Turcot 's Syndrome

Evidence for Autosomal Dominant Inheritance

JAMES H. LEWIS, MD, ALLEN L. GINSBERG, MD, AND KATHLEEN E. TOOMEY, MD

A case of Turcot's syndrome (colonic polyposis plus a malignant central nervous system tumor) occurring in a kindred with autosomal dominant colonic polyposis is presented. It is proposed that Turcot's syndrome patients can be classified into Type I where only siblings are affected and Type I1 where two or more generations have colonic polyposis. A third nonfamilial group cannot be classified into Type I or I1 based on available information. Evidence is presented suggesting Turcot's syndrome is best considered an additional phenotype of familial polyposis and is most likely inherited in an autosomal dominant manner.

Cancer 51524428, 1983.

ALIGNANT TUMORS Of the Central nervous System M (CNS) and multiple polyposis of the colon was first recognized as an inherited syndrome in 1959 by Turcot ef al.' We have been able to find 11 reports de- scribing this association in 18 Although an autosomal dominant pattern of inheritance has been firmly established for familial polyposis coli and Gard- ner's ~yndrome, '~- '~ the mode of genetic transmission for Turcot's syndrome remains unclear. Most authori- ties consider it to be autosomal recessive,6*' 1~12,17-19 al- though Smith and Kern contend that it is autosomal dominant.20

This report presents a patient with multiple colonic polyps who developed a malignant medulloblastoma. Upon constructing the family pedigree, it was discovered that the patient's mother and two siblings were affected by polyposis coli and a brother also had sebaceous cysts. This kindred, in addition to four ~ t h e r s , ~ , ~ . ~ . ' ' suggests that malignant CNS tumors may represent one of several phenotypes of an autosomal dominant colonic polyposis syndrome. In reviewing the other known cases of colonic polyposis with a CNS malignancy, a strong argument can be made for a variably expressive autosomal dom- inant gene being responsible for all cases of Turcot's syndrome.

From the Department of Medicine, The George Washington Uni- versity School of Medicine and Health Sciences and the Division of Medical Genetics, Children's Hospital National Medical Center, Washington, D. C.

Address for reprints: James H. Lewis, MD, Division of Gastroen- terology, 21 50 Pennsylvania Avenue, N. W., Washington, D. C. 20037.

The authors express their gratitude to Mrs. Evelyn Hughes for as- sistance in preparation of this manuscript.

Accepted for publication November 23, I98 I .

Case Report

The proband (111-3) is a 24-year-old man with polyposis coli diagnosed at age eight years. He underwent colectomy with ileorectal anastomosis at that time. The resected colon con- tained over 100 adenomatous polyps, none of which were malignant. The patient's mother (11-3) was diagnosed as having colonic polyposis at age 28 years, at which time a partial co- lectomy revealed approximately 300 adenomatous polyps. Several of these polyps were greater than 3 cm in diameter, and none were reportedly malignant. The mother's two siblings (individuals 11-4, 5) are both unaffected, as are the proband's three first cousins (111-6-8). The proband's maternal grand- mother (1-8) was thought to have died of colon carcinoma. Neither she nor any of her siblings were known to have been examined for the presence of colonic polyposis. Five of her seven siblings (1-3-7) died of carcinoma, the details of which are not known. Individual 11- 1 died of an osseous malignancy. but she was not known to have had colonic polyposis.

Of the proband's four siblings, two (1114.5) are also affected with colonic polyposis, diagnosed at ages 15 and 13 years, respectively. The proband's affected brother (111-4) has also undergone colectomy for multiple polyposis (greater than 100 polyps). Of interest is the fact that he has also been treated for sebaceous cysts occumng on the face and back. However, no osseous tumors or dental abnormalities have been diagnosed on x-ray examination of the skull and face. The proband's affected sister (111-5) is scheduled to undergo colectomy. Her colon also contains greater than 100 small adenomatous pol- yps. Two elder sisters (111-1, 2) were unaffected. The paternal family history is negative for colonic carcinoma, polyposis or other birth defects, and the parents are nonconsanginuous (Fig. 1).

HL-A typing revealed that the proband, his mother (11-3) and his affected sister (111-5) all share HL-A phenotypes A2, AW24 and B15. No other family members have been typed to date.

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No. 3

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TURCOT’S SYNDROME - Lewis et al. 525

of the proband‘s kindred. Colonic polyposis appears to be inherited in an autosomal dominant manner.

I 7-

another phenotype of familial polyposis.

III hl 2 6 v r 6 2 2 5 v r 4 & 2 4 v r byb5 2 1 vr 1 4 v r $6 2 4 vr $, 18 vr 6 8 16 vr . I

m. @ unaffected male or female BCNS tumor f proband

0. 0 not examined olher carcinoma t deceased

Following his colectomy, the proband did well until age 14 years when it was noticed that his grades began to fall in school and he became abusive and combative at home. He com- plained of headaches, blurred vision, and loss of coordination. Projectile vomiting and a marked change in personality prompted a neurologic evaluation which revealed a posterior fossa medulloblastoma, which was surgically removed. He then underwent a three-month course of postoperative cranial irradiation and has been well without symptoms for the past ten years. A recent CT scan of the brain continues to dem- onstrate no evidence of the primary tumor or recurrence.

In 1979, at age 22 years, residual rectal polyps were fulgu- rated proctoscopically. Rectal bleeding was noted in March 1981 at which time multiple, small (2-4 mm) polyps were discovered in the rectal stump. These were removed using a hot biopsy forceps (Olympus Corporation). Histologically all of the polyps were tubulovillous adenomas without evidence of malignant transformation. No polyps were seen in the ter- minal ileum. Endoscopic examination of the stomach, how- ever, revealed several small polyps present in the gastric fun- dus. They were similar in appearance to those in the rectum, and microscopically were tubular adenomas. The antrum and proximal duodenum were free of polyps and the ampulla of Vater was completely normal in appearance. Examination of the integument failed to reveal any perioral or buccal pig- mentation or sebaceous cysts. No osseous tumors were present on skull series and the dentition is normal.

Discussion

The association of multiple colonic polyps and ma- lignant tumors of the central nervous system (especially glioblastomas, medulloblastomas and astrocytomas) has been called Turcot’s syndrome. To our knowledge, fewer than 20 cases, including several nonfamilial case^,^*^.*.^

I

by history colonic polyposis I no issue ?-unconfirmed sebaceous cysts

colectomy ,, +age at colectomy

b-present age

have been reported. The colonic polyps are adenoma- tous and carry a high malignant potential. Most deaths, however, are attributable to the CNS neoplasm, usually within a few years of diagnosis. It is noteworthy that the patient reported here has survived for more than ten years following resection of his medulloblastoma.

Because of the small number of known familial cases, the genetic nature of this disorder remains controver- sial. 16-20 We propose that patients with Turcot’s syn- drome be classified into two types (Table 1). In Type I two or more siblings have multiple colonic polyps and a malignant brain tumor, however, neither the parents nor other generations are known to have colonic polyps or CNS tumors. Examples are best represented by Tur- cot’s original cases (1) and these reported by Baughman et aL6 and Itoh et al.I2 The parents ofthe sibship reported by Turcot and associates were third cousin^,'^ and the parents of the sibship reported by Itoh and coworkers were first cousins. I 2 The presence of such consanguinity and the absence of parental disease have led some au- thors to conclude that Turcot’s syndrome (Type I) is inherited in an autosomal recessive manner.6.17-19

In Type 11, affected individuals have an autosomal dominant colonic polyposis syndrome. Polyps usually occur in several generations and evidence for consan- guinity is lacking. At least four families have been de- scribed with an apparently autosomal dominant colonic polyposis syndrome in which one member has a malig- nant CNS tumor. Camiel et aL4 described two sisters with Gardner’s syndrome whose grandfather died of sig- moid carcinoma and whose father had colonic polyposis with sigmoid carcinoma and a brain tumor of unspec- ified type. Capps et al.’ mention that the brother of a

526 CANCER February 1 1983 Vol. 51

TABLE 1. Classification and Details of 18 Cases of Turcot's Syndrome

Age when Year AuthorR" Sex polyposis dx'd Relativds) affected CNS tumor Outcome

Type I: Cases where only siblings are affected 1959 Turcot et at.' M 15

F 13

1969 Baughman et a/.6 F 12 M 20 M NR F 22 F NR

1979 ltoh et a/." F 19 F 17

1 Sister

1 brother (parents 3rd cousins)

3 sibs 3 sibs 3 sibs 3 sibs 2nd cousin of above siblings

I sister 1 sister

Medulloblastoma of spinal cord, age 18

Glioblastoma, age 14

Glioblastoma, age 14 Glioblastoma, age 25 Glioblastoma, age 12 Glioblastoma, age 22 Ependymoma, age 3

Astrocytoma, age 22 Astrocytorna, age 2 1

Died age 18

Died age 14

Died age 14 Died age 26 Died age 12

NR NR

Died age 23 Died age 22

1976 Kawanani et a/.'' M 15 1 brother died of glioblastoma, Glioblastoma Died age 16 of colon Ca (also had the reticulum cell sarcoma of ileum resected age 12)

age 10 years; parents free of colonic polyposis

Type 11: Autosomal dominant colonic polyposis present in two or more generations 1968 Carnie1 et aL4 M NR 2 daughters with Gardner's Brain tumor, type Died with sigmoid

syndrome and papillary unspecified carcinoma thyroid adenocarcinoma; Grandfather died of sigmoid carcinoma

1968 Capps el a/? M NR 4 generations with colonic Brain tumor, type Died age 9 polyposis and colonic unspecified carcinoma

1970 Parks et a/.' M 14 3 generations with familial Brain tumor, type Died age 16 polyposis unspecified

1978 Binder ef al." F 15 3 generations with colonic Medulloblastoma, Died age 18 (subtotal polyps, sebaceous cysts, and age 18

colectomy) gastric polyps

Present Case

M 8 Mother and 2 sibs with Medulloblastorna, Alive age 24 colonic polyposis age 14

Indeterminant, isolated nonfamilial cases 1949 Crail' M 24 None

1964 Yaffee3 M NR Niece with Gardner's

1974 Rothman et a/.' M 28 None

syndrome

1974 Hamoudi et aL9 F 10 None

NR: not reported; CNS: central nervous system.

patient with multiple carcinomas and four generations affected by familial polyposis had a brain tumor and polyps of the colon. The patients described by Parks et a/.' had three generations of relatives affected by familial polyposis. Binder ef reported a patient with a me- dulloblastoma who had several generations of relatives affected by colonic and gastric polyps and sebaceous cysts. The kindred reported here represents a fifth family in which a malignant brain tumor occurs in conjunction

Medulloblastorna, Died age 24 (also had age 24 papillary carcinoma

of thyroid)

Died in 80's Glioblastoma, age 80

Medulloblastorna, Alive age 28

Astrocytoma, age 20

age 24

Died age 29 with multiple primary malignancies

with an apparently autosomal dominant colonic pol- yposis syndrome.

There is a third group of Turcot's syndrome patients which we were unable to classify as Type I or Type 11. Because they occur as isolated, nonfamilial cases,233~8'9 it is not possible to determine their genetic pattern of inheritance. It is possible that they are the result of spon- taneous gene mutation or an inapparent familial trait.

Because of the appearance of multiple sebaceous cysts

No. 3 TURCOT’S SYNDROME - Lewis et al. 527

in our proband’s affected brother (III4), a case can be made for our kindred, and possibly that of Binder et ul.,’ ’ being examples of Gardner’s syndrome. Gardner’s syndrome is characterized by adenomatous colonic pol- yps with soft tissue and osseous tumors inherited in an autosomal dominant manner.’431’ Since its original de- scription, several other malignant neoplasms have been described in association with Gardner’s syndrome, in- cluding papillary carcinoma of the thy r~ id ,~ .~ .~ ’ periam- pullary car~inoma,~,’. ’ 3,2 bladder carcinoma,’ osteo- genic sar~oma,’~ adrenal carcin0ma,2~ and retroperito- neal and mesenteric fibrosarcomas.” Apart from these extracolonic stigmata, the adenomatous colonic polyps of Gardner’s syndrome are histologically identical to those seen in familial polyposis coli. Although some au- th~rities’’.’~ believe that the gene responsible for Gard- ner’s syndrome is distinct from that resulting in familial polyposis coli, others do not share this view. Smith2’ believes that Gardner’s syndrome represents the com- plete expression of the many extracolonic phenotypes that may occur in familial polyposis coli. Smith and Kern2’ propose that the single, autosomal dominant, pleiotropic gene responsible for familial multiple pol- yposis may result in the primary phenotype of multiple colonic polyposis alone, or give rise to one of several secondary extracolonic phenotypes including the soft tissue and bony tumors of Gardner’s syndrome as well as extracolonic malignancies including brain tumors. Indeed, Turcot et al.’ in their classic paper, raised “the theory that hereditary transmission of familial polyposis as a dominant characteristic can be associated with other potentialities residing in the same gene.”

Further evidence that Gardner’s syndrome and fa- milial polyposis coli are the result of the same pleiotropic gene is found in reports documenting gastric, duodenal and ileal adenomas in patients with familial polyposis co1i,26-28 and a report describing occult osteomatous changes in the mandible of familial polyposis patients.29

The possibility that Turcot’s syndrome is a variant of Gardner’s syndrome has been suggested by McKusick3’ and Wennstrom et uI.l9 who cite as evidence the Gard- ner’s syndrome patient described by Yaffee3 whose uncle had Turcot’s syndrome.

Besides familial polyposis coli, there are numerous other examples of malignant and premalignant inherited disorders which may present as several different phe- notypes. These include Von Recklinghausen’s disease (neurofibromatosis), xeroderma pigmentosum, multiple nevoid basal cell carcinoma syndrome, neuroblastoma and hereditary cancer family syndrome among others, all of which are thought to result from single genes with variable expre~sivi ty .~’ .~~ Thus, diverse phenotypic expression of inherited syndromes is common, and it should not be surprising that the allegedly distinct ge-

notypes of Gardner’s syndrome, Turcot’s syndrome and perhaps other premalignant adenomatous polyposis syn- dromes may actually represent different phenotypes of familial polyposis.

As concerns the pattern of inheritance of Turcot’s syndrome, we believe it is unlikely that a recessive gene is involved in the Type I sibships reported by Turcot et ul.,’ Baughman et u1.,6 and Itoh et ul.” Statistically, only 25% of siblings should be affected by a recessive trait. However, in these Type I families, all siblings are af- fected by the same syndrome, including all four children reported by Baughman et aL6 The fact that the parents of these sibships were not known to be involved is not unusual. A negative family history is recorded in up to one third of patients with familial polyposis coli. l 3 Spon- taneous gene mutation as mentioned by DeCosse et ~ 1 . ’ ~ and incomplete gene penetrance as discussed by Pierce34 are two possible explanations why the parents of some Turcot’s syndrome patients are not affected themselves.

In this report, evidence has been presented that sug- gests CNS tumors (medulloblastomas, glioblastomas, and astrocytomas) represent one of several autosomal dominant extracolonic phenotypes of familial multiple polyposis or Gardner’s syndrome. An autosomal dom- inant inheritance pattern is apparent in at least four other kindreds we have classified as Turcot’s syndrome Type 11. In addition, it is difficult for us to believe that the sibships designated as Turcot’s syndrome Type I are affected by an autosomal recessive gene. The fact that all siblings are involved implies a dominant trait. Sim- ilarly, we believe that the nonfamilial cases with an in- determinant inheritance pattern may also be the prod- ucts of an autosomal dominant gene with either reduced penetrance of spontaneous mutation. We conclude that Turcot’s syndrome is best considered an additional phe- notype of familial polyposis and is most likely inherited to an autosomal dominant manner.

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