Turcot syndrome

K K Jain MD (Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.)
Rimas V Lukas MD, editor. (Dr. Lukas has received honorariums from AstraZeneca as an advisory board member and AbbVie as a guest speaker.)
Originally released September 28, 1999; last updated August 3, 2017; expires August 3, 2020

This article includes discussion of Turcot syndrome, brain tumor polyposis, glioma-polyposis syndrome, familial adenomatous polyposis coli, and hereditary nonpolyposis colorectal cancer. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Turcot syndrome is an association of primary neuroepithelial tumors of the central nervous system with familial adenomatous polyposis coli (APC) or hereditary nonpolyposis colorectal cancer. It is a genetic disorder, and more than 178 cases resembling Turcot syndrome have been reported in the literature to date. This article describes the pathogenesis and diagnosis of this syndrome. The management of patients with Turcot syndrome takes into consideration both the CNS lesions and colorectal lesions. Early detection of brain tumors in patients with familial adenomatous polyposis coli might improve outcome. Therefore, surveillance for brain tumors is considered worthwhile in these patients.

Key points

 

• Turcot syndrome is an association of primary neuroepithelial tumors of the central nervous system with familial adenomatous polyposis coli or hereditary nonpolyposis colorectal cancer.

 

• Turcot syndrome is now considered to be a genetic disorder associated with mutations of 2 germline genes.

 

• An important differential diagnosis is metastatic brain tumor in cases with colorectal carcinoma.

 

• Early detection of brain tumors in patients with familial adenomatous polyposis coli might improve outcome.

 

• Prognosis in advanced cases is poor, and death is usually due to malignant brain tumor, but some patients die due to colorectal malignancy.

Historical note and terminology

Turcot syndrome has been described as the association of primary malignant tumors of the CNS with adenomatous polyposis coli. The first case of polyposis coli associated with a medulloblastoma, as well as thyroid carcinoma, was described in a case report in 1949 (Crail 1949). In 1959, Turcot described 2 teenaged siblings with multiple adenomatous polypi of the colon that developed into adenocarcinoma and malignant CNS tumors, medulloblastoma involving the spinal cord in 1 sibling and glioblastoma multiforme in the other (Turcot et al 1959). The gene for adenomatous polyposis coli was mapped and cloned in 1991 (Groden et al 1991; Nishisho et al 1991). Familial adenomatous polyposis coli, Turcot syndrome, Gardner syndrome, and a few other syndromes were later considered to be associated with mutations in adenomatous polyposis coli gene. Another type of germline genetic defect, the mutation of a mismatch repair gene usually found in hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome, was demonstrated in 1995 in the family originally described by Turcot (Hamilton et al 1995). Controversy persists regarding the mode of inheritance and whether Turcot syndrome constitutes a distinct genetic disorder. One common feature of these syndromes is association with inheritance of germline mutations in the DNA mismatch repair genes. It is now proposed that inheritance of 2 mismatch repair mutations in an individual along with the unique tumor spectrum should be defined separately from Lynch syndrome I and II, or the subtypes Turcot and Muir-Torre and termed Lynch III, to identify individuals with constitutively compromised mismatch repair associated with biallelic mutations (Felton et al 2007). Turcot syndrome overlaps with “constitutional mismatch repair deficiency (CMMRD) syndrome”, a genetic disorder that results from biallelic germline mutations in 1 of the 4 MMR genes -- MLH1, MSH2, MSH6 or PMS2 – and manifests in childhood with a broad spectrum of cancer including mainly hematological, brain, and intestinal tract tumors. It includes cases of Lynch syndrome, and it is likely that the original 2 cases described by Turcot in 1959 were the first cases of CMMRD and many cases described subsequently as Turcot syndrome should retrospectively be considered CMMRD patients (Wimmer et al 2014).

At least 178 cases resembling Turcot syndrome have been reported in the literature to date. In some cases, the histological confirmation of the lesions is not available. Some of the case reports also include reviews of previously reported cases (Schroder et al 1983; Jarvis et al 1988; Jamjoom et al 1989; Zink et al 1992; Cervoni et al 1995; Hamada et al 1998; Tomaras et al 1998). Several classification systems have been proposed. Lewis proposed 3 groups (Lewis et al 1983):

 

(1) Cases in which siblings are affected and there is family history of brain tumors
(2) Cases in which 2 or more generations in a family presented with polyposis of the colon
(3) Isolated nonfamilial cases.

A classification of glioma-polyposis syndrome based on a review of 127 cases is as follows (Itoh et al 1993):

 

(1) Cases of Turcot syndrome that had characteristic colonic and brain manifestations
(2) Cases of familial adenomatous polyposis coli associated with glioma
(3) Suspicious cases of glioma polyposis
(4) Cases other than glioma-polyposis syndrome.

A simple classification based on molecular evidence and genetic background divides Turcot into 2 entities (Sunahara and Nakagawara 2000):

 

(1) True Turcot syndrome (autosomal recessive). Intestinal polyps are large, fewer in number than 100, and are apt to undergo a malignant change. Associated brain tumor is usually a glioblastoma or an astrocytoma. Mismatch repair genes might be involved.

 

(2) Familial adenomatous polyposis-associated type (autosomal dominant). There is a predisposition to development of medulloblastoma.

Definition. The earlier cases of Turcot syndrome included only brain tumors of neuroepithelial origin, but some authors have reported other tumors as well. One of the original cases of Turcot had a 3 mm chromophobe adenoma of the pituitary in addition to the glioblastoma multiforme. Several other tumors of organs besides the colon and brain have been reported in some cases of Turcot syndrome. It is difficult to define the exact components of this syndrome. The synonym “glioma-polyposis complex,” sometimes used to describe the syndrome, does not adequately describe it because it restricts the brain tumor to glioma and the colon lesions to polyposis. Because neuroepithelial tumors other than gliomas and nonpolyposis colorectal cancer are recognized as components of Turcot syndrome, the following definition of Turcot syndrome would be more appropriate: Turcot syndrome is an association of primary neuroepithelial tumors of the central nervous system with familial adenomatous polyposis coli or hereditary nonpolyposis colorectal cancer. It is generally agreed that CNS tumors of nonneuroepithelial origin such as meningiomas, pituitary tumors, craniopharyngioma, cerebral sarcoma, and cerebral lymphoma should not be included as components of Turcot syndrome.

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