家族性甲状腺乳头状癌

目的：探索家族性甲状腺乳头状癌的临床特征,诊断标准和处理原则。方法：在随机的145例甲状腺乳头状癌患进行前瞻性的调查共发现家族性甲状腺乳头状癌有7个家族17例患者,其中14例患者为本院手术,3例外院手术,17例患者病例均经本院病理科证实,占同期的甲状腺乳头状癌的9．65％（14／145）,结果：本组年龄30－74岁,平均年龄45岁,原发灶大小0．8－2．8cm,平均1．7cm,单侧9例,双侧8例（47．5％）;3个家族同时有3例患病（42．8％）;有4个家族的成员患有甲状良性肿瘤和非肿瘤性甲状腺疾病,17例患者中伴有结节性甲状腺肿的10例,全甲状腺切除8例,腺叶加峡部切除9例,行甲状腺癌联合根治术的6例,14例有不同区域的淋巴结转移,占82．3％,（14／17）。结论：家族性甲状腺乳头状癌占甲状腺乳头状癌10％左右,双侧病变近50％,淋巴结转移率高,处理基本同于散发性甲状腺乳头状癌,但是,患病家族成员应长期随访。     

Hereditary Non-medullary Thyroid Cancer

An estimated 5% of all non-medullary thyroid cancers are hereditary. If three or more first-degree relatives are affected, there is a greater than 94% chance that these cases are hereditary non-medullary thyroid cancer (HNMTC). Although, the susceptibility gene(s) for HNMTC has not been identified, there are enough epidemiologic studies and kindreds reported to suggest a hereditary predisposition to thyroid cancer. Until the susceptibility genes are identified, clinicians will have to rely on comprehensive history taking to identify at-risk families and clinically screen at-risk family members. When families are at risk for HNMTC, it is unclear whether neck examination and or neck ultrasound is most effective for screening. Hereditary non-medullary thyroid cancer is associated with more aggressive disease than sporadic HNMTC, especially in index cases, with higher rates of multicentric tumors, lymph node metastasis, and extrathyroidal invasion. Aggressive screening may benefit other members of the affected kindred because the outcome for the non-index cases is better. Although no studies have demonstrated any difference in mortality in patients with HNMTC versus sporadic disease, disease-free survival is shorter in HNMTC. Aggressive surgical and postoperative medical therapy is warranted in patients with HNMTC. It is likely that emerging molecular approaches may help identify the gene or genes involved in HNMTC which would have important clinical ramifications. Presented at the 42nd World Congress of Surgery of the International Society of Surgery and International Association of Endocrine Surgeons meeting, August 29th, 2007.     

Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity

In an evaluation of 213 patients from 15 kindreds with familial medullary thyroid carcinoma (MTC), we detected 41 subjects from two kindreds (L and O) who had MTC but no extra-thyroidal manifestations (hyperparathyroidism, phaeochromocytomas or mucosal neuromas) of multiple endocrine neoplasia (MEN) type IIa or IIb. In screening 178 members of the L and O kindreds, we found no evidence that any of them had died from MTC. To assess whether the malignancy was relatively indolent in these families, 20 selected subjects from the two kindreds were compared with 33 MEN IIa subjects. Both groups had clinically occult disease which was diagnosed biochemically by documenting elevated plasma calcitonin (CT) levels following stimulation with intravenous calcium and pentagastrin. There were no differences in the peak stimulated plasma CT levels at the time of diagnosis (1055 +/- 236 pg/ml versus 1096 +/- 191 pg/ml) or the incidence of regional lymph node metastases (0/20 versus 1/33) in the two groups. The mean age at diagnosis, however, was significantly higher in patients of the L and O kindreds than in patients with MEN IIa (43.1 +/- 3.4 years versus 21.1 +/- 2.2 years; P less than 0.001) indicating that in the two kindreds the MTC either developed at a later age or grew more slowly. This study demonstrates that MTC may occur in a familial pattern distinct from its presentation as MEN IIa or MEN IIb. In this setting it appears to be the least aggressive form of MTC yet described.     

Familial non-multiple endocrine neoplasia medullary thyroid carcinoma: Report of a case confirming a new clinical entity in Japan

Most hereditary medullary thyroid carcinomas (MTC) occur in association with multiple endocrine neoplasia (MEN) type 2 syndromes. Since Farndon et al. reported two kindreds, that is collections of relatives, with familial non-MEN MTC in 1986, only five kindreds with this disorder have been reported in the English literature. In this paper, we describe a rare Japanese kindred with familial non-MEN MTC, confirming the existence of this distinct clinical entity in Japan. A 42-year-old woman underwent a left hemithyroidectomy with modified neck dissection (MND) under a diagnosis of sporadic MTC at 28 years of age. She developed lymph node metastasis in the right neck region 7 years after the initial surgery, and underwent MND and right hemithyroidectomy. Although no findings of MTC were histologically confirmed in the resected right thyroid lobe, C-cell hyperplasia was observed. Hereditary MTC was strongly suspected, but we could not confirm specific manifestations associated with MEN type 2 in any family members. However, 7 years later, a paternal aunt and cousin were diagnosed with MTC. Other family members were evaluated by ultrasonography and calcium-pentagastrin provocation testing, and three additional patients with MTC across two generations were found. None of these patients had any extrathyroidal manifestations associated with MEN type 2, and the entity of familial non-MEN MTC was confirmed.     

Familial melanoma

Approximately 5% to 10% of cases of cutaneous melanoma occur in families that have a hereditary predisposition for this disease. In 20% to 40% of such melanoma families, germline mutations in the CDKN2A gene have been identified. Apart from a high risk of melanoma, a proportion of kindreds that have familial melanoma also have an increased risk of pancreatic carcinoma. Guidelines for management of familial melanoma and the issue of genetic testing for CDKN2A germline mutations are discussed.     

Does Genetic Predisposition Influence Surgical Results of Operations for Obesity?

Background: There is a familial predisposition to obesity. We wished to document the incidence of obesity (BMI > 40 kg m⁻²) in the immediate relatives (parents and siblings) of obese patients who were candidates for gastric restrictive surgery. We determined if a familial predisposition to obesity would influence the surgical results. Methods: The height, weight and BMI were obtained in 1841 relatives of obese patients and in 1059 relatives of normal weight controls. The results of gastric surgery after 52.9 ± 23.1 months were obtained in 44 patients with a familial history of obesity and in 34 patients without a familial history. Results: Patients presenting with a BMI > 40 kg m⁻² were 24.541 times more likely to have a first degree relative with morbid or super obesity than individuals in the control group. Mothers were twice as likely to be severely obese as fathers. A successful result (BMI < 35 kg m⁻² or less than 50% excess weight) occurred 52.9 ± 23.1 months in 77% of patients with a family history of obesity and in 73% of patients without a familial predisposition (p = 0.79). Conclusions: There is a strong familial predisposition to obesity but over one-half of the immediate family members of obese patients have a BMI < 30 kg m⁻². Gastric restrictive surgery induces satiety and produces a successful outcome regardless of familial predisposition. Patients who undergo surgery have a remarkably stable weight over the year prior to operation, suggesting they are defending a markedly elevated BMI.     

hMLH1 and hMSH2 gene mutation in Brazilian families with suspected hereditary nonpolyposis colorectal cancer

Background The aim of this study was to search for mutations in the humanmutS homolog 2 (hMSH2) and humanmutL homolog 1 (hMLH1) genes in 25 unrelated Brazilian kindreds with suspected hereditary nonpolyposis colorectal cancer (HNPCC). Methods The families were grouped according to the following clinical criteria: Amsterdam I or II; familial colorectal cancer (CRC); an early age of onset of CRC in the proband only; or with at least one or two relatives who had HNPCC-related cancers; CRC in the proband only. All patients were studied with direct sequencing. Results Ten mutations were detected (10 of 25 [40%]); of nine different mutations, seven were novel. ThehMLH1 gene had a higher mutation detection rate thanhMSH2 (8 of 25 [32%] vs. 2 of 25 [8%]). Only 3 of these 10 families fulfilled the Amsterdam criteria. Two different polymorphisms were detected in thehMLH1 gene and four in thehMSH2 gene. Conclusions ThehMLH1 gene had a higher mutation detection rate thanhMSH2. The physician who deals with CRC must take into consideration the heredity issue with patients who present with an early age of onset or a familial history of CRC- or HNPCC-related cancers, including gastric cancer, even if they do not fulfill the former Amsterdam criteria.     

Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre

BACKGROUND: Evidence that germline mutations in the RET proto-oncogene are the underlying cause of the familial form of medullary thyroid carcinoma (MTC) made it possible to identify gene carriers with a very high degree of accuracy. Aiming to define the mutational profile observed in our patients and to assess gene carriers' compliance with an early surgery, we reviewed results of molecular analysis of RET performed at our institution since 1994. METHODS: One hundred fifty-eight individuals were screened for germline mutations of the RET proto-oncogene. Seventy-seven patients had apparently sporadic MTC; 8 patients had both MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B despite a negative family history; 8 patients were known to belong to affected kindreds; and 65 individuals were at-risk individuals to develop MTC. RESULTS: A germline mutation in RET was identified in 4% of apparently sporadic MTC patients, in 100% of patients with MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B, and in 100% of probands of clinically established kindreds. The most affected codon was 634 (58%) followed by codon 804 (16%). Among at-risk individuals, 49% were identified as gene carriers. Seven individuals were submitted to prophylactic thyroidectomy (mean age, 17.7 +/- 12.5 years; range: 3-42 years), and all but 1 had MTC. CONCLUSIONS: RET mutational spectrum observed in the present population disclosed a higher frequency of codon 804 mutations than expected. Compliance with an early prophylactic surgery seemed to be influenced not only by medical advice and cultural factors but also by the aggressiveness of disease in gene carriers' families.     

Medullary thyroid carcinoma in Northern Ireland, 1967-1997

BACKGROUND: The experience of managing medullary thyroid carcinoma (MTC) in a specialist endocrine surgery unit was reviewed. METHODS: The case records of 38 patients (19 male, 19 female) treated over a 30 year period were studied. RESULTS: There were 23 (60.5%) patients with sporadic MTC while the remainder had familial MTC--12 multiple endocrine neoplasia (MEN) type 2A, two MEN type 2B, one non-MEN familial medullary thyroid carcinoma (FMTC). Sporadic MTC patients were significantly older at presentation (median 56 years, interquartile range 41.5-61.3 years) compared to MEN 2A patients (median 26 years interquartile range 17.5-34 years) and had more advanced stage of disease. Survival of MTC patients was significantly worse in sporadic disease than in those with MEN 2A (P < 0.0001). All familial cases had bilateral multifocal tumour whereas in sporadic patients only unilateral disease was seen. The availability of genetic testing now allows early identification of affected members of familial MTC kindreds. This has led to total thyroidectomy being performed on the basis of positive genetic screening alone in three patients (two MEN 2A, one FMTC), in all of whom widespread C-cell hyperplasia and microscopic multifocal invasive MTC were identified histologically. CONCLUSIONS: The management of MTC has changed during the study period with total thyroidectomy recommended as the primary procedure of choice for all patients. In the familial setting, positive genetic testing now allows thyroidectomy to be performed at an early pre-clinical stage, with the hope of permanent cure.     

Familial slipped capital femoral epiphysis

In 50 consecutive cases of slipped capital femoral epiphysis (SCFE) from 49 families, the heredity was analyzed by radiographic examination of the first-degree relatives and by interview regarding the second-degree relatives. In four of the 49 families, SCFE was obvious in one or more first-degree relatives; and in another 13 families (14 relatives), radiographic signs of SCFE were found besides the primary case. The familial accumulation was much higher than expected from incidence studies, indicating a hereditary factor in the etiology.     

我国家族性胃癌家系的临床病理特点及其相关肿瘤的分析

目的 研究我国南方家族性胃癌家系的发病特点和预后,及其家系中发生相关肿瘤的特点,探讨我国家族性胃癌的诊断和筛选方法.方法 通过家系调查,收集8个符合国际遗传性胃癌协作组制定的遗传性胃癌(ICG-HGC)家系和4个可疑ICG-HGC家系,绘制其家系图谱,分析其发病的病理特点及预后,同时了解其家族成员发生相关肿瘤的特点.结果 ICG-HGC家系和4个可疑ICG-HGC家系中共有肿瘤患者45例,发病年龄29～65岁,共有肿瘤病灶58个(包括1例多源癌),有胃癌病灶41个,其中胃病灶30个,以胃窦、体部为主,病理类型为中低分化腺癌;胃外肿瘤17个,其中结直肠肿瘤6个.11例先证者中根治术后4例生存时间大于3年,最长超过10年.结论 中国南方家族性胃癌表现为发病年龄轻,病理分化差,进展期胃癌常发生在远端胃,常伴发肠道肿瘤.遴选ICG-HGC家系时应注意与遗传性非息肉病性结直肠癌家系区分.     

Thin basement membrane disease in patients with familial IgA nephropathy

BACKGROUND: Immunoglobulin A nephropathy (IgAN) can exist as a primary glomerulonephritis (GN) or in association with various clinical conditions, suggesting that it could include several heterogeneous disorders. The familial form of IgAN has been increasingly recognized, supporting the suggestion that genetic factors could be involved in the disease pathogenesis, although it remains unclear whether the familial form is itself heterogeneous. METHODS: This study included 24 patients with a biopsy-proven IgAN from 11 unrelated families coming from five geographically distinct regions of Italy, and 90 of their relatives investigated for the presence of nephritis. Families were included in a genome-wide linkage analysis to identify loci responsible for the disease. RESULTS: Liver or systemic disease was not found in any case, and no hearing loss or ocular alterations were detected. Renal biopsy showed mesangial expansion at light microscopy, with glomerular sclerosis involving from 11 to 35% of glomeruli in eight patients. Ultrastructural examination revealed mesangial electron dense deposits along with a diffuse glomerular basement membrane (GBM) thinning typical of thin basement membrane disease (TBMD) in eight patients belonging to six families. Of the 90 relatives, 12 had "suspected IgAN", 73 were defined as "unaffected" and five as "probably unaffected". Families with co-existent TBMD failed to link to the IGAN1 locus. After a follow-up of 3-19 yrs, nine patients (37%) showed a progressive reduction in renal function and five of them reached end-stage renal disease (ESRD). CONCLUSION: These data demonstrate that familial IgAN is present outside geographically confined regions of Italy. Co-aggregation of IgAN with TBMD suggests that familial IgAN itself is a heterogeneous disorder and that inherited GBM abnormalities could be the first alteration, in some cases.     

Incidence of familial intracranial aneurysms in 200 patients: comparison among Caucasian,African-American,and Hispanic populations

OBJECTIVE: Although the cause of cerebral aneurysms remains unclear, there is clear evidence that genetic predisposition plays a role. Ten percent of patients report an aneurysm in a first-degree family member. However, studies to date have largely involved Caucasian populations. Our goal was to characterize the familial aggregation of intracranial aneurysms in different ethnic groups. METHODS: We began a prospective, single-center study on patients treated for intracranial aneurysms. Consenting subjects completed a detailed questionnaire regarding the medical history of family members. In families with two or more affected members, asymptomatic first-degree relatives were screened using computed tomographic or magnetic resonance angiography. RESULTS: In a 2-year period, 292 patients with intracranial aneurysms were treated and 200 were enrolled; these included 124 Caucasians (62%), 34 African-Americans (17%), 38 Hispanics (19%), and 4 Asian-Americans (2%). Forty patients had a family history (20%). The incidence of family history among the different ethnic groups was similar; it was 19.4% in Caucasians, 20.6% in African-Americans, and 21.6% in Hispanics. One Asian-American patient had a family history. Visual inspection of the pedigrees supported autosomal-dominant inheritance with variable penetrance in all ethnic groups. CONCLUSION: This study examined the incidence of familial cerebral aneurysms in three ethnic groups common to the United States: Caucasian, African-American, and Hispanic. We noted an equivalent rate of familial aneurysms, a finding that has immediate clinical implications. In families that have two or more members with cerebral aneurysms, screening of asymptomatic members should be recommended, regardless of ethnic background.     

Familial slipped capital femoral epiphysis

In 50 consecutive cases of slipped capital femoral epiphysis (SCFE) from 49 families, the heredity was analyzed by radiographic examination of the first-degree relatives and by interview regarding the second-degree relatives. In four of the 49 families, SCFE was obvious in one or more first-degree relatives; and in another 13 families (14 relatives), radiographic signs of SCFE were found besides the primary case.

The familial accumulation was much higher than expected from incidence studies, indicating a hereditary factor in the etiology.     

Familial slipped capital femoral epiphysis

In 50 consecutive cases of slipped capital femoral epiphysis (SCFE) from 49 families, the heredity was analyzed by radiographic examination of the first-degree relatives and by interview regarding the second-degree relatives. In four of the 49 families, SCFE was obvious in one or more first-degree relatives; and in another 13 families (14 relatives), radiographic signs of SCFE were found besides the primary case.

The familial accumulation was much higher than expected from incidence studies, indicating a hereditary factor in the etiology.     

Familial predisposition to discogenic low-back pain. An epidemiologic and immunogenetic study

The first-degree relatives (parents, siblings and children) of 284 patients complaining of discogenic low-back pain (Group I), 114 patients who had undergone surgery for lumbar disc herniation (Group II), and 280 individuals who had never complained of low-back pain (Group III) were surveyed by self-completed questionnaires. Of the families in Group I and Group II, 35 and 37%, respectively, had at least one member with a history of discogenic back pain and 5 and 10%, respectively, had one or two members who had undergone disc surgery. Of the asymptomatic subjects in Group III, only 12% had at least one or more affected relatives and 1% had a relative who had undergone disc surgery; of the affected families, 41% had two or more members with a history of back pain. The proportion of symptomatic relatives in the affected families was higher among sedentary workers and motor vehicle drivers than among heavy or light manual workers. An immunogenetic study comparing the frequencies of HLA-A, B, and C antigens in 39 patients who had undergone lumbar disc surgery with those in 60 asymptomatic individuals showed no significant differences between the two groups. This study indicates that there is a strong familial predisposition to discogenic low-back pain, and suggests that the etiology of degenerative disc disease is related to both genetic factors, not linked to the HLA antigen system, and environmental factors.     

Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment

Background

There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer.

甲状腺乳头状癌跳跃性侧颈区淋巴结转移的危险因素分析

目的探究甲状腺乳头状癌（PTC）颈部淋巴结跳跃性转移的临床病理特征及其危险因素。 方法回顾性分析2015年7月至2018年11月福建医科大学附属协和医院收治的259例PTC患者临床资料,探究跳跃性侧颈区淋巴结转移的危险因素。 结果PTC颈部淋巴结跳跃性转移的发生率为9.3%（24/259）。单因素分析显示,中央区淋巴结清扫数目在跳跃性转移组中更少（P=0.031）;肿瘤最大径<1 cm（P<0.001）及肿瘤位于腺体上部（P=0.012）与PTC患者跳跃性转移的发生有关。多因素分析显示,肿瘤最大径<1 cm（OR=5.934,P<0.001）和肿瘤位于腺体上部（OR=2.812,P=0.023）是PTC患者颈部淋巴结跳跃性转移的独立危险因素。 结论肿瘤最大径<1 cm和肿瘤位于腺体上部的PTC患者侧颈区淋巴结更易发生跳跃性转移。     

Mutational analysis of 206 families with cavernous malformations

OBJECT: A gene contributing to the autosomal-dominant cerebral cavernous malformation (CCM) phenotype, KRIT1 (an acronym for Krev Interaction Trapped 1), has been identified through linkage analysis and mutation screening. The authors collected blood samples from 68 patients with familial CCM and 138 patients with apparently sporadic CCM as well as from their families, in an effort to characterize the prevalence and spectrum of disease-causing sequence variants in the KRIT1 gene. METHODS: The authors used single-strand conformational polymorphism analysis to identify genomic variants in KRIT1, which were sequenced to determine the specific mutation. Among 43 Hispanic-American kindreds who immigrated to the southwestern US from northern Mexico, 31 share an identical founder mutation. This Q455X mutation is found in 18 (86%) of 21 persons with a positive family history and in 13 (59%) of 22 persons with apparently sporadic CCM. This mutation was not found among 13 persons with CCM who were recruited from Mexico. These findings establish the key role of a recent founder mutation in Hispanic persons with CCM who live in the US. Although nearly all Hispanic families in the US in which there are multiple CCM cases linked to the CCM1 locus, only 13 of 25 non-Hispanic CCM-carrying families have displayed evidence of linkage to the CCM1 locus. Among these 13 families, the authors identified eight independent mutations in nine kindreds. They identified four additional mutations among 22 familial CCM kindreds with no linkage information, bringing the total number of independent mutations to 12. Inherited KRIT1 mutations were not detected among 103 non-Hispanic persons in whom a family history of CCM was rigorously excluded. CONCLUSIONS: All mutations were nonsense mutations, frame-shift mutations predicting premature termination, or splice-site mutations located throughout the KRIT1 gene, suggesting that these are genetic loss-of-function mutations. These genetic findings, in conjunction with the clinical phenotype, are consistent with a two-hit model for the occurrence of CCM.     

Association between the clinical presentation and epidemiological features of familial prostate cancer in patients selected for radical prostatectomy

OBJECTIVE: We evaluated if epidemiological features of familial prostate cancer are associated with certain clinical or histopathological characteristics of the disease. METHODS: 463 German patients with familial prostate cancer who underwent radical prostatectomy were stratified according to several epidemiological criteria: (1). the apparent mode of disease transmission, (2). the average age of onset and (3). number of affected relatives/family, (4). whether or not they met the Johns Hopkins criteria of hereditary prostate cancer. The variables analysed included the Prostate Specific Antigen (PSA) and the digital rectal examination at diagnosis, histopathological characteristics of the prostatectomy specimen and relapse free 5-year survival rates. These characteristics were compared within the subsets of familial patients and compared to 492 control patients with sporadic prostate cancer. RESULTS: Age of onset was the only clinical parameter differentiating familial and sporadic prostate cancer. Otherwise there was no association between epidemiological features of familial predisposition and the clinical presentation or outcome of the disease. CONCLUSIONS: Familial and sporadic prostate cancer seem to be the same disease. Alternatively it may be concluded that the common epidemiological features of familial prostate cancer are not useful to tell tumours that are based on inherited susceptibility apart from those that are not. Whether hereditary prostate cancer is clinically distinct from sporadic forms cannot be determined before the underlying genetic alterations are identified.