FaCD Online Syndrome Fact Sheet

Last updated: 30 Jan 2013

Name: Familial Gastrointestinal Stromal Tumors

Synonym: Familial GIST, incl. Multiple Familial Gastrointestinal Autonomic Nerve Tumors (GANT)

Mode of Inheritance: AD

OMIM number: 164920  


KIT, mapped to 4q12
PDGFRA, mapped to 4q12
SDHA, mapped to 5p15
SDHB, mapped to 1p36.1-p35
SDHC, mapped to 1q21
SDHD, mapped to 11q23

Tumor features

autonomic nerve tumor (GANT) of the small intestine
gastrointestinal stromal tumor (GIST)

Non-tumor features

neuronal dysplasia of the small intestine

Non-tumor features (possible)

mast-cell hyperplasia
perineal skin, hyperpigmentation of
urticaria pigmentosum (cutaneous mastocytosis)


Nishida et al.[1] reported a 4 generation family with multiple gastrointestinal stromal tumors (GISTs), benign as well as malignant. Four males and 3 females were affected. Male-to-male transmission was observed. Main symptom was intestinal obstruction. The authors suggested, referring to a families reported by Marshall et al.[2] and El-Omar et al.[3] with similar gastrointestinal tumors, that perineal skin hyperpigmentation and mast-cell hyperplasia might also be symptoms of the disorder. Perineal skin hyperpigmentation was said to be present in two of their own patients, but the authors were not allowed to examine them. No details were given on the age of onset of the disease.

Germline activating cKIT mutations have been detected in the family reported by Nishida et al.[1] (see Piebaldism for the disorder associated with loss of function of cKIT). A few additional families have been reported since [4-7].
A disorder traditionally referred to as 'intestinal 'neurofibromatosis', but in fact reclassified as 'intestinal stromal tumors' has been associated with germline PDGFRA gene mutations and is suggested to be a variant of this syndrome.[8] Although somatic activating Kit mutations have been detected in the skin lesions of sporadic mastocytosis patients, no cKIT mutations were observed in familial mastocytosis[9].

O’Brien et al.[10] reported a mother and daughter, both of whom were diagnosed with multiple gastrointestinal autonomic nerve tumors (GANT) of the small intestine, diagnosed at age 69 and 52 years, respectively. Diffuse hyperplasia and dysplasia of the Auerbach’s mesenteric plexus were also present. GANT are a subtype of GIST and a germline cKIT mutation was detected in the family reported by O’Brien[4]. For a review, check [11]. Germline SDHB and SDHC mutations have been identified in sporadic GIST cases without somatic cKIT and PDGFRA mutations[12]. Germline SDHA and D mutations have been associated with GIST as well [13-15].


[1] Nishida T, Hirota S, Taniguchi M, Hashimoto K, Isozaki K, Nakamura H, Kanakura Y, Tanaka T, Takabayashi A, Matsuda H, Kitamura Y. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet 19[4], 323-324. 1998.
[2] Marshall JB, Diaz-Arias AA, Bochna GS, Vogele KA. Achalasia due to diffuse esophageal leiomyomatosis and inherited as an autosomal dominant disorder: report of a family stury. GASTROENTEROLOGY 1990; 98:1358-1365.
[3] El-Omar M, Davies J, Gupta S, Ross H, Thompson R. Leiomyosarcoma in leiomyomatosis of the small intestine. Postgrad Med J 1994; 70:661-664.
[4] Hirota S, Okazaki T, Kitamura Y, O'Brien P, Kapusta L, Dardick I. Cause of familial and multiple gastrointestinal autonomic nerve tumors with hyperplasia of interstitial cells of Cajal is germline mutation of the c-kit gene [letter]. Am J Surg Pathol 2000; 24(2):326-327.
[5] Chompret A, Kannengiesser C, Barrois M, Terrier P, Dahan P, Tursz T, Lenoir GM, Bressac-De Paillerets B. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 2004; 126(1):318-21.
[6] Wozniak A, Rutkowski P, Sciot R, Ruka W, Michej W, Debiec-Rychter M. Rectal gastrointestinal stromal tumors associated with a novel germline KIT mutation. International journal of cancer 2008; 122(9):2160-4.
[7] Li FP, Fletcher JA, Heinrich MC, Garber JE, Sallan SE, Curiel-Lewandrowski C, Duensing A, van de Rijn M, Schnipper LE, Demetri GD. Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. Journal of clinical oncology 2005; 23(12):2735-43.
[8] de Raedt T, Cools J, Debiec-Rychter M, Brems H, Mentens N, Sciot R, Himpens J, de Wever I, Schöffski P, Marynen P, Legius E. Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA. Gastroenterology 2006; 131(6):1907-12.
[9] Longley BJJr, Metcalfe DD, Tharp M, Wang XM, Tyrrell L, Lu SZ, Heitjan D, Ma YS. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci U S A 96, 1609-1614. 1999.
[10] O'Brien P, Kapusta L, Dardick I, Axler J, Gnidec A. Multiple familial gastrointestinal autonomic nerve tumors and small intestinal neuronal dysplasia. Am J Surg Pathol 23[2], 198-204. 1999.
[11] Agarwal R, Robson M.Inherited predisposition to gastrointestinal stromal tumor. Hematol Oncol Clin North Am. 2009 Feb;23(1):1-13, vii.
[12] Janeway KA, Kim SY, Lodish M, Nosé V, Rustin P, Gaal J, Dahia PL, Liegl B, Ball ER, Raygada M, Lai AH, Kelly L, Hornick JL; NIH Pediatric and Wild-Type GIST Clinic, O'Sullivan M, de Krijger RR, Dinjens WN, Demetri GD, Antonescu CR, Fletcher JA, Helman L, Stratakis CA. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations.Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):314-8.
[13] Oudijk L, Gaal J, Korpershoek E, van Nederveen FH, Kelly L, Schiavon G, Verweij J, Mathijssen RH, den Bakker MA, Oldenburg RA, van Loon RL, O'Sullivan MJ, de Krijger RR, Dinjens WN. SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors.Mod Pathol. 2012 Nov 23. doi: 10.1038/modpathol.2012.186. [Epub ahead of print]
[14] Wagner AJ, Remillard SP, Zhang YX, Doyle LA, George S, Hornick JL. Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors. Mod Pathol. 2012 Sep 7. doi: 10.1038/modpathol.2012.153. [Epub ahead of print]