A Novel Germline KIT Mutation (p.L576P) in a Family Presenting With Juvenile Onset of Multiple Gastrointestinal Stromal Tumors, Skin Hyperpigmentations, and Esophageal Stenosis

Abstract

Familial gastrointestinal stromal tumor (GIST) syndrome is a rare autosomal dominant genetic disorder. We report on a kindred in which 3 family members carry a germline mutation (c.1727T>C, p.L576P) in exon 11 of the KIT gene. This mutation was not reported so far in familial GISTs. Apart from multiple GISTs in 2 of the mutation carriers, all of them had multiple hyperpigmented skin macules and a history of achalasia-like stenosis of the esophagus in early childhood. In the index patient >100 tumors and a diffuse Cajal cell hyperplasia of the small bowel occurred. Sequencing of DNA extracted from tumor tissue of one of his GISTs revealed the KIT mutation in exon 11 (c.1727T>C). By array comparative genomic hybridization whole chromosomal gains 3, 5, 7, 9, 12, 15, and 18 were detected. In addition, we could identify a gain on chromosome 4, spanning the KIT gene. Together with the family described here, 24 unrelated cases with proven germline mutations in KIT have been reported. In these families the diagnosis was established from the age of 30 years onwards. Because in 1 patient reported here the GIST was a coincidental finding at the age of 15 years, the tumors might occur at a very young age and remain unnoticed until they-either due to increasing size, ulceration, or malignant progression-become symptomatic. Therefore, we propose to start screening patients with known KIT mutations from a younger age.

Increased risk of additional cancers among patients with gastrointestinal stromal tumors: A population‐based study

“…In particular, the data pointed to the possibility of many new, clinically relevant associations between GIST and cancers distinct from known disorders such Carney’s triad/quadrad (e.g., gastric GIST, pulmonary chondroma, extra-adrenal paraganglioma, adrenal adenomas) 27–29 , familial GIST syndromes (e.g., activating germline mutations in KIT and PDGFRα with multifocal GIST) 3, 30–33 , neurofibromatosis type 1 (e.g., GIST, sarcomas, periampullary/pancreatic neuroendocrine tumors, and pheochromocytoma) 34–39 , and Carney-Stratakis syndrome (e.g., GIST and paragangliomas) 40–42 . Because sarcomas and neuroendocrine tumors, which are found in neurofibromatosis, comprised only 4.0% and 3.1% of the 1,208 additional cancers, respectively, this suggests that other etiologies might be responsible for the observed trends.…”

Familial Gastrointestinal Stromal Tumor Syndrome: Report of 2 Cases with KIT Exon 11 Mutation

“…Six cases have been reported of familial GIST syndrome due to mutations in KIT exon 13 and 4 cases have been reported due to mutations in exon 17. 4,6,8,9 By comparison, exon 9 mutations account for 15% of KIT mutations in the setting of sporadic GIST, whereas exons 13 and 17 account for 2% and 1%, respectively.…”

“…Twenty families with familial GIST have arisen from exon 11 of KIT as described by Neuhann et al, 4 Nakai et al, 5 Adela et al, 7 and the cases presented here. KIT and PDGFRA are members of the family of class 3 tyrosine kinase receptors.…”

Genetics of Gastrointestinal Stromal Tumors

“…27,28 Since their original description by Nishida and colleagues, 29 an additional 27 families with familial GIST have been identified. 27,30 These mutations are identical to those found in sporadic tumors, and are inherited in an autosomal dominant pattern. 29,31-33 Every family member who harbors a germline KIT mutation will develop Cajal cell hyperplasia and eventually, one or more GISTs, usually at a much younger age when compared with sporadic tumors.…”