Atypical juvenile polyposis

Two cases of atypical juvenile polyposis are described in males of 9 months and 25 years-of-age. The first was associated with congenital megacolon and presented as juvenile polyps with features suggesting mild dysplasia. In the second case six histological lesions are found: 1 hyperplastic polyps; 2 juvenile polyps; 3 hyperplastic polyps with adenomatous areas; 4 juvenile polyps with areas of dysplastic epithelium; 5 adenomas; and 6 adenocarcinomas. On the basis of the morphological features we propose a pathogenetic sequence of focal mucosal hyperplasia to adenoma and carcinoma through stages of non-neoplastic and non premalignant polyps. Finally, the possibility that hyperplastic epithelium can in some circumstances have a greater dysplastic potential than normal colorectal mucosa is raised.     

Undifferentiated columnar cells in colorectal adenomas and familial adenomatous polyposis

We have observed and defined morphometrically and histochemically groups of undifferentiated columnar cells within the surface epithelium in colorectal mucosa. They were present within both non-polypoid and polypoid mucosa in familial adenomatous polyposis, and within non-hereditary adenomatous polyps of the colon and rectum. The cells show some evidence of proliferative activity and appear similar to cells previously described in the stomach which were proposed as precursors to type 3 sulphomucin-secreting intestinal metaplasia in atrophic gastritis. To our knowledge, these observations have not been previously described. It is possible that the cells represent the cellular basis of the shift in the proliferative zone from the normal site at the crypt base to the colorectal mucosal surface, which is known to precede adenomatous polyp formation. The cells may therefore be involved in the early stages of colorectal adenoma formation.     

家族性腺瘤性息肉病与高脂血症的关系

家族性腺瘤性息肉病（familial adenomatous polyposis,FAP）是由APC（adenomatous polyposis coli）基因突变引起的常染色体显性遗传病。高脂血症作为FAP的肠外伴随症状逐渐被关注,同时在FAP的经典模型Apc基因突变的Min小鼠上也出现了高血脂症状。本文从高脂血症、FAP以及APC基因突变的角度,阐述三者的相互联系,期望对病人的预防与治疗提供有价值的参考。     

中国人家族性腺瘤性患肉病患者结肠腺瘤性患肉病基因的胚系突变

目的 探讨中国人家族性腺瘤性息肉病(familial adenomatous polyposis,FAr)患者的结肠腺瘤性息肉病(adenomatous polyposis coli,APC)基因的胚系突变类型.方法 对9个FAP家系18名成员进行多重连接依赖性探针扩增(multiplex ligation-dependent probe amplification,MLPA)检测APC基因有无大片段缺失.再应用PCR扩增APC基因的15个外显子区域,经变性高效液相色谱(denaturing high performance liquid chromatography,DHPLC)对每个扩增片段进行筛查,流出峰异常的片段,经DNA测序验证小片段的改变.结果 9个家系中有3个家系发现有APC基因的胚系突变:家系2为c.3184-3187 del CAhA,家系4为c.5432C＞T,家系9为c.3925-3929 del AAAAG.3种突变中c.5432C＞T在数据库中未见报道.结论 中国人不同的APC基因的胚系突变可引起FAP;无APC胚系突变的FAP患者的发病可能存在其他的机制.     

Non-allelic heterogeneity of familial adenomatous polyposis

Linkage studies on familial adenomatous polyposis (FAP) reported so far suggest that FAP is a genetically homogeneous disease. Recently, we found that the putative gene for Turcot syndrome, an apparently autosomal recessive clinical variant of FAP, is not allelic to FAP. Here we describe another family, segregating for an autosomal dominant disease clinically indistinguishable from FAP but genetically not linked to the APC locus, adding further evidence for the occurrence of non-allelic heterogeneity of FA. These observations have implications to the linkage-based genetic counselling of persons at risk for FAP especially when they are drawn from small families giving insufficient information. © 1993 Wiley-Liss, Inc.     

Thyroid carcinoma associated with familial adenomatous polyposis

 

Aims:

Thyroid carcinoma is an extracolonic manifestation that is present in about 1% to 2% of patients with familial adenomatous polyposis (FAP). Less than 100 cases have been reported in detail. We have investigated the suggestion that FAP associated thyroid carcinoma is significantly different morphologically from both papillary and follicular types and can be considered as a separate entity.  

Methods and results:

Specimens from three patients with FAP associated thyroid tumours, all but one having single nodules, have been analysed. All three patients belonged to an extended kindred (23 siblings in four generations) who had genetic analysis and intensive screening for thyroid nodules. Seven patients had the same APC mutation at codon 1061. Pathological examination revealed a typical papillary carcinoma, encapsulated variant, in all patients, with follicular areas in one case. All thyroid specimens, in addition to histological and immunohistological examinations, were also specifically studied for activation of the RET-PTC oncogene, that seems to be restricted to papillary thyroid carcinoma. Two of the three patients had RET-PTC activation (PTC₁ isoform).  

Conclusions:

The findings suggest that the tumours were certainly papillary, at least in the present kindred. Further studies in different families are required for a better understanding of this peculiar tumour and of its biological behaviour.     

Genomic and functional analyses of MUTYH in Japanese patients with adenomatous polyposis

The present study was undertaken to elucidate germ line mutations of the base excision repair gene, MUTYH , in Japanese patients with adenomatous polyposis. We screened germ line mutations of adenomatous polyposis coli ( APC ) gene and MUTYH in 66 Japanese patients with adenomatous polyposis. APC was screened by the protein truncation test, while MUTYH was screened by polymerase chain reaction-based single-strand conformation polymorphism and direct sequencing. The nicking assay was applied in order to evaluate the DNA glycosylase activity of the identified MUTYH variant. In this study, Seven MUTYH variants were identified in 16 of 21 APC-negative patients. Q324H mutation was the most frequent mutation, with an allele frequency of 49%. Two patients carried biallelic mutations other than Q324H; a patient had biallelic G272E and A359V mutations, while the other had compound heterozygotes of P18L and G25D mutations. Nicking assay for G272E using the corresponding mouse MUTYH mutant with G257E revealed that G272E is a variant to cause an impaired DNA glycosylase activity. Homozygous MUTYH mutation accounts for approximately 10% of Japanese patients with adenomatous polyposis. G272E may be one of the mutations specific to patients with adenomatous polyposis in East Asia.     

Metaplastic polyps and polyposis of the colorectum

Five hundred and fifty-four colorectal metaplastic polyps have been studied histologically. Whilst most lesions were small and sessile, 16.1% measured greater than 0.5 cm in diameter and 0.9% were greater than 1 cm. The larger polyps were frequently pedunculated and occasionally showed a tubulo-villous or villous pattern. A structural similarity between the larger metaplastic polyps and colorectal adenomas is illustrated and the importance of the distinction of metaplastic from dysplastic epithelium in the differentiation of these lesions is stressed. Other unusual features of metaplastic polyps are described. Evidence is given to suggest that males have a greater propensity to develop metaplastic polyps than females. A search for metaplastic-like areas in other colorectal polyps revealed that they are rare (0.6%) in adenomas, but relatively frequent (20.8%) in juvenile polyps. Finally, seven patients with multiple metaplastic polyps of the colorectum are described, in whom a diagnosis of adenomatous polyposis had been made at some stage in their management. Six of the seven patients were males and the mean age at presentation was 37.4 years. Larger metaplastic polyps were frequent in these cases. The necessity for histological confirmation in all cases of intestinal polyposis is stressed, and the possibility that 'metaplastic polyposis' is a pathological entity is discussed.     

Molecular and clinical characteristics in 32 families affected with familial adenomatous polyposis

Germ‐line mutations in the 5′ half of the Adenomatous Polyposis Coli (APC) gene are found in about 80% of the patients affected with familial adenomatous polyposis (FAP). The vast majority of these are nonsense or frameshift mutations which result in the loss of the carboxyl terminus of the APC protein. Using an in vivo assay in yeast, we have identified pathogenic germ‐line mutations in 26 of 32 (81%) unrelated Swiss families affected with FAP. Nine mutations were novel and eight families were shown to harbor two recurrent mutations. Correlations were attempted between the location of APC germ‐line mutations and clinical manifestations of the disease. © 2001 Wiley‐Liss, Inc.     

Strategies and outcomes of PGD of familial adenomatous polyposis

Owing to adult onset of hereditary cancer, prenatal diagnosis (PND) raises numerous ethical issues on the acceptability to terminate an affected pregnancy (TOP). PND for these disorders is often considered as unacceptable by couples as well as geneticists and legal or ethical authorities, but preimplantation genetic diagnosis (PGD), even if subject to controversy, seems to be a more acceptable option. Therefore, many couples, who do not want to transmit their cancer to their children, consider PGD as their only reproductive option. This article describes our experience of PGD for familial adenomatous polyposis (FAP). Twelve couples were referred between 2000 and 2005. We developed PGD tests to detect the mutation alone, but we rapidly set up multiplex PCR combining mutation detection and indirect diagnosis. Finally, we set up duplex and triplex indirect diagnoses to be able to offer a PGD, whatever mutation was involved in familial cases. PGD strategies were based on (i) a new double allele-specific PCR approach (D-ARMS) allowing the detection of the wild-type and mutated allele; (ii) PCR fragments sizing and (iii) restriction length polymorphisms. For the 12 referrals, we developed eight tests, and 11 cycles have been performed for four couples, resulting in eight embryo transfers and five pregnancies, with the birth of one healthy boy and two ongoing pregnancies. We are now able to propose PGD to most couples at risk of transmitting FAP to their offspring, whether the mutation is familial or occurred de novo.     

Pulmonary sclerosing hemangioma associated with familial adenomatous polyposis

A 45-year-old woman presented with asymptomatic solid tumor in the lower right lobe of the lung. Histologically, the tumor comprised a monolayer of surface cells and round stromal cells displaying sclerotic areas. Immunohistochemical studies suggested a diagnosis of sclerosing hemangioma. Interestingly, morular lesions were also observed. Analyses of the gastrointestinal (GI) tract showed mild familial adenomatous polyposis (FAP) and numerous fundal gland polyps, indicating attenuated FAP (AFAP). All components of the sclerosing hemangioma displayed aberrant nuclear and cytoplasmic expression of beta-catenin. However, such findings were much weaker in adenomas of the GI tract and were barely observed in fundal gland polyps. These results strongly suggest an association between sclerosing hemangioma and the AFAP. To the best of our knowledge, this is only the second report of lung tumor associated with FAP and is the first describing an association with sclerosing hemangioma. A new category of FAP-associated lung tumors may be indicated.     

应用变性高效液相色谱检测31例家族性腺瘤性息肉病家系结肠腺瘤性息肉病基因突变

目的 应用变性高效液相色谱(denaturing high performance liquid chromatography,DHPLC)技术检测我国家族性腺瘤性息肉病(familial adenomatons polyposis,FAP)家系的结肠腺瘤性息肉病(adenoinatous pelyposis coli,APC)基因变异特征,研究其病因机制.方法 采集31个家系的先证者、患者和家系成员的外周血淋巴细胞,抽提DNA并以降落式PCR扩增APC基因各外显子和启动子.基因突变检测先由DHPLC进行筛选,发现异常峰者进行测序鉴定并TA克隆鉴定,结果与网络数据进行比对.结果 31个家系中共有15个家系检出了12种不同的突变类型,FAP家系APC基因的突变检出率为48.39%.发现了4种新的突变及3例不同的内含子突变.4个新的突变分别位于255、677、1192、1403密码子,均为移码突变.证明了DHPLC能检出APC基因的突变.在APC基因的突变中,移码突变占86.67%,无义突变占13.33%,说明移码突变是中国人APC基因突变的主要方式.在突变位点上,第15外显子突变最常见,约占86.67%.结论 FAP家系APC基因的突变检出率为48.39%,发现了4种新的导致蛋白编码改变的突变.证实中国人FAP家系中APC基因突变位点以第15外显子最常见,类型以移码突变为主.     

Risk of hepatoblastoma in familial adenomatous polyposis

Infantile and childhood hepatoblastoma occurs more frequently in persons heterozygous for the familial adenomatous polyposis (FAP) gene than in the general population. This observation is based on numerous case reports plus the results of an international survey of FAP registries. However, the frequency of this rare tumor in FAP patients is unknown. In a retrospective review of our family history data, 2/470 (0.42%) children born to 241 patients with FAP had hepatoblastoma. This figure is significantly higher than the 1/100,000 incidence of hepatoblastoma in the general population. However, for genetic counseling purposes, an empiric risk of <1% for hepatoblastoma can be cited to persons with FAP for their children. © 1992 Wiley-Liss, Inc.     

Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis

A small fraction of families with familial adenomatous polyposis (FAP) display an attenuated form of FAP (AFAP). We aimed to assess the presence of germline mutations in the MUTYH and adenomatous polyposis coli (APC) genes in AFAP families and to compare the clinical features between the two causative genes. Families with clinical AFAP were selected from the Dutch Polyposis Registry according to the following criteria: (a) at least two patients with 10-99 adenomas diagnosed at age >30 years or (b) one patient with 10-99 adenomas at age >30 years and a first-degree relative with colorectal cancer (CRC) with a few adenomas, and, applying for both criteria, no family members with more than 100 polyps before the age of 30 years. All probands were screened for germline mutations in the APC and MUTYH genes. Twenty-five of 315 Dutch families with FAP (8%) met our criteria for AFAP. These families included 146 patients with adenomas and/or CRC. Germline APC mutations were identified in nine families and biallelic MUTYH mutations in another nine families. CRC was identified at a mean age of 54 years (range 24-83 years) in families with APC and at 50 years (range 39-70 years) in families with MUTYH (p = 0.29). APC and biallelic MUTYH mutations are responsible for the majority of AFAP families. Based on our results and those reported in the literature, we recommend colonoscopy once every 2 years in AFAP families, starting surveillance from the late teens in APC mutation carriers and from age 20-25 years in biallelic MUTYH mutation carriers.     

Syndromic gastric polyposis and hereditary gastric cancers

Although the majority of gastric carcinomas are sporadic neoplasms, approximately 10% show familial aggregation, and a hereditary cause is determined in 1–3% cases. Of these, hereditary diffuse gastric cancer (HDGC) is the most recognized predisposition syndrome. Although rare, some of the less commonly reported syndromes (including polyposis syndrome), also confer a markedly increased risk for development of gastric cancer. Identification and characterization of these syndromes requires a multidisciplinary effort involving oncologists, surgeons, genetic counselors, and pathologists.     

Familial adenomatous polyposis and the small bowel: a loco-regional review and current management strategies

Small-bowel tumours are an important cause of morbidity and death in patients with familial adenomatous polyposis. Intensive endoscopic surveillance is now standard in the long-term management of this condition. Thus, lesions occurring throughout the small bowel are increasingly noted by oesophagogastroduodenoscopy and flexible pouchoscopy. Some occur commonly de novo (in stomach, duodenum and ampulla), while others may occur following surgery (polyps of the ileostomy, ileoanal pouch, or small bowel above an anastomosis). These differ widely in incidence, natural history and management. This review provides a regional overview of these lesions, in terms of current research findings and management protocols.     

Del(10)(q22.3q24.1) associated with juvenile polyposis

Juvenile polyps are the most frequent gastrointestinal polyps with a malignant potential for which the genetic basis is unknown. Juvenile polyps, with a normal epithelium but hypertrophic lamina propria, are histologically quite distinct from adenomatous polyps which have dysplastic changes in epithelial nuclei. Furthermore, the adenomatous polyposis coli (APC) gene on Chr 5, mutated somatically in adenomatous polyps and mutated in the germline of patients with familial adenomatous polyposis, is not linked to hereditary juvenile polyposis. We provide the first report indicating that a tumor suppressor gene associated with juvenile polyposis may be located at 10q22.3q24.1. Cytogenetic studies of a patient with juvenile polyposis and multiple congenital abnormalities of the head, extremities, and abdomen revealed a de novo interstitial deletion of Chr 10 as the only defect, del(10)(10q22.3q24.1). Am. J. Med. Genet. 70:361–364, 1997. © 1997 Wiley-Liss, Inc.     

Hypertrophic and polypoid gastropathy associated with juvenile adenomatous polyposis coli

Juvenile Polyposis is a syndrome with gastrointestinal polyps and increased cancer risk. The commonest form of this syndrome is inherited as autosomal dominant trait and presents as Familial Juvenile Polyposis Coli. Another variant involves mainly the stomach and another is generalized throughout the gastrointestinal tract. We present the case of two brothers with polyposis coli complicated by colonic cancer. The polyps were of juvenile, adenomatous and mixed types. The two patients after a decade of colonic endoscopic polypectomies presented gastric involvement by polyps and needed multiple endoscopic gastric resections. One brother underwent total gastrectomy. This stomach showed diffuse polyposis of hyperplastic and fundic gland types within an unexpected background of foveolar and glandular hypertrophic gastropathy. The patients at present are followed up with endoscopic procedures.     

遗传性非腺瘤病性结直肠癌结肠腺瘤病基因突变研究

目的 分析遗传性非腺瘤病性结直肠癌(hereditary non-polyposis colorectal cancers，HNPCC)结肠腺瘤病(adenomatous polyposis coli，APC)基因突变的特点及错配修复缺陷对其影响。方法 采用体外蛋白合成试验和序列分析确定19例HNPCC病例APC体细胞突变。结果 19例病例中有11例(13个突变点)发生APC突变，发生率为58％(11／19)，其中移码突变9个，无义突变4个，移码突变占多数(69％)。所有移码突变表现为1—2个碱基的缺失或插入，大多(7／9)发生在简单核苷酸重复序列，特别是单腺苷酸重复序列(A)n(5／9)。检出的由单个碱基替换而导致的无义突变都发生在CpG岛，表现为C向T的转换。结论 多于半数的HNPCC发生APC突变，其突变多发生在编码区单核苷酸重复序列(移码突变)或CpG岛(点突变)上，提示APC基因失活在HNPCC为常见的分子事件；错配修复缺陷所致的微卫星DNA不稳定性等内源性机理可能对APC突变产生影响。