Gist-Plus Syndrome

A number sign (#) is used with this entry because of evidence that GIST-plus syndrome (GISTPS) is caused by heterozygous mutation in the PDGFRA gene (173490) on chromosome 4q12.

Description

GIST-plus syndrome (GISTPS) is an autosomal dominant disorder characterized by incomplete penetrance of multiple mesenchymal tumors of the gastrointestinal tract, including gastrointestinal stromal tumor (GIST), inflammatory fibroid polyps (IFP), and fibroid tumors (FT). Some patients have been reported with coarse facies and skin, broad hands and feet, and premature tooth loss. Isolated GISTs and IFPs are seen in patients with somatic PDGFRA mutations (summary by Manley et al., 2018).

Clinical Features

Verhest et al. (1981) described a Belgian family in which several individuals had 'intestinal neurofibromatosis.' In a follow-up of this family, Heimann et al. (1988) reported that onset of symptoms was in adulthood and that some gene carriers remained asymptomatic into middle and late adulthood. A reciprocal balanced chromosomal translocation involving chromosomes 12 and 14 was identified, but did not segregate completely with the disorder and was thus considered to be a fortuitous finding (Verhest et al., 1988). Verhest et al. (1988) concluded that the disorder in this family was phenotypically distinct from neurofibromatosis I (NF1; 162210). De Raedt et al. (2006) provided further analysis of the Belgian family reported by Verhest et al. (1981) and Heimann et al. (1988). There were 5 affected members, including 3 living sisters who were examined. All had benign intestinal tumors, constipation, large hands, and coarse facies, and 2 had bowel obstruction necessitating several surgical interventions. Five tumors from 1 sister were available for pathologic investigation and showed a moderately cellular spindle cell proliferation with a typical wavy nature of a collagenous background. Although the histology was suggestive of neurofibromas, S100 protein expression was negative. Further studies showed negative staining for CD34 (142230), DOG1 (605882), and KIT (164920).

Chompret et al. (2004) reported a French family in which 5 individuals developed multiple GISTs between 40 and 60 years of age. None had hyperpigmentation, mast cell disorders, or dysphagia, but all 5 had large hands, which was not present in unaffected family members.

Pasini et al. (2007) reported a woman with GISTs and other mesenchymal tumors. She developed intestinal obstruction at age 32 years and was found to have multiple mesenchymal fibroid intestinal tumors. Tumor tissue showed multiple secondary genetic changes, including loss of heterozygosity of several chromosomal regions such as 14q. Of note, the patient had a history of a duodenal lipoma, which had not previously been reported in patients with GISTs.

Ricci et al. (2015) reported a 3-generation family with GIST-plus syndrome, which the authors called 'PGDFRA-mutant syndrome.' The proband was diagnosed at age 67 years with a palpable abdominal mass that on CT imaging showed a 12-cm lesion originating from the gastric wall. Esophagogastroduodenoscopy (EGD) showed a 2-cm polyp in the gastric antrum. Partial gastrectomy removed 2 pathologically proven GIST and an 8-cm IFPs and 3 fibrous tumors of the duodenum were also removed. The patient responded well to surgery and imatinib. His father had died of 'gastric cancer' and his paternal half sister had surgery for gastric, ileal, and colonic tumors. After identification of a germline PGDFRA mutation (173490.0014), an additional 11 family members were screened; 2 did not carry the familial variant. The paternal half sister, aged 43, had IFP and FT; the proband's 40-year-old daughter had an undefined gastrointestinal tumor; his 37-year-old daughter had IFP and FT; and his 31-year-old son had IFP. None of the 5 carrier grandchildren, ranging in age from 4 to 19 years, had endoscopy or evidence of any gastrointestinal tumors. Ricci et al. (2015) suggested that the disorder be considered when any individual has 2 or more inflammatory fibrous polyps, including fibrous tumors, and/or GISTs. Lipomas and/or large hands may also be present. Carrier individuals in a family should undergo endoscopy combined with endoscopic ultrasound and/or CT enterography.

Manley et al. (2018) reported a 2-generation pedigree in which a proband, her 2 sisters, and one of her daughters had a missense mutation in the PDGFRA gene (173490.0015). The 62-year-old proband had hundreds of inflammatory fibroid polyps and one GIST, as well as a coarse face, broad hands and feet, and premature tooth loss (necessitating dentures in her 40s). No other affected family members had any intestinal tumors at ages ranging from 35 to 64 years, but all had coarse facies and broad hands and feet.

Molecular Genetics

In affected members of a French family with multiple GISTs, Chompret et al. (2004) identified a heterozygous germline mutation in the PDGFRA gene (D846Y; 173490.0009).

In 3 affected sisters from the Belgian family with GISTs reported by Verhest et al. (1981) and Heimann et al. (1988), De Raedt et al. (2006) identified a heterozygous germline mutation in the PDGFRA gene (Y555C; 173490.0010).

In a patient with a combination of multiple fibrous polyps and lipomas of the small intestine and multiple GISTS, Pasini et al. (2007) identified a heterozygous germline mutation in the PDGFRA gene (V561D; 173490.0004).

Ricci et al. (2015) described a 3-generation family with GIST-plus syndrome segregating a heterozygous germline mutation in the PDGFRA gene (P653L; 173490.0014). Four mutation carriers had GIST, inflammatory fibroid polyps, and/or fibroid tumors, whereas 5 mutation carriers in the third generation had no gastrointestinal tumors.

Manley et al. (2018) described a 2-generation family with GIST-plus syndrome segregating a heterozygous germline mutation in the PDGFRA gene (D846V; 173490.0015).

Somatic Mutations

Heinrich et al. (2003) found that approximately 35% (14 of 40) of GISTs lacking KIT mutations had somatic intragenic activation mutations in the PDGFRA gene (see, e.g., 173490.0001-173490.0007). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Heinrich et al. (2003) concluded that KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.

Genotype/Phenotype Correlations

Patients with familial GISTs usually have multiple tumors; those with germline mutations in the KIT gene may also have hyperpigmentation, mast cell tumors, or dysphagia, whereas those with mutations in the PDGFRA gene often have large hands (Chompret et al., 2004).

Nomenclature

GIST-plus syndrome had previously been referred to as 'intestinal neurofibromatosis' and symbolized NF3B.

History

Lipton and Zuckerbrod (1966) described familial intestinal neurofibromatosis without other features of neurofibromatosis-1.

Anthony et al. (1984) reported a family from Devon, England, in which a female in each of 3 successive generations had multiple inflammatory fibroid polyps. The grandmother had had 9 polyps resected over 11 years; the mother, 7 over 18 years; and the daughter, 6 over 6 years. Characteristically, inflammatory fibroid polyps are solitary tumors in the stomach which consist of loosely organized, vascular and fibrous tissue with a variable number of eosinophils. Recurrence or familial occurrence had not previously been encountered. Conventional histology, electron microscopy, and immunohistology suggested to Anthony et al. (1984) that the lesion is a self-limiting proliferation of histiocytes. The initiating event or stimulus was not known. None of the patients or their relatives were known to have allergies, dietary fads, or gastrointestinal infections. The grandmother's polyps were removed from the ileum and gastric antrum; in the other 2 patients, they were removed from the ileum, where they had caused intussusception. Allibone et al. (1992) reported an update on the Devon family. Two additional females in the third generation were affected. All but the grandmother had polyps in the ileum.