Familial adenomatous polyposis in two brothers with hepatoblastoma: implications for diagnosis and screening

Two brothers with hepatoblastoma were noted to have a family history of early onset colon cancer. Genetic testing of the younger brother revealed a deletion in exon 15 of the adenomatous polyposis coli (APC) gene (2710-2711delAG), consistent with a diagnosis of familial adenomatous polyposis (FAP). We review the clinical and molecular aspects of the relationship between hepatoblastoma and FAP, and the implications for diagnostic testing and cancer screening in affected patients.     

Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations?

BACKGROUND: Hepatoblastoma (HB) is the most frequent liver tumor in childhood, occurring in the first few years of life. Surgery combined with chemotherapy has resulted in dramatic improvements in prognosis. However, even today, about one quarter of affected children do not survive the disease. Compared to the general population, the risk of HB is 750-7,500 times higher in children predisposed to familial adenomatous polyposis (FAP), an autosomal-dominant cancer predispostion syndrome caused by germline mutations in the tumor suppressor gene APC. Only limited data exist about the frequency of APC germline mutations in cases of apparently sporadic HB without a family history of FAP. PROCEDURE: In our sample of 1,166 German FAP families, all known cases of HB were registered. In addition, 50 patients with apparently sporadic HB were examined for APC germline mutations. RESULTS: In the FAP families, seven unrelated cases of HB are documented; three had been detected at an advanced stage. In patients with apparently sporadic HB, germline mutations in the APC gene were identified in 10%. CONCLUSIONS: These data raise the issue of the appropriate screening for HB in children of FAP patients. To date, the efficiency of surveillance for HB is unclear. In Beckwith-Wiedemann syndrome (BWS), recent studies suggest an earlier detection of both Wilms tumor and HB by frequent screening. We discuss the rationale and implications of a screening program; besides the examination procedure itself, screening for HB in children of FAP patients would have important consequences for the policy of predictive testing in FAP. In a substantial fraction of sporadic HB, the disease is obviously the first manifestation of a de novo FAP. These patients should be identified by routine APC mutation screening and undergo colorectal surveillance thereafter.     

Hepatoblastoma in familial adenomatous polyposis

A case of hepatoblastoma in a patient who had a family history of familial adenomatous polyposis (FAP) and then went on to develop FAP is presented. The seven similar cases available in the literature are reviewed and discussed. Our patient is the first who did not exhibit lesions of congenital hypertrophy of the retinal pigment epithelium.     

Genetic predisposition to colorectal cancer: new pieces in the pediatric puzzle

Colorectal cancer is rare in childhood. The 2 best characterized familial syndromes, hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) and familial adenomatous polyposis (FAP), are autosomal dominant inherited disorders. HNPCC is relevant to pediatric gastroenterology practice because children and adolescents with underlying colorectal cancer can have germ-line mutations of mismatch repair genes. Recent attention has focused on characterizing genetic predisposition to attenuated FAP in individuals who do not have germ-line mutations in the APC gene. The identification of a second mechanistic explanation called MYH-associated polyposis (MAP), which is an autosomal-recessive condition, has important implications for both screening and management strategies. Hereditary colorectal cancer including HNPCC, FAP, attenuated FAP and MYH-associated polyposis in children are the subject of this review.     

Colorectal cancer in two pre-teenage siblings with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder that characteristically presents with colon cancer in early adult life. We describe a Pakistani FAP family in which two sons had an unusually early manifestation of colorectal cancer. The index patient presented at 11 years of age with abdominal pain, rectal bleeding and iron deficiency anaemia. Colonoscopy showed that the colon was carpeted with a myriad of polyps. Oesophago-gastric and duodenal endoscopy revealed that polyps had also developed in the duodenum. Multiple biopsies indicated neoplastic lesions. The patient underwent a proctocolectomy and endoscopic duodenal mucosectomy. The diagnosis of an adenocarcinoma of the colon and further adenomatous polyps with low-grade and high-grade dysplasia was confirmed by histology. Family screening including a blood test for anaemia and bowel examination revealed that his 12-year-old brother was also affected. Conclusion:Children with familial adenomatous polyposis are at risk for colon cancer and emphasise the need for early tumour recognition. Gastrointestinal symptoms in children should be thoroughly evaluated and standard screening for colonic polyposis should be performed in all individuals with a positive family history and/or known mutations in cancer-associated genes, particularly in children who are under 10 years of age.     

Chromosome Rearrangement with No Apparent Gene Mutation in Familial Adenomatous Polyposis and Hepatocellular Neoplasia

We have identified a constitutional inversion in chromosome 5 associated with familial adenomatous polyposis in three generations of a Mexican family. Two of three siblings developed hepatic neoplasia in infancy. The gene truncation assay failed to demonstrate a truncated protein in the segment harboring the adenomatous polyposis coli (APC) genes. Polymerase chain reaction (PCR) amplification of APC gene coding exons and sequencing of PCR products did not reveal any significant mutation. The data suggest that in this family, the phenotype may be the result of a “position effect.” Received May 21, 2001; accepted July 23, 2001.     

Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: Clinical characteristics and rationale for surveillance screening

Familial adenomatous polyposis (FAP) due to APC mutation is associated with an increased risk of hepatoblastoma. All cases of hepatoblastoma in patients with FAP reported in the literature were reviewed. One hundred and nine patients were identified. Thirty‐five patients (of 49 with data) were diagnosed with hepatoblastoma prior to a later diagnosis of FAP (often in association with advanced colorectal carcinoma), emphasizing a need to identify patients earlier with germline APC mutations for early colorectal carcinoma screening. Hepatoblastoma may present at birth, and screening for hepatoblastoma in infancy in families with FAP prior to APC mutation testing results may be warranted.     

Nuclear accumulation of beta-catenin occurs commonly in the epithelial cells of juvenile polyps

In the two conditions juvenile polyps (JPs) and juvenile polyposis coli (JPC), colonic polyps may have overlapping histologic and phenotypic appearance, but JPC confers a significant risk for colon adenocarcinoma. Although not thought to contain adenomatous polyposis coli (APC) mutations, the status of beta-catenin and full-length APC protein expression in JPs is not known. We evaluated beta-catenin and full-length APC protein expression in JPs from children with JPs and JPC. Cases were identified through endoscopic procedure records. Immunohistochemistry was performed for beta-catenin and full-length APC protein. Loss of heterozygosity at the APC gene locus on chromosome 5 was assessed using two APC-linked microsatellite markers. Polyp and normal colonic tissue were analyzed from 36 children with JPs and 9 with JPC. Both APC and beta-catenin immunoreactivity were present in epithelial cells from all samples but in different patterns. In all normal colon and polyp samples, APC expression was cytoplasmic with maximal immunoreactivity in the goblet cells. In contrast, beta-catenin immunoreactivity in epithelial cells was limited to the plasma membrane in normal colon but was both cytoplasmic and nuclear in all 45 JPs. No evidence of APC gene loss of heterozygosity was found. In polyps from children with JPs and JPC, nuclear beta-catenin accumulation is a consistent feature, and it is not due to APC gene mutation or loss of full-length APC protein expression. Thus, beta-catenin accumulation may be intrinsic to the formation of juvenile-type polyps through an as-yet-undefined mechanism.     

Intracranial desmoid tumor with familial adenomatous polyposis coli

Intracranial desmoid tumors are extremely rare. The association of desmoid tumors with familial adenomatous polyposis coli was reported previously, with the tumors involving trunk and extremities. We report a 3.5-year-old girl with intracranial desmoid tumor with familial adenomatous polyposis coli. This condition in a child is rarely reported. Follow-up of the patient after cranial surgery and of the family for this premalignant inherited condition is necessary.     

Control of beta-catenin/Tcf-directed transcription in medulloblastoma

The beta-catenin, glycogen synthase kinase 3beta (GSK-3beta), and adenomatous polyposis coli (APC) gene products interact to form a network that influences the rate of cell proliferation. Medulloblastoma occurs as part of Turcot's syndrome and patients with Turcot's syndrome, who develop medulloblastomas, have been shown to harbor germline APC mutations. While APC mutations have been investigated and not identified in sporadic medulloblastomas, the status of the beta-catenin and GSK-3beta genes has not been evaluated in this tumor. This study shows that 3 of 67 medulloblastomas harbor beta-catenin mutations, each of which converts a GSK-3beta phosphorylation site from serine to cysteine. The beta-catenin mutation seen in the tumors was not present in matched constitutional DNA in the 2 cases where matched normal DNA was available. A loss of heterozygosity (LOH) analysis of 32 medulloblastomas with paired normal DNA samples was performed with 4 microsatellite markers flanking the GSK-3beta locus; LOH with at least one marker was identified in 7 tumors. Sequencing of the remaining GSK-3beta allele in these cases failed to identify any mutations. Taken together, these data suggest that activating mutations in the beta-catenin gene may be involved in the development of a subset of medulloblastomas. The GSK-3beta gene does not appear to be a target for inactivation in this tumor.     

An unusually severe phenotype for familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a dominantly inherited predisposition to the development of many hundreds to thousands of adenomatous polyps of the colon. The mean age of onset is around 15 years, symptoms may arise in the third decade, and the median age for the development of colonic cancer is 35-40 years. Prophylactic colectomy reduces the risk of death from colorectal cancer to such an extent that late sequelae such as upper gastrointestinal tumours have become the main cause of mortality in appropriately managed patients. The age at which colonic surveillance begins reflects the natural history of the disease. Onset of polyp formation and cancer in childhood is very unusual, but has recently been associated with a specific mutation at codon 1309 in exon 15 where a more severe phenotype is sometimes observed. The case histories of two families are reported in which there is childhood onset of polyps in the youngest generation and in one case a carcinoma, in whom mutations have been identified in exon 11 of the APC gene. Several other affected relatives were diagnosed at ages ranging from 5-48 years, some already with a cancer at the time of first screening. Since the aim of screening for colonic polyps is prevention of colonic cancer, family members at risk should be offered genetic assessment and direct mutation testing where this is possible, usually in the early teens. In the absence of a genetic test (the situation in about one third of families) or in a known gene carrier, annual colonoscopy examination is advised from the same age. Clinicians should take note of the family history and be prepared to consider much earlier intervention if symptoms occur in a child with a family history of FAP. Where childhood onset of polyps has occurred, other children at risk in the family must be offered earlier genetic testing and endoscopic surveillance.

     

Control of β-catenin/Tcf-directed transcription in medulloblastoma

The β-catenin, glycogen synthase kinase 3β (GSK-3β), and adenomatous polyposis coli (APC) gene products interact to form a network that influences the rate of cell proliferation. Medulloblastoma occurs as part of Turcot's syndrome and patients with Turcot's syndrome, who develop medulloblastomas, have been shown to harbor germline APC mutations. While APC mutations have been investigated and not identified in sporadic medulloblastomas, the status of the β-catenin and GSK-3β genes has not been evaluated in this tumor. This study shows that 3 of 67 medulloblastomas harbor β-catenin mutations, each of which converts a GSK-3β phosphorylation site from serine to cysteine. The β-catenin mutation seen in the tumors was not present in matched constitutional DNA in the 2 cases where matched normal DNA was available. A loss of heterozygosity (LOH) analysis of 32 medulloblastomas with paired normal DNA samples was performed with 4 microsatellite markers flanking the GSK-3β locus; LOH with at least one marker was identified in 7 tumors. Sequencing of the remaining GSK-3β allele in these cases failed to identify any mutations. Taken together, these data suggest that activating mutations in the β-catenin gene may be involved in the development of a subset of medulloblastomas. The GSK-3β gene does not appear to be a target for inactivation in this tumor.     

Rhabdomyosarcoma associated with familial adenomatous polyposis

We report a case of a 16 year old girl with orbital rhabdomyosarcoma who during chemotherapy developed bloody diarrhoea. On investigation she was found to have multiple colonic polyps. Cytogenetic analysis has shown a pattern typical of familial adenomatous polyposis. We present a review of the literature concerning the associations of familial adenomatous polyposis. The association of familial adenomatous polyposis with rhabdomyosarcoma has not been previously reported.     

DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome

Embryonal rhabdomyosarcoma (ERMS) is the most common childhood sarcoma and is a component of the familial pleuropulmonary blastoma (PPB)-predisposition syndrome. Using the PPB model, we hypothesized that DICER1 mutations would be found in familial and sporadic forms of ERMS. Blood samples from four children with familial PPB and ERMS, and 52 sporadic ERMS tumors were tested for DICER1 mutations. Germline DICER1 mutations were found in all four patients with familial PPB and 2 of 52 (3.8%) sporadic ERMS had somatic mutations. Our findings confirm the pathogenetic relationship between ERMS and PPB suggesting that ERMS may result from abnormal miRNA regulation.     

Familial Adenomatous Polyposis Coli and Clear Cell Sarcoma of the Kidney

Familial adenomatous polyposis coli is an inherited multiple neoplasia syndrome that is associated with an increased risk for development of another primary tumor. We report a case of a 14-year-old boy who had a proctocolectomy for familial adenomatous polyposis coli. He had survived radical nephrectomy, chemotherapy, and radiotherapy for a congenital clear cell sarcoma of the right kidney. Perhaps the presence of the familial adenomatous polyposis gene induces chromosomal instability in affected persons.     

Juvenile polyposis in a tropical country

The clinical profile, malignant potential, and management of 17 children with juvenile polyposis (more than five juvenile polyps) were evaluated clinically and endoscopically. Colonoscopy and polypectomy were done three weekly until colonic clearance was achieved, and thereafter two yearly. All polyps were subjected to histological examination. Mean age was 7.7 years, with a male preponderance (3:1). Presentation was with rectal bleeding (94%), pallor (65%), stunted growth (53%), and oedema (47%), and the mean (SD) duration of symptoms was 33 (27) months. None had a positive family history or any congenital anomaly. Two children had six polyps up to the transverse colon; the rest had numerous polyps all over the colon. All children had juvenile polyps on histology and 10 (59%) had adenomatous changes (dysplasia). Total colectomy was done in six for intractable symptoms. Colon clearance was achieved in eight after an average 3.4 polypectomy sessions, and three were still on the polypectomy programme. In conclusion, juvenile polyposis is commonly associated with low grade dysplasia. Serial colonoscopic polypectomy is effective but colectomy is required for intractable symptoms and when clearance of the colon is not possible.     

Colorectal neoplasia in juvenile polyposis or juvenile polyps.

Juvenile (retention) polyps are usually solitary lesions in the colorectum but may be multiple in juvenile polyposis. The association between juvenile polyps and colorectal neoplasia is controversial. We present three patients with juvenile polyposis who had colorectal adenomas or adenomatous epithelium in juvenile polyps at ages 3, 4, and 7 years. In a retrospective study of 57 additional patients with one or more juvenile polyps, 10 patients (18%) had colorectal neoplasia including three with adenocarcinoma, two with tubular adenoma, and six with adenomatous epithelium in a juvenile polyp (one had both adenomatous epithelium and an adenocarcinoma). Nine of these 10 patients had juvenile polyposis defined by the presence of at least three juvenile polyps; and eight of the nine had a family history of juvenile polyps. Colorectal neoplasia occurred at young age (mean (SEM) 37 (5) years). Our findings suggest that patients with juvenile polyps who have three or more juvenile polyps or a family history of juvenile polyps should undergo surveillance for colorectal neoplasia.     

Early detection of adenomatous polyposis coli in Gardner's syndrome.

Gardner's syndrome, an autosomal dominant disorder, consists of multiple polyposis of the colon associated with various soft- and hard-tissue tumors. The appearance of adenomatous hyperplasia and polyposis in at-risk patients before adolescence has not been full appreciated. Four preadolescent children from a kindred with Gardner's syndrome were examined by use of colonoscopy and mucosal biopsy. In three children (18 months, 6 years, and 9 years old) adenomatous hyperplasia or polyposis was found. The colon of the fourth child (3 years old) was normal. The three affected children were asymptomatic. The youngest had a barium enema and results were normal. The oldest child had polyps. Biopsies revealed focal atypical hyperplasia of the glands with pseudostratification of the epithelial cells, frequent mitotic figures, and the absence of goblet cells. More severe manifestations were noted in the splenic flexure than in the sigmoid flexure or rectum. The youngest patient showed early adenomatous hyperplasia characterized by a marked reduction of the goblet cells, especially in the surface epithelium. Colonoscopy and mucosal biopsies are mandatory in at-risk children. By deferring colonic examination until adolescence, a patient is placed at risk for malignant degeneration of the adenomatous tumor.     

Polypoid disease of colon in children

Polyps in gastrointestinal tract are mostly benign and result from hamartomas or lymphoid hyperplasia of submucosa. They usually occur as isolated lesions in children and are referred to as juvenile polyps. Multiple polyps with inherited origin are called polyposis and can be seen as a part of the syndrome. The polyps with adenomatous histopathology have malignant potential and necessitate genetic testing and colonoscopy to define the risk of cancer. Although simple endoscopic removal is adequate in the treatment of juvenile polyps, children with familial adenomatous polyposis (FAP) need total colectomy with ileorectal anastomosis (IRA) or ileal pouch-anal anastomosis (IPAA). The timing of prophylactic colectomy and the type of surgical treatment are controversial in children. The clinical features, the assessment of cancer risk, and the alternatives of the surgical treatment of polyps are reviewed in this paper.     

Familial juvenile polyposis coli with congenital heart disease

Seven cases of familial juvenile polyposis coli (FSPC) and one case of familial adenomatous polyposis coli (FAPC) were described in two generations of a family. Of five siblings, one had FJPC with mitral insufficiency, one had Fallot's tetralogy, and the other three, also with FJPC, had had pulmonic stenosis and died. Congenital heart disease was observed in neither the father nor the aunt. The grandfather also had FAPC, without congenital heart disease. To the best of our knowledge, this association has not previously been reported in the literature. For this paper members of the family were studied and the literature was reviewed.Presented at the 6th International Congress of Pediatric Surgery, Istanbul, 29th August – 1st September, 1989 Offprint requests to: M. Pul