The association of multiple polyps of the colon with malignant Tumours of the CNS is known as Turcot syndrome (Turcot et al. 1959). The condition seems to be rare. The colorectal polyps are characteristically not as numerous as in FAP (fewer than 100), and are larger, developing in the second decade of life, but the brain Tumours may occur in childhood. Medulloblastomas and glioblastomas predominate. Café-au-lait spots and pigmented spots have been noted (Itoh and Ohsato 1985), and sebaceous cysts and BCC may occur (Michels and Stevens 1982).
Despite original suggestions that the condition was only an autosomal recessive trait, it is clearly autosomal dominant in some families (Costa et al. 1987; Kumar et al. 1989). Current evidence suggests that in some families, Turcot syndrome is allelic with FAP, especially where medulloblastomas predominate, and truncating germline APC mutations have been found in families with autosomal dominant Turcot syndrome (Hamilton et al. 1995). In other Turcot families (particularly those with glioblastomas), germline mismatch repair gene mutations have been reported (Tops et al. 1992; Liu et al. 1995). In these families, genomic instability was demonstrated in the brain and colonic Tumours of affected individuals (Paraf et al. 1997). This has also been seen in normal tissue from patients with Turcot syndrome, perhaps suggesting that the single mutation in PMS2 identified in this report was actually accompanied by another, hidden mutation (Miyaki et al. 1997). Clear evidence for autosomal recessive Turcot syndrome was provided by the report of two siblings who were diagnosed with a brain Tumours and a colorectal cancer, respectively, at very young ages (De Rosa et al. 2000; Giunti et al. 2009). The authors identified two germline mutations in PMS2 in the two children: 1221delG and 2361delCTTC, both of which were inherited from the patient’s unaffected parents. A literature review of individuals with café-au-lait spots and early-onset colorectal cancer revealed excesses of early-onset brain Tumours and lymphoma and/or leukemia. Several could be accounted for by homozygous mutations in PMS2 or heterozygous mutations in MLH1 (Trimbath et al. 2001a, b), and the condition is now known as constitutional mismatch repair deficiency syndrome (CMMRD), due to biallelic mutations in MSH2, MLH1, MSH6, and PMS2. Other Tumours have been reported in children with this condition including rhabdomyosarcoma and nephroblastomas; there is a suggestion that the MMR mutations causing this condition are less penetrant than those causing the usual type of Lynch syndrome because of the relatively low incidence of Lynch syndrome-type cancers in the families of affected children (Ostergaard et al. 2005; Giunti et al. 2009a, b).
Homozygous PMS2 mutations occur in some children with brain Tumours, but these cases are not strictly Turcot syndrome, as the supratentorial primitive neuroectodermal Tumours (PNETs) that occur (along with café-au- lait lesions and susceptibility to hematological malignancies) (De Vos et al. 2004) are not usually associated with a personal on family history of colorectal cancer. However, De Vos et al. identified two germline PMS2 mutations in the two siblings who were described by Turcot in 1959.
Previously, a single PMS2 mutation p.Arg134X had been identified in the two affected sibs and their father (Hamilton et al. 1995; Trimbath et al. 2001), and although the parents were unaffected, it was assumed to be a dominantly inherited disorder in that family. The identification of another mutation, 2184delTC, and its presence in the mother, confirms the original Turcot pedigree as an example of autosomal recessive Turcot syndrome. This stresses the need for genomic analysis of PMS2 in families with childhood supratentorial PNETs and/or other brain Tumours, particularly if café-au-lait spots are present. Surveillance of first-degree relatives at risk for Turcot syndrome should include regular colonoscopies from age of 25 years in cases associated with Lynch syndrome or surveillance appropriate for FAP if this is the underlying condition.