinical phenotype involving hyperpigmentation and GIST predisposition was seen in a Spanish family with an alternative exon 11 KIT mutation consisting of a duplication of the sequence CAACTT.
Missense mutations involving exon 11 have been implicated in similar familial GIST syndromes. Several families have to found with germline point mutations leading to the substitution of alanine for valine (559) in the KIT juxta-membrane domain. Another exon 11 KIT juxta-membrane missense mutation (W557R) was described in a family consisting of 19 individuals of Italian ancestry who had variable expression of clinical phenotype involving hyperpigmentation and dysphagia. Although the development of GIST was nearly uniform in this kindred, not all family members harboring this specific germline mutation had hyperpigmentation or dysphagia, suggesting a degree of variability of expression, even within a family with a specific KIT germline mutation.
KIT exon 11 mutations are not the only KIT mutations implicated in familial GIST syndromes. Hirota et al. (2002) reported the first identified family with a germline mutation in exon 17, encoding the KIT tyrosine kinase II domain. Though the precise clinical phenotype of KIT mutations may be influenced by reporting, none of the members of this family with KIT tyrosine kinase II domain mutations had hyperpigmentation, differing from some families with KIT exon 11 mutations. Dysphagia, however, was a common similar complaint and suggests dysphagia may be a feature more characteristic of germline KIT mutations in general, rather than associated with a specific mutation.
A third KIT mutation in exon 13 encoding the tyrosine kinase I domain, has also been implicated in familial GIST syndrome. Families have been described that have single base mutations in the tyrosine kinase I domain resulting in a substitution of Glu for Lys (642)[33, 34]. A predisposition to GIST was present in these families but not hyperpigmentation or urticaria pigmentosa, providing further support to the fact that specific KIT germline mutations may lead to variable clinical phenotypes.
Mouse models with “knock-in” mutations, representing inherited GIST syndromes, additionally support the slightly different clinical phenotypes associated with specific KIT mutations. Mice with the V558del mutation (corresponding to the human exon 11 deletion mutation) as well as the D818Y mutation (corresponding to human exon 17 missense mutation) had interstitial cell of Cajal hyperplasia and GISTs[41, 42]. Only mice with V558del had increased dermal mast cells, a finding not seen in mice with the D818Y mutation. This suggests the specific KIT exon 11 mutation may be required for the feature of urticaria pigmentosa whereas development of GIST may be a more generalized phenomenon, associated with a broad spectrum of KIT activating germline mutations. Despite the suggestion of genotype specific clinical features, variability in patient reporting of additional components of the inherited GIST syndrome may complicate precise genotype-phenotype correlations as suggested in one report.